TLR3 binds to bicyclic peptide ligand

Abstract

This invention relates to peptide ligands capable of binding to TLR3. Specifically, the invention describes bicyclic peptide ligands comprising the peptide ligand described herein and a molecular scaffold, wherein three cysteine ​​residues of the peptide ligand are covalently bonded to the molecular scaffold to form two circular sequences. The invention also includes pharmaceutical compositions, polymeric binding complexes, and pharmaceutical conjugates comprising the said peptide ligand, and the use of the said peptide ligand in the prevention, inhibition, or treatment of TLR3-mediated diseases or conditions, such as autoimmune diseases, inflammatory conditions, and cancer.

Description

Technical Field

[0001] This invention relates to peptide ligands capable of binding to TLR3. Specifically, the invention describes bicyclic peptide ligands comprising the peptide ligand described herein and a molecular scaffold, wherein three reactive groups of the peptide ligand (e.g., cysteine ​​residues) covalently bond with the molecular scaffold to form two cyclic sequences. The invention also includes pharmaceutical compositions, polymeric binding complexes, and pharmaceutical conjugates comprising the peptide ligand, and the use of the peptide ligand in the prevention, inhibition, or treatment of TLR3-mediated diseases or conditions (e.g., autoimmune diseases, inflammatory conditions, and cancer). Background Technology

[0002] Cyclic peptides can bind to protein targets with high affinity and target specificity, making them a highly attractive class of molecules for therapeutic drug development. In fact, several cyclic peptides have been successfully used clinically, such as the antimicrobial peptide vancomycin, the immunosuppressive drug cyclosporine, and the anticancer drug octreotide (Driggers et al., (2008), Nat Rev Drug Discov 7(7), 608-24). The relatively large interaction surface formed between the peptide and the target, along with the reduced conformational flexibility of the cyclic structure, contributes to their excellent binding properties. Typically, macrocyclic compounds can bind to surfaces of hundreds of square angstroms, such as the cyclic peptide CXCR4 antagonist CVX15 (400 Å). 2 Wu et al., (2007), Science 330, 1066-71, cyclic peptides with Arg-Gly-Asp motifs bind to integrin αVβ3 (355 Å). 2 (Xiong et al., (2002), Science 296 (5565), 151-5), or the cyclic peptide inhibitor upain-1 binds to urokinase-type plasminogen activator (603 Å). 2 ;Zhao et al., (2007), J Struct Biol 160 (1), 1-10).

[0003] Due to their cyclic configuration, macrocyclic peptides are less flexible than linear peptides, resulting in less entropy loss upon target binding and thus higher binding affinity. Reduced flexibility also locks in a target-specific conformation, enhancing binding specificity compared to linear peptides. This effect has been demonstrated with a potent and selective matrix metalloproteinase 8 (MMP-8) inhibitor, which loses selectivity for other MMPs when its ring is opened (Cherney et al., (1998), J MedChem 41 (11), 1749-51). The advantageous binding properties achieved through macrocyclization are more pronounced in polycyclic peptides with more than one peptide ring, such as vancomycin, nisin, and actinomycin.

[0004] Different research teams have previously linked peptides containing cysteine ​​residues to synthetic molecular structures (Kemp and McNamara (1985), J. Org. Chem; Timmerman et al., (2005), ChemBioChem). Meloen and colleagues used tris(bromomethyl)benzene and related molecules to rapidly and quantitatively cyclize multiple peptide rings onto synthetic scaffolds for structural simulation of protein surfaces (Timmerman et al., (2005), ChemBioChem). Methods for generating candidate drug compounds are disclosed in WO 2004 / 077062 and WO2006 / 078161, wherein the compounds are generated by linking cysteine-containing peptides to molecular scaffolds (e.g., tris(bromomethyl)benzene).

[0005] Combinatorial methods based on phage display have been developed to generate and screen large libraries of macrocyclic peptides targeting targets of interest (Heinis et al., (2009), Nat Chem Biol 5 (7), 502-7 and WO 2009 / 098450). In short, linear peptide combinatorial libraries containing three cysteine ​​residues and two six-amino acid regions (Cys-(Xaa)6-Cys-(Xaa)6-Cys) are displayed on phages and cyclized by covalently linking cysteine ​​side chains to a small molecule scaffold. Summary of the Invention

[0006] According to a first aspect of the invention, a peptide ligand is provided comprising a polypeptide having an amino acid sequence selected from:

[0007] C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1);

[0008] CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC (SEQ ID NO: 2);

[0009] X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X25 -X 26 -X 27 -X 28 -X 29 (SEQ ID NO: 3);

[0010] CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4);

[0011] CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5); and

[0012] X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 (SEQ ID NO: 6);

[0013] in:

[0014] X1 represents D, N, P, Y, 26DiMeTyr, 2FTyr, 3FTyr, or 4FPhe;

[0015] X2 represents A, I, N, P, S, T, Aze, Cba, cis-HyP, tBuAla, or tBuGly;

[0016] X3 represents A, G, N, P, Q, R, Aib, Aze, cis-HyP, dA, HyP, or Pip;

[0017] X4 represents L, S, or Cba;

[0018] X5 represents K, P, R, W, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me) or Trp(S);

[0019] X6 represents M, R, or HArg;

[0020] X7 represents A, F, Q, Y, 2FTyr, 3FTyr, 3tBuTyr or 4FPhe;

[0021] X8 represents H, I, N, V, Cbg, His1Me, His3Me, or tBuGly;

[0022] X9 represents D, F, L, 1Nal, 2Nal, 4tBuPhe, Cba, or tBuAla;

[0023] X 10 Represents S or T;

[0024] X 11 Represents K or S;

[0025] X 12 Represents E or Q;

[0026] X 13 Represents R or V;

[0027] X 14 Represents H or R;

[0028] X 15 Represents C or dC;

[0029] X 16 Represents A, D, H, I, L, M, N, P, S, T, W, CF3Nva, dP, HyP, Nle, Nva, or TfNle;

[0030] X 17 Represents E, L, N, P, Q, S, T, Y, 26DiMeTyr, Cba, dL, or tBuAla;

[0031] X 18 Represents D, E, L, P, R, T, Agb, Cba, Cit, dD, HArg, or tBuAla;

[0032] X 19Represents A, E, I, L, M, Q, V, AlloIle, Cba, CF3Ala, dL, HLeu, Nle or tBuAla;

[0033] X 20 Represents C or dC;

[0034] X 21 Represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe or dE;

[0035] X 22 Represents A, R, V, Y, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, DOPA, or dY;

[0036] X 23 Represents A, D, W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, dW, Gla, or Trp(S);

[0037] X 24 Represents A, D, E, H, M, Q, S, Y, dS, K(PYA) or Nle;

[0038] X 25 Represents E, F, L, N, S, T, V, Cba, or dS;

[0039] X 26 Represents R, W, Y, 1Nal, 2FTyr, 2MeTrp, 2Nal, 3FTyr, 4FTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, Cit, dR, HArg or Trp(Me);

[0040] X 27 Represents G, R, S, Agb, Cit, dA, dE, or HArg;

[0041] X 28 Represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro;

[0042] X 29 Represents C, dC, or Cysam;

[0043] X 30 Represents P, cis-HyP, HyP, or Pip;

[0044] X 31 Represents E, Q, or R;

[0045] X 32 Represents P, Aze, cis-HyP, or HyP;

[0046] X 33 Represents F, Y, 2FTyr, 2Nal, 3FTyr, 4FPhe or 4tBuPhe;

[0047] X 34 Represents N, S, or Dap;

[0048] X 35 Represents T or Dap;

[0049] X 36 Represents W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, 5MeoTrp, 6ClTrp, 6FTrp, AzaTrp, or Trp(S);

[0050] X 37 Represents P, Aze, cis-HyP, HyP, or Pip;

[0051] X 38 Represents E or P;

[0052] X 39 Represents D or N;

[0053] X 40 Represents W or Y;

[0054] X 41 Represents C or dC;

[0055] X 42 Represents A, D, E, G, K, N, P, S, T, V, Y, 3HyV, Aib, CF3Ala, dA, Dap, dK(PYA), dS, HSer or K(PYA);

[0056] X 43 Represents N, T, or 3HyV;

[0057] X 44 Represents D, E, P, 4FlPro, cis-HyP, HyP, or trans-4FlPro;

[0058] X 45Represents A, H, M, Q, S, V, Y, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, or HSe;

[0059] X 46 Represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla or TfNle;

[0060] X 47 Represents A, E, S, T, W, 1Nal, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, AzaTrp, CF3Ala or Dap;

[0061] X 48 Represents K, R, Y, 2FTyr, 3FTyr, Agb, DOPA, HArg, or Orn;

[0062] X 49 Represents A, D, L, V, W, 1Nal, 2Nal, 3HyV, 4FTrp, 5FTrp, 5MeoTrp, 6FTrp, AzaTrp, C5g, Cbg, tBuGly, or Trp(S);

[0063] X 50 Represents E, M, Q, R, S, T, Arg(Me), Dap, HArg, or PG;

[0064] X 51 Represents A, E, K, M, R, S, T, 3HyV, Cit, HArg, or Orn;

[0065] X 52 Represents A, G, L, M, N, P, Q, Cba, dA, dK(PYA), K(PYA), Nle, Nva, R-aMeLys(PYA), S-aMeLys(PYA) or tBuAla;

[0066] X 53 Representing D, I, L, M, V, EPA, Nle, Nva, or tBuGly; and

[0067] X 54 Represents C, dC, or Cysam;

[0068] Or its modified derivatives and / or pharmaceutically acceptable salts.

[0069] According to another aspect of the invention, a bicyclic peptide ligand or a pharmaceutically acceptable salt thereof capable of binding TLR3 is provided, comprising a peptide ligand containing a polypeptide (e.g., the peptide ligand described herein) having three reactive groups, wherein the polypeptide is linked to a molecular scaffold.

[0070] According to another aspect of the invention, a pharmaceutical composition is provided comprising the peptide ligand or bicyclic peptide ligand described herein, and one or more pharmaceutically acceptable excipients.

[0071] According to another aspect of the invention, a multipolymer binding complex is provided comprising at least two bicyclic peptide ligands as defined herein, wherein the peptide ligands may be the same or different.

[0072] According to another aspect of the invention, a pharmaceutical conjugate is provided comprising a peptide ligand, a bicyclic peptide ligand, or a polymeric conjugate as described herein, conjugated to one or more effectors and / or functional groups.

[0073] According to another aspect of the invention, peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymeric binding complexes or pharmaceutical conjugates as described herein are provided for the prevention, inhibition or treatment of diseases or conditions mediated by TLR3. Brief description of the attached diagram

[0075] Figure 1 Image of the selected bicyclic peptide of the present invention after incubation with monocyte-derived macrophages. Invention Details

[0077] definition

[0078] Unless otherwise specifically defined herein, all terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention pertains. Practitioners may in particular refer to Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Press, Plainsview, New York (2012); and Ausubel et al., Current Protocols in Molecular Biology (Supplement 114), John Wiley & Sons, New York (2016) for definitions and terminology in the art.

[0079] The term "amino acid" is used in its broadest sense within the context of this disclosure, referring to an organic compound containing an amino (NH2) and a carboxyl (COOH) functional group, as well as a side chain (e.g., an R group) characteristic of each amino acid. In some embodiments, amino acid refers to a naturally occurring L α-amino acid or residue. Common single-letter and three-letter abbreviations for naturally occurring amino acids are used herein: A=Ala; C=Cys; D=Asp; E=Glu; F=Phe; G=Gly; H=His; I=Ile; K=Lys; L=Leu; M=Met; N=Asn; P=Pro; Q=Gln; R=Arg; S=Ser; T=Thr; V=Val; W=Trp and Y=Tyr (Lehninger, AL, (1975) Biochemistry, 2nd ed., pp. 71-92, Worth Press, New York). The general term “amino acid” further includes D-amino acids, reverse-reverse amino acids, and chemically modified amino acids, such as amino acid analogs, naturally occurring amino acids that are not typically incorporated into proteins (e.g., ortholeucine), and chemically synthesized compounds that possess the characteristics of amino acids known in the art, such as β-amino acids. For example, analogs or mimics of phenylalanine or proline that exhibit the same conformational restriction to peptides as natural Phe and Pro are included in the definition of an amino acid. Such analogs and mimics are referred to herein as “functional equivalents” of the corresponding amino acids. Other examples of amino acids are listed by Roberts and Vellaccio, *The Peptides: Analysis, Synthesis, Biology, Gross and Meiehofer*, vol. 5, p. 341, Academic Press, New York, 1983, the contents of which are incorporated herein by reference. The chemical properties of the 20 major amino acids are shown in Table A below.

[0080]

[0081] The terms “polypeptide” and “peptide / peptide ligand” are used interchangeably herein to refer to polymers of amino acid residues and their variants and synthetic analogs. Therefore, these terms apply to amino acid polymers in which one or more amino acid residues are synthetically non-naturally occurring amino acids (such as chemical analogs of the corresponding naturally occurring amino acids), as well as to naturally occurring amino acid polymers. Polypeptides may also undergo maturation or post-translational modifications, which may include, but are not limited to, glycosylation, proteolytic cleavage, lipolysis, signal peptide cleavage, propeptide cleavage, phosphorylation, etc.

[0082] Peptides and peptide ligands

[0083] This invention provides peptides capable of binding TLR3. The TLR3-binding peptides provided herein may be contained, for example, in a peptide ligand that is covalently bound to a molecular scaffold (e.g., a molecular scaffold described more specifically herein), thereby forming two or more peptide rings on the molecular scaffold. The peptide ligand may be directly or indirectly (e.g., via a linker, spacer, or hinge portion) linked to another peptide ligand (i.e., two or more peptide ligands may be linked together, and they may be the same or different) to form a complex described more specifically herein. The peptide, peptide ligand, or complex containing multiple peptide ligands may be directly or indirectly (e.g., via a linker) linked to one or more effector groups and / or functional groups, such as one or more cytotoxic agents, radiochelates, or chromophores.

[0084] Therefore, in one embodiment, this document provides peptide ligands, or modified derivatives thereof, or pharmaceutically acceptable salts thereof, comprising polypeptides having an amino acid sequence selected from SEQ ID NO: 1 to 366 as defined herein.

[0085] In some embodiments, the peptide is capable of binding to TLR3. In some embodiments, the peptide is specific for TLR3.

[0086] TLR3 binding peptide

[0087] Toll-like receptors (TLRs) are a family of transmembrane proteins that play a crucial role in the innate immune system by recognizing various pathogen-associated molecular patterns (PAMPs) and initiating immune responses. One member of this family is Toll-like receptor 3 (TLR3; also known as CD283 (differentiation cluster 283)), which is best known for its ability to detect double-stranded RNA (dsRNA), a common molecular pattern associated with viral pathogens.

[0088] First discovered in the late 1990s, TLR3 is a pattern recognition receptor involved in recognizing viral infections. It is expressed in a variety of immune cells, including dendritic cells, macrophages, and natural killer cells, as well as non-immune cells such as epithelial cells.

[0089] The structure of TLR3 includes an extracellular domain with leucine-rich repeat (LRR) sequences responsible for ligand recognition, a transmembrane domain, and an intracellular Toll / interleukin-1 receptor (TIR) ​​domain that initiates downstream signaling pathways upon activation. Unlike other TLRs, TLR3 does not rely on the aptamer MyD88 for signal transduction; instead, it utilizes the interferon-β-induced aptamer (TRIF) containing the TIR domain, also known as TICAM-1.

[0090] Upon binding to dsRNA, TLR3 dimerizes (Leonard et al. (2008) PNAS 105(1), 258-263), leading to TRIF recruitment to the TIR domain. This triggers a signaling cascade that ultimately activates transcription factors such as interferon regulators (IRF) and nuclear factor κB (NF-κB) (Gosu et al. (2019) Sci Rep 9, 3652; Bell et al. (2006) PNAS 103(23), 8792-8797). These transcription factors induce the expression of type I interferon (IFN), pro-inflammatory cytokines, and other molecules involved in antiviral defense.

[0091] Activation of TLR3, and the subsequent production of type I interferon and pro-inflammatory cytokines, contribute to the antiviral immune response. Type I interferon is crucial for establishing an antiviral state in neighboring cells, inhibiting viral replication, and activating immune cells. Furthermore, TLR3 activation can enhance the antigen-presenting capacity of dendritic cells, promoting the initiation of adaptive immune responses.

[0092] TLR3 has been shown to participate in the immune response to a variety of viral infections, including RNA viruses such as influenza, small RNA viruses, and coronaviruses. The role of TLR3 in antiviral defense makes it an attractive target for developing antiviral therapies and vaccine adjuvants. Furthermore, dysregulation of TLR3 signaling is associated with autoimmune diseases and chronic inflammatory conditions.

[0093] In summary, Toll-like receptor 3 (TLR3) is a crucial component of the innate immune system, recognizing viral double-stranded RNA and initiating an immune response. TLR3 activation triggers the production of type I interferon and pro-inflammatory cytokines, promoting antiviral defense and shaping adaptive immune responses. Research on TLR3 provides valuable insights into host-virus interactions and has potential implications for developing therapeutic interventions against viral infections.

[0094] Understandably, the therapeutic effect of agents binding to TLR3 will depend on whether the binding produces an agonistic or antagonistic effect. In recent years, numerous studies have demonstrated the effectiveness of TLR3 agonists in enhancing tumor-specific immune responses in mice and patients, particularly when used in combination with other therapies (Le Naour et al. (2020) Oncoimmunology 9(1), 1771143). A detailed review of the link between TLRs and oncology can be found in Naour and Kroemer (2023) Oncoimmunology 12(1), 2180237.

[0095] In one embodiment, the peptide ligand is specific to TLR3 (i.e., binds to TLR3). The peptide ligand may be specific to a specific epitope of TLR3 (i.e., binds to a specific epitope), such as the soluble extracellular domain of human TLR3. In some embodiments, the peptide ligand is specific to the proximal C-terminus of TLR3 (i.e., binds to the proximal C-terminus). In some embodiments, the peptide ligand is specific to the interior of the horseshoe-shaped structure of TLR3 (i.e., binds to the horseshoe interior), which contacts one-third of the 27 β-chains (residues 18-26) of the LRR motif.

[0096] In some embodiments, the peptide ligand comprises a polypeptide having the following amino acid sequence:

[0097] C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1)

[0098] X1 to X9 are each independently selected from D, N, P, Y, A, I, S, T, G, Q, R, L, K, W, M, F, H, V, dA, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, 4tBuPhe, Aze, Cba, HyP, cis-HyP, tBuAla, 1Nal, 2Nal, tBuGly, Aib, Pip, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me), Trp(S), Cbg, His1Me, and His3Me; or their modified derivatives and / or pharmaceutically acceptable salts. In some implementations, X1 to X3 are each independently selected from D, N, P, Y, A, I, S, T, G, Q, R, F, dA, 26DiMeTyr, 2FTyr, 3FTyr, 4FPhe, Aze, Cba, HyP, cis-HyP, tBuAla, tBuGly, Aib, and Pip. In some implementations, X4 to X9 are each independently selected from L, S, K, P, R, W, M, A, F, Q, Y, H, I, N, V, D, Cba, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me), Trp(S), 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, Cbg, His1Me, His3Me, tBuGly, 1Nal, 2Nal, 4tBuPhe, and tBuAla.

[0099] In some implementations, X1 represents D, N, P, Y, 26DiMeTyr, 2FTyr, 3FTyr, or 4FPhe;

[0100] X2 represents A, I, N, P, S, T, Aze, Cba, cis-HyP, tBuAla, or tBuGly; X3 represents A, G, N, P, Q, R, Aib, Aze, cis-HyP, dA, HyP, or Pip; X4 represents L, S, or Cba; X5 represents K, P, R, W, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me), or Trp(S); X6 represents M, R, or HArg; X7 represents A, F, Q, Y, 2FTyr, 3FTyr, 3tBuTyr, or 4FPhe; X8 represents H, I, N, V, Cbg, His1Me, His3Me, or tBuGly; and / or X9 represents D, F, L, 1Nal, 2Nal, 4tBuPhe, Cba, or tBuAla. In some embodiments, X1-X2-X3 are PPG. In some embodiments, X5 is P and / or X6 is R. In some embodiments, X4-X5-X6-X7-X8-X9 are SPRF / YHL.

[0101] In some embodiments, the peptide ligand comprises a polypeptide having the following amino acid sequence:

[0102] CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC (SEQ ID NO: 2)

[0103] Where X 10 To X 14 Each is independently selected from S, T, K, E, Q, R, V, and H; or their modified derivatives and / or pharmaceutically acceptable salts. In some embodiments, X 10 and X 11 Each is independently selected from S, T, and K. In some implementations, X 12 To X 14 Each is independently selected from E, Q, R, V, and H.

[0104] In some implementation schemes, X 10 Represents S or T; X 11 Represents K or S; X 12 Represents E or Q; X 13 Represents R or V; and / or X 14 Represents H or R.

[0105] In some embodiments, the peptide ligand comprises a polypeptide having the following amino acid sequence:

[0106] X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 (SEQ ID NO: 3);

[0107] Where X 16 To X 19 and X 21 To X 28 Each is independently selected from A, D, H, I, L, M, N, P, S, T, W, E, Q, Y, R, V, F, R, G, K, CF3Nva, dP, HyP, Nle, Nva, TfNle, 26DiMeTyr, Cba, dL,tBuAla, Agb, Cit, dD, HArg, AlloIle, CF3Ala, HLeu, 1Nal, 2FPhe, 2MePhe, 2Nal,3FPhe, 3MePhe, 4FPhe, 4MePhe, dE, 2FTyr, 3FTyr, 3tBuTyr, DOPA, dY, 4MeoTrp,5FTrp, dW, Gla, Trp(S), dS, K(PYA), 2MeTrp, 4FTrp, 5MeTrp. 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, dR, Trp(Me), dA, 44DFP, 4FlPro, Aze, Pip, and trans-4FlPro; X 15 It is C or dC; X 20 It is C or dC; and X 29 It is C, dC, or Cystam; or its modified derivatives and / or pharmaceutically acceptable salts. In some embodiments, X 16 To X 19Each is independently selected from A, D, H, I, L, M, N, P, S, T, W, E, Q, Y, R, V, CF3Nva, dP, HyP, Nle, Nva, TfNle, 26DiMeTyr, Cba, dL, tBuAla, Agb, Cit,dD, HArg, AlloIle, CF3Ala, and HLeu. In some embodiments, X 21 To X 28 Each is independently selected from A, E, F, L, Q, R, T, W, Y, V, D, H, M, Q, S, N, G, P, K, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe, dE, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, DOPA, dY, 4MeoTrp, 5FTrp, dW, Gla, Trp(S), dS, K(PYA), Nle, Cba, 2MeTrp, 4FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, Cit, dR, HArg, Trp(Me), Agb, dA, 44DFP, 4FlPro,Aze, dL, HyP, Pip, tBuAla, and trans-4FlPro.

[0108] In some implementation schemes, X 16 Represents A, D, H, I, L, M, N, P, S, T, W, CF3Nva, dP, HyP, Nle, Nva, or TfNle; X 17 Represents E, L, N, P, Q, S, T, Y, 26DiMeTyr, Cba, dL, or tBuAla; X 18 Represents D, E, L, P, R, T, Agb, Cba, Cit, dD, HArg, or tBuAla; X 19 Represents A, E, I, L, M, Q, V, AlloIle, Cba, CF3Ala, dL, HLeu, Nle or tBuAla; 21 Represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe or dE; X 22Represents A, R, V, Y, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, DOPA, or dY; X 23 Represents A, D, W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, dW, Gla, or Trp(S); X 24 Represents A, D, E, H, M, Q, S, Y, dS, K (PYA) or Nle; X 25 Represents E, F, L, N, S, T, V, Cba, or dS; X 26 Represents R, W, Y, 1Nal, 2FTyr, 2MeTrp, 2Nal, 3FTyr, 4FTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, Cit, dR, HArg or Trp(Me); X 27 Represents G, R, S, Agb, Cit, dA, dE, or HArg; and / or X 28 Represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro; where X 15 Represents C or dC; X 20 Represents C or dC; and X 29 Represents C, dC, or Cysam. In some implementations, X 16 -X 17 -X 18 -X 19 It is PLDL. In some implementations, X 16 -X 17 -X 18 -X 19 It is M / CF3Nva-YRA. In some implementations, X 22 It is Y; and / or X 23 It is W or 5FTrp. In some implementations, X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 It is EYW / 5FTrp-SS / VRGL. In some implementations, X 26 It is W or 1 Nal, and / or X 27 It is R, and / or X 28It is P. In some implementations, X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 It is W / FV / YA / DE / DEW / 1Nal-RP.

[0109] In some embodiments, the peptide ligand comprises a polypeptide having the following amino acid sequence:

[0110] CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4)

[0111] Where X 30 To X 37 Each is independently selected from P, E, Q, R, F, Y, N, S, T, W, A, cis-HyP, HyP, Pip, Aze, 2FTyr, 2Nal, 3FTyr, 4FPhe, 4tBuPhe, Dap, 1Nal, 4MeoTrp, 5FTrp, 5MeoTrp, 6ClTrp, 6FTrp, AzaTrp, and Trp(S); or modified derivatives thereof and / or pharmaceutically acceptable salts. In some embodiments, X 30 and X 31 Each is independently selected from P, E, Q, R, cis-HyP, HyP, and Pip. In some implementations, X 32 To X 37 Each is independently selected from P, F, Y, N, S, T, W, A, Aze, cis-HyP, HyP, 2FTyr, 2Nal, 3FTyr, 4FPhe, 4tBuPhe, Dap, 1Nal, 4MeoTrp, 5FTrp, 5MeoTrp, 6ClTrp, 6FTrp, AzaTrp, Trp(S), and Pip.

[0112] In some implementation schemes, X 30 Represents P, cis-HyP, HyP, or Pip; X 31 Represents E, Q, or R; X 32Represents P, Aze, cis-HyP or HyP; X 33 Represents F, Y, 2FTyr, 2Nal, 3FTyr, 4FPhe, or 4tBuPhe; X 34 Represents N, S, or Dap; X 35 Represents T or Dap; X 36 Represents W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, 5MeoTrp, 6ClTrp, 6FTrp, AzaTrp, or Trp(S); and / or X 37 Represents P, Aze, cis-HyP, HyP, or Pip. In some implementations, X 30 It is P. In some implementations, X 30 -X 31 It's a PR / Q. In some implementations, X 36 It is W. In some implementations, X 32 -X 33 -X 34 -X 35 -X 36 -X 37 It is PF / YSTWP.

[0113] In some embodiments, the peptide ligand comprises a polypeptide having the following amino acid sequence:

[0114] CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5)

[0115] Where X 38 To X 40 Each is independently selected from E, P, D, N, W and Y; or their modified derivatives and / or pharmaceutically acceptable salts.

[0116] In some implementation schemes, X 38 Represents E or P; X 39 Represents D or N; and / or X 40 Represents W or Y.

[0117] In some embodiments, the peptide ligand comprises a polypeptide having the following amino acid sequence:

[0118] X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 (SEQ ID NO: 6)

[0119] Where X 42 To X 53 Each is independently selected from A, D, E, G, K, N, P, S, T, V, Y, H, M, Q, F, I, W, R, L, 3HyV, Aib, CF3Ala, dA, Dap, dK(PYA), dS, HSer, K(PYA), 4FlPro, cis-HyP, HyP, trans-4FlPro, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA,2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, TfNle, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp. AzaTrp, Agb, HArg, Orn, 5MeoTrp,C5g, Cbg, tBuGly, Trp(S), Arg(Me), PG, Cit, R-aMeLys(PYA), S-aMeLys(PYA), and EPA; X 41 It is C or dC; X 54 It is C, dC, or Cystam; or its modified derivatives and / or pharmaceutically acceptable salts. In some embodiments, X 42 To X 49Each is independently selected from A, D, E, G, K, N, P, S, T, V, Y, H, M, Q, F, I, W, R, L, 3HyV, Aib, CF3Ala, dA, Dap, dK(PYA), dS, HSer, K(PYA), 4FlPro, cis-HyP, HyP, trans-4FlPro, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA,2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, TfNle, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp. AzaTrp, Agb, HArg, Orn, 5MeoTrp, C5g, Cbg, tBuGly, and Trp(S). In some implementations, X 50 To X 53 Each of these is independently selected from E, M, Q, R, S, T, A, K, G, L, N, P, Q, D, I, V, Arg(Me), Dap, HArg, PG, 3HyV, Cit, Orn, Cba, dA, dK(PYA), K(PYA), Nle, Nva, R-aMeLys(PYA), S-aMeLys(PYA), tBuAla, EPA, and tBuGly.

[0120] In some implementation schemes, X 42 Represents A, D, E, G, K, N, P, S, T, V, Y, 3HyV, Aib, CF3Ala, dA, Dap, dK(PYA), dS, HSer, or K(PYA); X 43 Represents N, T, or 3HyV; X 44 Represents D, E, P, 4FlPro, cis-HyP, HyP, or trans-4FlPro; X 45 Represents A, H, M, Q, S, V, Y, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, or HSe; X 46 Represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, or TfNle; X 47Represents A, E, S, T, W, 1Nal, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, AzaTrp, CF3Ala or Dap; X 48 Represents K, R, Y, 2FTyr, 3FTyr, Agb, DOPA, HArg, or Orn; X 49 Represents A, D, L, V, W, 1Nal, 2Nal, 3HyV, 4FTrp, 5FTrp, 5MeoTrp, 6FTrp, AzaTrp, C5g, Cbg, tBuGly, or Trp(S); X 50 Represents E, M, Q, R, S, T, Arg(Me), Dap, HArg, or PG; X 51 Represents A, E, K, M, R, S, T, 3HyV, Cit, HArg, or Orn; X 52 Represents A, G, L, M, N, P, Q, Cba, dA, dK(PYA), K(PYA), Nle, Nva, R-aMeLys(PYA), S-aMeLys(PYA) or tBuAla; X 53 Represents D, I, L, M, V, EPA, Nle, Nva, or tBuGly; where X 41 Representing C or dC and X 54 Represents C, dC, or Cysam. In some implementations, X 48 Is it Y and / or X 49 It is W and / or 5FTrp. In some implementations, X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 It is N / DNP / EVM / ITYW / 5FTrp. In some implementations, X 47 It is W, and / or X 48 It is K, and / or X 49 It is V. In some implementations, X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X49 It is T / STDM / YM / Nle-WKV. In some implementations, X 50 -X 51 -X 52 -X 53 It is T / QK / RGI. In some implementations, X 50 It is R. In some implementations, X 50 -X 51 -X 52 -X 53 It is an RTLD.

[0121] In one embodiment, the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) comprises an amino acid sequence selected from the following:

[0122] CDIACLKMYNFC (SEQ ID NO: 7);

[0123] CDIGCLRMYNFC (SEQ ID NO: 8);

[0124] CD[tBuAla]GCLRMYNFC (SEQ ID NO: 9);

[0125] CD[tBuGly]GCLRMYNFC (SEQ ID NO: 10);

[0126] CD[Cba]GCLRMYNFC (SEQ ID NO: 11);

[0127] CDI[dA]CLRMYNFC (SEQ ID NO: 12);

[0128] CDI[Aib]CLRMYNFC (SEQ ID NO: 13);

[0129] CDIGC[Cba]RMYNFC (SEQ ID NO: 14):

[0130] CDIGCL[HArg]MYNFC (SEQ ID NO: 15):

[0131] CDIGCL[Agb]MYNFC (SEQ ID NO: 16);

[0132] CDIGCLRMYN[1Nal]C (SEQ ID NO: 17);

[0133] CDIGCLRMYN[2Nal]C (SEQ ID NO: 18);

[0134] CDIGCLRMYN[4tBuPhe]C (SEQ ID NO: 19);

[0135] CDIQCLRMYNFC (SEQ ID NO: 20);

[0136] CNIQCLRMYNFC (SEQ ID NO: 21);

[0137] CDIRCLRMYNFC (SEQ ID NO: 22);

[0138] CDINCLRMYNFC (SEQ ID NO: 23);

[0139] CPPGCSPRFHLC (SEQ ID NO: 24);

[0140] CPPGCSPRYHLC (SEQ ID NO: 25; when complexed with a derivative of TATB having the following structure, it is referred to herein as BCY21542:

[0141]

[0142] in (Indicates the junction of three cysteine ​​residues);

[0143] CP[cis-HyP]GCSPRYHLC (SEQ ID NO: 26);

[0144] CP[Aze]GCSPRYHLC (SEQ ID NO: 27);

[0145] CPPGCSP[HArg]YHLC (SEQ ID NO: 28);

[0146] CPPGCSPR[4FPhe]HLC (SEQ ID NO: 29);

[0147] CPPGCSPR[3tBuTyr]HLC (SEQ ID NO: 30):

[0148] CPPGCSPR[3FTyr]HLC (SEQ ID NO: 31);

[0149] CPPGCSPR[2FTyr]HLC (SEQ ID NO: 32);

[0150] CPPGCSPRY[His1Me]LC (SEQ ID NO: 33);

[0151] CPPGCSPRY[His3Me]LC (SEQ ID NO: 34);

[0152] CPPGCSPRYH[tBuAla]C (SEQ ID NO: 35);

[0153] CPPGCSPRYH[Cba]C (SEQ ID NO: 36);

[0154] CPPGCSPRYNLC (SEQ ID NO: 37);

[0155] CYNPCLWRQVDC (SEQ ID NO: 38; when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure, it is referred to herein as BCY21497:

[0156]

[0157] in (Indicates the junction of three cysteine ​​residues);

[0158] CYAPCLWRQVDC (SEQ ID NO: 39);

[0159] CYNPCLWRAVDC (SEQ ID NO: 40);

[0160] C[4FPhe]NPCLWRQVDC (SEQ ID NO: 41);

[0161] C[26DiMeTyr]NPCLWRQVDC (SEQ ID NO: 42);

[0162] C[3FTyr]NPCLWRQVDC (SEQ ID NO: 43);

[0163] C[2FTyr]NPCLWRQVDC (SEQ ID NO: 44);

[0164] CYN[HyP]CLWRQVDC (SEQ ID NO: 45);

[0165] CYN[cis-HyP]CLWRQVDC (SEQ ID NO: 46);

[0166] CYN[Aze]CLWRQVDC (SEQ ID NO: 47);

[0167] CYN[Pip]CLWRQVDC (SEQ ID NO: 48);

[0168] CYNPC[Cba]WRQVDC (SEQ ID NO: 49);

[0169] CYNPCL[6MeTrp]RQVDC (SEQ ID NO: 50);

[0170] CYNPCL[6FTrp]RQVDC (SEQ ID NO: 51);

[0171] CYNPCL[5FTrp]RQVDC (SEQ ID NO: 52);

[0172] CYNPCL[6ClTrp]RQVDC (SEQ ID NO: 53);

[0173] CYNPCL[5MeoTrp]RQVDC (SEQ ID NO: 54);

[0174] CYNPCL[Trp(S)]RQVDC (SEQ ID NO: 55);

[0175] CYNPCL[Trp(Me)]RQVDC (SEQ ID NO: 56);

[0176] CYNPCLWRQ[tBuGly]DC (SEQ ID NO: 57);

[0177] CYNPCLWRQ[Cbg]DC (SEQ ID NO: 58);

[0178] CYNPCLWRQIDC (SEQ ID NO: 59);

[0179] CYSPCLWRQVDC (SEQ ID NO: 60); and

[0180] CYTPCLWRQVDC (SEQ ID NO: 61).

[0181] In one embodiment, C-X 10 " -X 11 -Y-Y-C-X 12 -Q-T-X 13 -X 14The peptide ligand of -FC (SEQ ID NO: 2) comprises an amino acid sequence selected from the following:

[0182] CTSYYCEQTRHFC (SEQ ID NO: 62);

[0183] CTKYYCEQTRHFC (SEQ ID NO: 63); and

[0184] CSKYYCQQTVRFC (SEQ ID NO: 64).

[0185] In one implementation, X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) comprises an amino acid sequence selected from the following:

[0186] CTNEVCTYWYNRGLC (SEQ ID NO: 65);

[0187] CANEVCEYWYNRGLC (SEQ ID NO: 66);

[0188] CPLDLCEYWSFRGLC (SEQ ID NO: 67);

[0189] CTNEVCRYWYNRGLC (SEQ ID NO: 68);

[0190] CDSPVCEYWSFRGLC (SEQ ID NO: 69);

[0191] CHNEVCEYWSFRGLC (SEQ ID NO: 70);

[0192] CSNEVCEYWSFRGLC (SEQ ID NO: 71);

[0193] CSNPVCEYWSFRGLC (SEQ ID NO: 72);

[0194] CNNPVCEYWSFRGLC (SEQ ID NO: 73);

[0195] CDNEVCEYWSFRGLC (SEQ ID NO: 74);

[0196] CTSEVCEYWSFRGLC (SEQ ID NO: 75);

[0197] CSTLVCQRDQLYSLC (SEQ ID NO: 76);

[0198] CHNEVCLYWYNRGLC (SEQ ID NO: 77);

[0199] CWNPVCEYWYNRGLC (SEQ ID NO: 78);

[0200] CATLQCQRDMLYGLC (SEQ ID NO: 79);

[0201] CSTLVCQRDQLYGLC (SEQ ID NO: 80);

[0202] CST[tBuAla]VCQRDQLYGLC (SEQ ID NO: 81);

[0203] CST[Cba]VCQRDQLYGLC (SEQ ID NO: 82);

[0204] CSTL[tBuAla]CQRDQLYGLC (SEQ ID NO: 83);

[0205] CSTLVCQRD[Nle]LYGLC (SEQ ID NO: 84);

[0206] CSTLVCQRDQ[Cba]YGLC (SEQ ID NO: 85);

[0207] CSTLVCQRDQLY[dA]LC (SEQ ID NO: 86);

[0208] CSTLVCQRDQLYG[tBuAla]C (SEQ ID NO: 87);

[0209] CSTLVCQRDQLYG[Cba]C (SEQ ID NO: 88);

[0210] CST[tBuAla]VCQRDQLY[dA]LC (SEQ ID NO: 89);

[0211] CNPLICQRDQLYGLC (SEQ ID NO: 90);

[0212] CISLACQRDQLYGLC (SEQ ID NO: 91);

[0213] CSTLECQRDQLYGLC (SEQ ID NO: 92);

[0214] CNTLVCQRDQLYGLC (SEQ ID NO: 93);

[0215] CTQLMCQRDQLYGLC (SEQ ID NO: 94);

[0216] CTELMCQRDQLYGLC (SEQ ID NO: 95);

[0217] CTE[tBuAla]MCQRDQLY[dA]LC (SEQ ID NO: 96);

[0218] CTELMCQRDQLY[dA]LC (SEQ ID NO: 97);

[0219] CTE[tBuAla]MCQRDQLYGLC (SEQ ID NO: 98);

[0220] CTELACQRDQLYGLC (SEQ ID NO: 99);

[0221] CTEL[Nle]CQRDQLYGLC (SEQ ID NO: 100);

[0222] CTEL[HLeu]CQRDQLYGLC (SEQ ID NO: 101);

[0223] CTELMCQR[Gla]QLYGLC (SEQ ID NO: 102);

[0224] CTELMCQRDQL[3FTyr]GLC (SEQ ID NO: 103);

[0225] CTELMCQRDQL[2FTyr]GLC (SEQ ID NO: 104);

[0226] CANTVCAYWETRGLC (SEQ ID NO: 105);

[0227] CANTVCAY[5FTrp]ETRGLC (SEQ ID NO: 106);

[0228] CPLDLCEYWSVRGLC (SEQ ID NO: 107);

[0229] CPLDLCEYWSSRGLC (SEQ ID NO: 108);

[0230] C[HyP]LDLCEYWSSRGLC (SEQ ID NO: 109);

[0231] CP[tBuAla]DLCEYWSSRGLC (SEQ ID NO: 110);

[0232] CP[Cba]DLCEYWSSRGLC (SEQ ID NO: 111);

[0233] CPLD[AlloIle]CEYWSSRGLC (SEQ ID NO: 112);

[0234] CPLD[tBuAla]CEYWSSRGLC (SEQ ID NO: 113);

[0235] CPLD[Cba]CEYWSSRGLC (SEQ ID NO: 114);

[0236] CPLDVCEYWSSSRGLC (SEQ ID NO: 115);

[0237] CPLDLCE[4FPhe]WSSRGLC (SEQ ID NO: 116);

[0238] CPLDLCEY[2Nal]SSRGLC (SEQ ID NO: 117);

[0239] CPLDLCEY[1Nal]SSRGLC (SEQ ID NO: 118);

[0240] CPLDLCEY[5FTrp]SSRGLC (SEQ ID NO: 119);

[0241] CPLDLCEY[4MeoTrp]SSRGLC (SEQ ID NO: 120);

[0242] CPLDLCEY[Trp(S)]SSRGLC (SEQ ID NO: 121);

[0243] CPLDLCEYWSS[HArg]GLC (SEQ ID NO: 122);

[0244] CPLDLCEYWSS[Cit]GLC (SEQ ID NO: 123);

[0245] CPLDLCEYWSSR[dA]LC (SEQ ID NO: 124);

[0246] CPLDLCEYWSSRG[tBuAla]C (SEQ ID NO: 125);

[0247] CPLDLCEYWSSRG[Cba]C (SEQ ID NO: 126);

[0248] [dC][dP][dL][dD][dL][dC][dE][dY][dW][dS][dS][dR]G[dL][dC] (SEQ ID NO:127);

[0249] CP[Cba]DLCEY[5FTrp]SSRGLC (SEQ ID NO: 128);

[0250] CPLDLCEYW[K(PYA)]SRGLC (SEQ ID NO: 129, referred to herein as BCY21632 when complexed with a derivative of TATA having the following structure):

[0251]

[0252] in (Indicates the junction of three cysteine ​​residues);

[0253] CPLDLCEYW[K(PYA)]SRGL[Cysam] (SEQ ID NO: 130, referred to herein as BCY21637 when complexed with a derivative of TATA having the following structure:

[0254]

[0255] in (Indicates the junction of three cysteine ​​residues);

[0256] CPLDLCEY[5FTrp]ESRGLC (SEQ ID NO: 131);

[0257] CPNDLCEY[5FTrp]SSRGLC (SEQ ID NO: 132);

[0258] CPLDLCEY[5FTrp]SSR[dA]LC (SEQ ID NO: 133);

[0259] CPLDLCEY[5FTrp]SSR[dE]LC (SEQ ID NO: 134);

[0260] CPLD[tBuAla]CEY[5FTrp]SS[HArg][dA]LC (SEQ ID NO: 135);

[0261] CP[Cba]DLCEY[5FTrp]SS[HArg][dA]LC (SEQ ID NO: 136);

[0262] CPNDLCEYWSVRGLC (SEQ ID NO: 137);

[0263] CITLQCARDMLYGLC (SEQ ID NO: 138);

[0264] CSTLQCERDMLYGLC (SEQ ID NO: 139);

[0265] CISLACARDMLYGLC (SEQ ID NO: 140);

[0266] CSTLQCQRDMLYGLC (SEQ ID NO: 141);

[0267] CMYRACWVAEEWRPC (SEQ ID NO: 142);

[0268] CMYRACYYDHEWRPC (SEQ ID NO: 143);

[0269] CMYRACFYDDEWRPC (SEQ ID NO: 144);

[0270] CMYRACAYDDEWRPC (SEQ ID NO: 145);

[0271] CMYRACFADDEWRPC (SEQ ID NO: 146);

[0272] CMYRACFYADEWRPC (SEQ ID NO: 147);

[0273] CMYRACFYDAEWRPC (SEQ ID NO: 148);

[0274] C[Nle]YRACFYDDEWRPC (SEQ ID NO: 149);

[0275] C[Nva]YRACFYDEWRPC (SEQ ID NO: 150);

[0276] C[TfNle]YRACFYDDEWRPC (SEQ ID NO: 151);

[0277] C[CF3Nva]YRACFYDDEWRPC (SEQ ID NO: 152);

[0278] CM[26DiMeTyr]RACHYDEWRPC (SEQ ID NO: 153);

[0279] CMY[HArg]ACFYDDEWRPC (SEQ ID NO: 154);

[0280] CMY[Agb]ACFYDDEWRPC (SEQ ID NO: 155);

[0281] CMY[Cit]ACFYDDEWRPC (SEQ ID NO: 156);

[0282] CMYR[CF3Ala]CFYDDEWRPC (SEQ ID NO: 157);

[0283] CMYRAC[1Nal]YDEWRPC (SEQ ID NO: 158);

[0284] CMYRAC[2Nal]YDEWRPC (SEQ ID NO: 159);

[0285] CMYRAC[4MePhe]YDEWRPC (SEQ ID NO: 160);

[0286] CMYRAC[3MePhe]YDEWRPC (SEQ ID NO: 161);

[0287] CMYRAC[2MePhe]YDEWRPC (SEQ ID NO: 162);

[0288] CMYRAC[4FPhe]YDDEWRPC (SEQ ID NO: 163);

[0289] CMYRAC[3FPhe]YDDEWRPC (SEQ ID NO: 164);

[0290] CMYRAC[2FPhe]YDDEWRPC (SEQ ID NO: 165);

[0291] CMYRACF[4FPhe]DDEWRPC (SEQ ID NO: 166);

[0292] CMYRACF[3tBuTyr]DDEWRPC (SEQ ID NO: 167);

[0293] CMYRACF[26DiMeTyr]DDEWRPC (SEQ ID NO: 168);

[0294] CMYRACF[3FTyr]DDEWRPC (SEQ ID NO: 169);

[0295] CMYRACF[2FTyr]DDEWRPC (SEQ ID NO: 170);

[0296] CMYRACF[DOPA]DDEWRPC (SEQ ID NO: 171);

[0297] CMYRACFYDDE[1Nal]RPC (SEQ ID NO: 172);

[0298] CMYRACFYDDE[2Nal]RPC (SEQ ID NO: 173);

[0299] CMYRACFYDDE[4FTrp]RPC (SEQ ID NO: 174);

[0300] CMYRACFYDDE[5FTrp]RPC (SEQ ID NO: 175);

[0301] CMYRACFYDDE[6FTrp]RPC (SEQ ID NO: 176);

[0302] CMYRACFYDDE[7FTrp]RPC (SEQ ID NO: 177);

[0303] CMYRACFYDDE[Trp(Me)]RPC (SEQ ID NO: 178);

[0304] CMYRACFYDDE[2MeTrp]RPC (SEQ ID NO: 179);

[0305] CMYRACFYDDE[5MeTrp]RPC (SEQ ID NO: 180);

[0306] CMYRACFYDDE[6MeTrp]RPC (SEQ ID NO: 181);

[0307] CMYRACFYDDE[7MeTrp]RPC (SEQ ID NO: 182);

[0308] CMYRACFYDDEW[HArg]PC (SEQ ID NO: 183);

[0309] CMYRACFYDDEW[Agb]PC (SEQ ID NO: 184);

[0310] CMYRACFYDDEW[Cit]PC (SEQ ID NO: 185);

[0311] CMYRACFYDDEWR[HyP]C (SEQ ID NO: 186);

[0312] CMYRACFYDDEWR[Aze]C (SEQ ID NO: 187);

[0313] CMYRACFYDDEWR[Pip]C (SEQ ID NO: 188);

[0314] CMYRACFYDDEWR[44DFP]C (SEQ ID NO: 189);

[0315] CMYRACFYDDEWR[4FlPro]C (SEQ ID NO: 190);

[0316] CMYRACFYDDEWR[trans-4FlPro]C (SEQ ID NO: 191);

[0317] C[CF3Nva]YRACFYDDE[1Nal]RPC (SEQ ID NO: 192);

[0318] C[CF3Nva]YRAC[4MePhe]YDDE[1Nal]RPC (SEQ ID NO: 193);

[0319] CLYRACFYDDEWRPC (SEQ ID NO: 194);

[0320] CLYRAC[4MePhe]YDDE[1Nal]RPC (SEQ ID NO: 195);

[0321] CHYRACFYDDEWRPC (SEQ ID NO: 196);

[0322] In one implementation, CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 The peptide ligand of -C (SEQ ID NO:4) contains an amino acid sequence selected from the following:

[0323] CQPTPRCPFSTWPC (referred to in this document as SEQ ID NO: 197);

[0324] CQPTPQCPYSTWPC (referred to herein as SEQ ID NO: 198, and referred to herein as BCY20723 when complexed with a derivative of TATB having the following structure)

[0325]

[0326] in (Indicates the junction of three cysteine ​​residues);

[0327] CQPT[HyP]QCPYSTWPC (referred to in this paper as SEQ ID NO: 199);

[0328] CQPT[cis-HyP]QCPYSTWPC (referred to herein as SEQ ID NO: 200);

[0329] CQPT[Pip]QCPYSTWPC (referred to in this document as SEQ ID NO: 201);

[0330] CQPTPECPYSTWPC (referred to in this document as SEQ ID NO: 202);

[0331] CQPTPQC[HyP]YSTWPC (referred to in this paper as SEQ ID NO: 203);

[0332] CQPTPQC[cis-HyP]YSTWPC (referred to herein as SEQ ID NO: 204);

[0333] CQPTPQC[Aze]YSTWPC (referred to herein as SEQ ID NO: 205);

[0334] CQPTPQCP[2Nal]STWPC (referred to herein as SEQ ID NO: 206);

[0335] CQPTPQCP[4tBuPhe]STWPC (referred to herein as SEQ ID NO: 207);

[0336] CQPTPQCP[4FPhe]STWPC (referred to herein as SEQ ID NO: 208);

[0337] CQPTPQCP[3FTyr]STWPC (referred to herein as SEQ ID NO: 209);

[0338] CQPTPQCP[2FTyr]STWPC (referred to herein as SEQ ID NO: 210);

[0339] CQPTPQCPY[Dap]TWPC (referred to herein as SEQ ID NO: 211);

[0340] CQPTPQCPYS[Dap]WPC (referred to herein as SEQ ID NO: 212);

[0341] CQPTPQCPYST[2Nal]PC (referred to in this paper as SEQ ID NO: 213);

[0342] CQPTPQCPYST[1Nal]PC (referred to herein as SEQ ID NO: 214);

[0343] CQPTPQCPYST[6FTrp]PC (referred to herein as SEQ ID NO: 215);

[0344] CQPTPQCPYST[5FTrp]PC (referred to herein as SEQ ID NO: 216);

[0345] CQPTPQCPYST[6ClTrp]PC (referred to herein as SEQ ID NO: 217);

[0346] CQPTPQCPYST[4MeoTrp]PC (referred to herein as SEQ ID NO: 218);

[0347] CQPTPQCPYST[5MeoTrp]PC (referred to herein as SEQ ID NO: 219);

[0348] CQPTPQCPYST[Trp(S)]PC (referred to herein as SEQ ID NO: 220);

[0349] CQPTPQCPYST[AzaTrp]PC (referred to in this paper as SEQ ID NO: 221);

[0350] CQPTPQCPYSTW[HyP]C (referred to in this paper as SEQ ID NO: 222);

[0351] CQPTPQCPYSTW[cis-HyP]C (referred to herein as SEQ ID NO: 223);

[0352] CQPTPQCPYSTW[Aze]C (referred to in this paper as SEQ ID NO: 224);

[0353] CQPTPQCPYSTW[Pip]C (referred to herein as SEQ ID NO: 225); and

[0354] CQPTPECPYNTWPC (referred to herein as SEQ ID NO: 226).

[0355] In one implementation, CYYX 38 -X 39 -X 40 The peptide ligand of -YACLDC (SEQ ID NO: 5) contains an amino acid sequence selected from the following:

[0356] CYYPDYYACLDC (referred to as SEQ ID NO: 227 in this document);

[0357] CYYENYYACLDC (referred to herein as SEQ ID NO: 228); and

[0358] CYYPDWYACLDC (referred to in this document as SEQ ID NO: 229).

[0359] In one implementation, X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) comprises an amino acid sequence selected from the following:

[0360] CNNPVMTYWCTKGIC (referred to in this article as SEQ ID NO: 230);

[0361] CNNPVMTYWCEKGIC (referred to in this article as SEQ ID NO: 231);

[0362] CDNEVITYWCTKGIC (referred to as SEQ ID NO: 232 in this article);

[0363] CDNEV[tBuAla]TYWCTKGIC (referred to in this paper as SEQ ID NO: 233);

[0364] CDNEVFTYWCTKGIC (referred to in this article as SEQ ID NO: 234);

[0365] CDNEV[Cba]TYWCTKGIC (referred to in this article as SEQ ID NO: 235);

[0366] CDNEVITY[2Nal]CTKGIC (referred to as SEQ ID NO: 236 in this paper);

[0367] CDNEVITY[1Nal]CTKGIC (referred to as SEQ ID NO: 237 in this paper);

[0368] CDNEVITYWCT[Orn]GIC (referred to as SEQ ID NO: 238 in this article);

[0369] CDNEVITYWCT[HArg]GIC (referred to as SEQ ID NO: 239 in this paper);

[0370] CDNEVITYWCTK[dA]IC (referred to herein as SEQ ID NO: 240);

[0371] CDNEVITYWCTKG[tBuGly]C (referred to as SEQ ID NO: 241 in this paper);

[0372] CDNEVIT[DOPA]WCTKGIC (referred to in this paper as SEQ ID NO: 242);

[0373] CDNPVFTYWCTKGIC (referred to in this article as SEQ ID NO: 243);

[0374] CNNPVMAYWCTKGIC (referred to in this article as SEQ ID NO: 244);

[0375] CPNPVITYWCTKGIC (referred to in this article as SEQ ID NO: 245);

[0376] CDNEVITYWCQMGVC (referred to in this document as SEQ ID NO: 246);

[0377] CDNEVITYWCQRGVC (referred to as SEQ ID NO: 247 in this document);

[0378] CDNEVITYWCMRGIC (referred to in this article as SEQ ID NO: 248);

[0379] CDNEVITYWCQRGIC (referred to in this article as SEQ ID NO: 249);

[0380] CDNEVITY[6FTrp]CQRGIC (referred to in this paper as SEQ ID NO: 250);

[0381] CDNEVITY[5FTrp]CQRGIC (referred to in this paper as SEQ ID NO: 251);

[0382] CDNEVITY[5MeoTrp]CQRGIC (referred to as SEQ ID NO: 252 in this document);

[0383] CDNEVITY[Trp(S)]CQRGIC (referred to as SEQ ID NO: 253 in this paper);

[0384] CDNEVITY[AzaTrp]CQRGIC (referred to as SEQ ID NO: 254 in this document);

[0385] CDNEVITYWCQ[HArg]GIC (referred to as SEQ ID NO: 255 in this paper);

[0386] CDNEVITYWCQ[Cit]GIC (referred to as SEQ ID NO: 256 in this document);

[0387] CDNEVFEYWCTKGIC (referred to in this article as SEQ ID NO: 257);

[0388] CDNEVITYWCERGIC (referred to in this article as SEQ ID NO: 258);

[0389] CDNEVITYWCEMGIC (referred to in this article as SEQ ID NO: 259);

[0390] CSNPVFAYWCSRQMC (referred to in this document as SEQ ID NO: 260);

[0391] CSNPVFAYWCERGIC (referred to herein as SEQ ID NO: 261, and referred herein as BCY21615 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure):

[0392]

[0393] in (Indicates the junction of three cysteine ​​residues);

[0394] CSNPVFAYWCER[K(PYA)]IC (referred to herein as SEQ ID NO: 262);

[0395] CSNPVFAYWCER[dK(PYA)]IC (referred to herein as SEQ ID NO: 263);

[0396] CSNPVFAYWCER[S-aMeLys(PYA)]IC (referred to herein as SEQ ID NO: 264);

[0397] CSNPVFAYWCER[R-aMeLys(PYA)]IC (referred to herein as SEQ ID NO: 265);

[0398] C[K(PYA)]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 266);

[0399] CSNPVFAY[5FTrp]CERGIC (referred to in this paper as SEQ ID NO: 267);

[0400] CSNPVFAYWCERGI[Cysam] (referred to herein as SEQ ID NO: 268, and referred herein as BCY21623 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure):

[0401]

[0402] in (Indicates the junction of three cysteine ​​residues);

[0403] C[K(PYA)]NPVFAYWCERGI[Cysam] (referred to as SEQ ID NO: 269 in this paper);

[0404] CSNPVFAYWC[Dap]RGIC (referred to herein as SEQ ID NO: 270);

[0405] CKNPVFAYWC[PG]RGIC (referred to in this paper as SEQ ID NO: 271);

[0406] CENPVFAYWCERGIC (referred to in this article as SEQ ID NO: 272);

[0407] C[dA]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 273);

[0408] CGNPVFAYWCERGIC (referred to in this article as SEQ ID NO: 274);

[0409] C[Aib]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 275);

[0410] CSN[trans-4FlPro]VFAYWCERGIC (referred to herein as SEQ ID NO: 276);

[0411] CSN[4FlPro]VFAYWCERGIC (referred to herein as SEQ ID NO: 277);

[0412] CSN[HyP]VFAYWCERGIC (referred to in this document as SEQ ID NO: 278);

[0413] CSN[cis-HyP]VFAYWCERGIC (referred to herein as SEQ ID NO: 279);

[0414] CSNP[HSer]FAYWCERGIC (referred to in this article as SEQ ID NO: 280);

[0415] CSNPV[2FPhe]AYWCERGIC (referred to in this paper as SEQ ID NO: 281);

[0416] CSNPV[4CF3Phe]AYWCERGIC (referred to in this paper as SEQ ID NO: 282);

[0417] CSNPVFSYWCERGIC (referred to in this article as SEQ ID NO: 283);

[0418] CSNPVF[Dap]YWCERGIC (referred to in this paper as SEQ ID NO: 284);

[0419] CSNPVF[CF3Ala]YWCERGIC (referred to in this paper as SEQ ID NO: 285);

[0420] CSNPVFA[2FTyr]WCERGIC (referred to herein as SEQ ID NO: 286);

[0421] CSNPVFA[3FTyr]WCERGIC (referred to in this paper as SEQ ID NO: 287);

[0422] CSNPVFAY[4FTrp]CERGIC (referred to in this paper as SEQ ID NO: 288);

[0423] CSNPVFAYWCE[Cit]GIC (referred to in this paper as SEQ ID NO: 289);

[0424] CSNPVFAYWCER[dA]IC (referred to herein as SEQ ID NO: 290);

[0425] CSNPVFAYWCERG[Nva]C (referred to in this paper as SEQ ID NO: 291);

[0426] CSNPVFAYWCERG[Nle]C (referred to in this paper as SEQ ID NO: 292);

[0427] CSNPVFAYWCERG[EPA]C (referred to in this document as SEQ ID NO: 293);

[0428] CSNPVFAYWCERG[tBuGly]C (referred to in this paper as SEQ ID NO: 294);

[0429] CSN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 295 in this document);

[0430] C[Aib]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 296 in this document);

[0431] C[dS]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 297 in this paper);

[0432] C[K(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 298 in this document);

[0433] C[dK(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 299 in this paper);

[0434] [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 300 in this document);

[0435] CSN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to as SEQ ID NO: 301 in this document);

[0436] [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to as SEQ ID NO: 302 in this document);

[0437] CSNPVFAYWCSRNLC (referred to in this paper as SEQ ID NO: 303);

[0438] CSNPVFAYWCSRGLC (referred to in this document as SEQ ID NO: 304);

[0439] CTTDMMWKVCRTLDC (referred to as SEQ ID NO: 305 in this document);

[0440] CATDHMWKVCRTLDC (referred to as SEQ ID NO: 306 in this document);

[0441] CKTDAMWKVCRTLDC (referred to as SEQ ID NO: 307 in this article);

[0442] CSTDQMWKVCRTLDC (referred to as SEQ ID NO: 308 in this document);

[0443] CSTDYMWKVCRTLDC (referred to herein as SEQ ID NO: 309, and referred herein as BCY23141 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure):

[0444]

[0445] in (Indicates the junction of three cysteine ​​residues);

[0446] CSTDY[Nle]WKVCRTLDC (referred to as SEQ ID NO: 310 in this document);

[0447] CATDYMWKVCRTLDC (referred to as SEQ ID NO: 311 in this document);

[0448] CSTDAMWKVCRTLDC (referred to as SEQ ID NO: 312 in this document);

[0449] CSTDYAWKVCRTLDC (referred to as SEQ ID NO: 313 in this document);

[0450] CSTDYMWKACRTLDC (referred to in this document as SEQ ID NO: 314);

[0451] CSTDYMWKVCRALDC (referred to in this document as SEQ ID NO: 315);

[0452] CSTDYMWKVCRTADC (referred to in this paper as SEQ ID NO: 316);

[0453] C[CF3Ala]TDYMWKVCRTLDC (referred to as SEQ ID NO: 317 in this document);

[0454] C[HSer]TDYMWKVCRTLDC (referred to as SEQ ID NO: 318 in this document);

[0455] CTTDYMWKVCRTLDC (referred to as SEQ ID NO: 319 in this document);

[0456] C[3HyV]TDYMWKVCRTLDC (referred to as SEQ ID NO: 320 in this document);

[0457] CS[3HyV]DYMWKVCRTLDC (referred to as SEQ ID NO: 321 in this document);

[0458] C[Dap]TDYMWKVCRTLDC (referred to in this document as SEQ ID NO: 322);

[0459] CSTD[4FPhe]MWKVCRTLDC (referred to as SEQ ID NO: 323 in this document);

[0460] CSTD[1Nal]MWKVCRTLDC (referred to as SEQ ID NO: 324 in this paper);

[0461] CSTD[2Nal]MWKVCRTLDC (referred to as SEQ ID NO: 325 in this document);

[0462] CSTD[26DiMeTyr]MWKVCRTLDC (referred to herein as SEQ ID NO: 326);

[0463] CSTD[3FTyr]MWKVCRTLDC (referred to in this paper as SEQ ID NO: 327);

[0464] CSTD[2FTyr]MWKVCRTLDC (referred to in this paper as SEQ ID NO: 328);

[0465] CSTD[DOPA]MWKVCRTLDC (referred to in this document as SEQ ID NO: 329);

[0466] CSTDY[Nva]WKVCRTLDC (referred to as SEQ ID NO: 330 in this document);

[0467] CSTDY[TfNle]WKVCRTLDC (referred to as SEQ ID NO: 331 in this document);

[0468] CSTDYEWKVCRTLDC (referred to as SEQ ID NO: 332 in this document);

[0469] CSTDY[CF3Nva]WKVCRTLDC (referred to as SEQ ID NO: 333 in this document);

[0470] CSTDYM[1Nal]KVCRTLDC (referred to as SEQ ID NO: 334 in this paper);

[0471] CSTDYM[4FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 335);

[0472] CSTDYM[5FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 336);

[0473] CSTDYM[6FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 337);

[0474] CSTDYM[7FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 338);

[0475] CSTDYM[2MeTrp]KVCRTLDC (referred to as SEQ ID NO: 339 in this paper);

[0476] CSTDYM[4MeTrp]KVCRTLDC (referred to as SEQ ID NO: 340 in this paper);

[0477] CSTDYM[5MeTrp]KVCRTLDC (referred to as SEQ ID NO: 341 in this paper);

[0478] CSTDYM[6MeTrp]KVCRTLDC (referred to as SEQ ID NO: 342 in this paper);

[0479] CSTDYM[7MeTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 343);

[0480] CSTDYM[AzaTrp]KVCRTLDC (referred to as SEQ ID NO: 344 in this paper);

[0481] CSTDYMW[HArg]VCRTLDC (referred to in this paper as SEQ ID NO: 345);

[0482] CSTDYMW[Orn]VCRTLDC (referred to in this document as SEQ ID NO: 346);

[0483] CSTDYMW[Agb]VCRTLDC (referred to in this document as SEQ ID NO: 347);

[0484] CSTDYMWK[tBuGly]CRTLDC (referred to in this paper as SEQ ID NO: 348);

[0485] CSTDYMWK[Cbg]CRTLDC (referred to in this document as SEQ ID NO: 349);

[0486] CSTDYMWK[C5g]CRTLDC (referred to herein as SEQ ID NO: 350);

[0487] CSTDYMWK[3HyV]CRTLDC (referred to herein as SEQ ID NO: 351);

[0488] CSTDYMWKVC[HArg]TLDC (referred to in this paper as SEQ ID NO: 352);

[0489] CSTDYMWKVC[Arg(Me)]TLDC (referred to in this paper as SEQ ID NO: 353);

[0490] CSTDYMWKVCR[3HyV]LDC (referred to in this paper as SEQ ID NO: 354);

[0491] CSTDYMWKVCRT[tBuAla]DC (referred to herein as SEQ ID NO: 355);

[0492] CSTDYMWKVCRT[Cba]DC (referred to herein as SEQ ID NO: 356);

[0493] CSTDYMWKVCRT[Nva]DC (referred to herein as SEQ ID NO: 357);

[0494] CSTDYMWKVCRT[Nle]DC (referred to herein as SEQ ID NO: 358);

[0495] CTTDMAWRDCRTLDC (referred to in this document as SEQ ID NO: 359);

[0496] CTTDMAWRLCRTLDC (referred to in this article as SEQ ID NO: 360);

[0497] CTTDMVWKVCRTLDC (referred to as SEQ ID NO: 361 in this document);

[0498] CVTDYMWKVCRTLDC (referred to as SEQ ID NO: 362 in this document);

[0499] CYTDSMWKVCRTLDC (referred to as SEQ ID NO: 363 in this document);

[0500] CTTDMMWKVCREPDC (referred to in this document as SEQ ID NO: 364);

[0501] CTTDMMWKVCRSMDC (referred to herein as SEQ ID NO: 365); and

[0502] CTTDMMWKVCRTLDC (referred to in this document as SEQ ID NO: 366).

[0503] In some embodiments, the polypeptide comprising the above-described amino acid sequence, its modified derivatives, or salts thereof, extends at the N-terminus. In some embodiments, the polypeptide extends at the N-terminus with one or more (e.g., 1 to about 20, 1 to about 10, or 1 to about 5, e.g., 1, 2, 3, 4, or 5) additional amino acids or the like. In some embodiments, the polypeptide extends at the C-terminus. In some embodiments, the polypeptide extends at the C-terminus with one or more (e.g., 1 to about 20, 1 to about 10, or 1 to about 5, e.g., 1, 2, 3, 4, or 5) additional amino acids or the like. In some embodiments, the polypeptide extends at both the N-terminus and C-terminus. In some embodiments, the polypeptide extends at both the N-terminus and C-terminus with one or more (e.g., 1 to about 20, or 1 to about 10, or 1 to about 5, e.g., 1, 2, 3, 4, or 5) additional amino acids or the like.

[0504] In some embodiments, the polypeptide is modified at the N-terminus and / or C-terminus. In some embodiments, the polypeptide is modified at both the N-terminus and C-terminus. Examples of N-terminal modification include elongation of the peptide by one or more amino acids or amino acid analogs (e.g., alanine (A) or its variants (e.g., dA), lysine (K) or its variants, guanidinoacetic acid (GuanAc), pentynoic acid (PYA)), N-terminal acetylation (denoted by "Ac"), or N-terminal carboxymidylation (wherein the N-terminal amide of the peptide is modified with a -C(=N)NH2 group to form a guanidino group, denoted by "CIA"). In some embodiments, the polypeptide is modified at the N-terminus by a sequence extension of 1 to 10 amino acids, for example, 1 to 5 amino acids, or 3 to 5 amino acids. The amino acids may be natural amino acids. In some embodiments, the peptide is modified at its N-terminus by an amino acid sequence extension selected from TVKTP, YYYEW, MRQ, EHM, EPKRQ, ANYAN, FSFHQ, AHGG, AIKP, ADST, ALNG, ALEQN, AHAGT, VNENI, and TNEGI.

[0505] Examples of C-terminal modifications include peptide elongation via one or more amino acids or amino acid analogs, such as alanine (A) or its variants (e.g., CF3Ala or dA), glutamic acid (E), serine (S), sarcosine (Sar), KFI, lysine (K), or its variants. An example of C-terminal modification is amidation; that is, the C-terminal carboxylic acid group (-C(O)OH or -C(O)O). - The peptide is converted to an amide (-C(O)NH2). In some embodiments, the C-terminus of the peptide is amidated. In some embodiments, the peptide is modified at the C-terminus by extending a sequence of 1 to 10 amino acids, such as 1 to 8 amino acids, 1 to 6 amino acids, or 3 to 6 amino acids. The amino acids may be natural amino acids. In some embodiments, the peptide is modified at the C-terminus by extending an amino acid sequence selected from DKTTV, DIHNN, VYNVN, AGAAAE, KMTHE, NDSLN, SVNAN, QGHTPL, EMEHSN, ETP, TQS, EVHA, QHEA, QHPA, PLSA, NLNLK, RNPHD, and IHNNG.

[0506] Examples of lysine variants include K(Ac), where Ac represents acetyl; and KFl, where Fl represents fluorescein. Another example of a lysine variant is K(PYA) or dK(PYA), where PYA represents pentynic acid (e.g., 4-pentynic acid). In some embodiments, K(PYA) has the following structure (e.g., before being attached to, for example, a linker such as an azide group contained in the linker):

[0507]

[0508] In one embodiment, the polypeptide further comprises an N-terminal addition, which is an alanine residue or Ac, and a C-terminal addition, which is an alanine residue and / or K(PYA). In one embodiment, the polypeptide further comprises an N-terminal addition (which is an alanine residue) and a C-terminal addition (which is an alanine residue and / or K(PYA)) (e.g., a C-terminal addition of -A-[K(PYA)]). In one embodiment, the polypeptide further comprises an N-terminal addition (which is an alanine residue) and a C-terminal addition (which is an alanine residue). Typically, the C-terminus is amidated.

[0509] In one embodiment, the peptide ligand further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from:

[0510] A-(SEQ ID NO: 7)-A-[Sar6]-[KFl];

[0511] A-(SEQ ID NO: 7)-A;

[0512] A-(SEQ ID NO: 8)-A;

[0513] A-(SEQ ID NO: 8)-A-[K(PYA)];

[0514] A-(SEQ ID NO: 9)-A;

[0515] A-(SEQ ID NO: 10)-A;

[0516] A-(SEQ ID NO: 11)-A;

[0517] A-(SEQ ID NO: 12)-A;

[0518] A-(SEQ ID NO: 13)-A;

[0519] A-(SEQ ID NO: 14)-A);

[0520] A-(SEQ ID NO: 15)-A);

[0521] A-(SEQ ID NO: 16)-A;

[0522] A-(SEQ ID NO: 17)-A;

[0523] A-(SEQ ID NO: 18)-A;

[0524] A-(SEQ ID NO: 19)-A;

[0525] A-(SEQ ID NO: 20)-A;

[0526] A-(SEQ ID NO: 21)-A;

[0527] A-(SEQ ID NO: 22)-A;

[0528] A-(SEQ ID NO: 23)-A;

[0529] A-(SEQ ID NO: 24)-A;

[0530] A-(SEQ ID NO: 25)-A;

[0531] A-(SEQ ID NO: 25)-A-[K(PYA)];

[0532] A-(SEQ ID NO: 25);

[0533] Ac-A-(SEQ ID NO: 25);

[0534] (SEQ ID NO: 25)-A;

[0535] Ac-(SEQ ID NO: 25)-A;

[0536] Ac-(SEQ ID NO: 25);

[0537] Ac-A-(SEQ ID NO: 25)-A;

[0538] A-(SEQ ID NO: 25)-DKTTV;

[0539] TVKTP-(SEQ ID NO: 25)-A;

[0540] A-(SEQ ID NO: 25)-DIHNN;

[0541] A-(SEQ ID NO: 26)-A;

[0542] A-(SEQ ID NO: 27)-A;

[0543] A-(SEQ ID NO: 28)-A;

[0544] A-(SEQ ID NO: 29)-A;

[0545] A-(SEQ ID NO: 30)-A;

[0546] A-(SEQ ID NO: 31)-A;

[0547] A-(SEQ ID NO: 32)-A;

[0548] A-(SEQ ID NO: 33)-A;

[0549] A-(SEQ ID NO: 34)-A;

[0550] A-(SEQ ID NO: 35)-A;

[0551] A-(SEQ ID NO: 36)-A;

[0552] A-(SEQ ID NO: 37)-A;

[0553] A-(SEQ ID NO: 38)-A;

[0554] A-(SEQ ID NO: 38)-A-[K(PYA)];

[0555] A-(SEQ ID NO: 38);

[0556] (SEQ ID NO: 38)-A;

[0557] Ac-(SEQ ID NO: 38);

[0558] YYYEW-(SEQ ID NO: 38)-A;

[0559] A-(SEQ ID NO: 39)-A;

[0560] A-(SEQ ID NO: 40)-A;

[0561] A-(SEQ ID NO: 41)-A;

[0562] A-(SEQ ID NO: 42)-A;

[0563] A-(SEQ ID NO: 43)-A;

[0564] A-(SEQ ID NO: 44)-A;

[0565] A-(SEQ ID NO: 45)-A;

[0566] A-(SEQ ID NO: 46)-A;

[0567] A-(SEQ ID NO: 47)-A;

[0568] A-(SEQ ID NO: 48)-A;

[0569] A-(SEQ ID NO: 49)-A;

[0570] A-(SEQ ID NO: 50)-A;

[0571] A-(SEQ ID NO: 51)-A;

[0572] A-(SEQ ID NO: 52)-A;

[0573] A-(SEQ ID NO: 53)-A;

[0574] A-(SEQ ID NO: 54)-A;

[0575] A-(SEQ ID NO: 55)-A;

[0576] A-(SEQ ID NO: 56)-A;

[0577] A-(SEQ ID NO: 57)-A;

[0578] A-(SEQ ID NO: 58)-A;

[0579] A-(SEQ ID NO: 59)-A;

[0580] A-(SEQ ID NO: 59)-VYNVN;

[0581] A-(SEQ ID NO: 60)-A;

[0582] A-(SEQ ID NO: 61)-A;

[0583] A-(SEQ ID NO: 62)-A;

[0584] A-(SEQ ID NO: 63)-A;

[0585] A-(SEQ ID NO: 63)-A-[K(PYA];

[0586] A-(SEQ ID NO: 64)-A;

[0587] A-(SEQ ID NO: 65)-A;

[0588] A-(SEQ ID NO: 65)-A-[Sar6][KFl];

[0589] Ac-(SEQ ID NO: 66)-A-[K(PYA)];

[0590] Ac-(SEQ ID NO: 66)-[K(PYA)];

[0591] A-(SEQ ID NO: 66)-A-[K(PYA)];

[0592] A-(SEQ ID NO: 67)-A;

[0593] A-(SEQ ID NO: 68)-A;

[0594] A-(SEQ ID NO: 69)-A;

[0595] A-(SEQ ID NO: 70)-A;

[0596] A-(SEQ ID NO: 71)-A;

[0597] A-(SEQ ID NO: 72)-A;

[0598] A-(SEQ ID NO: 73)-A;

[0599] A-(SEQ ID NO: 74)-A;

[0600] A-(SEQ ID NO: 75)-A;

[0601] A-(SEQ ID NO: 76)-A;

[0602] A-(SEQ ID NO: 76)-A-[Sar6]-[KFl];

[0603] A-(SEQ ID NO: 76)-A-[K(PYA)];

[0604] A-(SEQ ID NO: 77)-A;

[0605] A-(SEQ ID NO: 78)-A;

[0606] A-(SEQ ID NO: 79)-A;

[0607] A-(SEQ ID NO: 80)-A;

[0608] A-(SEQ ID NO: 80)-A-[Sar6]-[KFl];

[0609] Ac-(SEQ ID NO: 80);

[0610] A-(SEQ ID NO: 80)-A-[Sar6]-[K(Ac)];

[0611] A-(SEQ ID NO: 80)-AGAAAE;

[0612] A-(SEQ ID NO: 81)-A;

[0613] A-(SEQ ID NO: 82)-A);

[0614] A-(SEQ ID NO: 83)-A;

[0615] A-(SEQ ID NO: 84)-A;

[0616] A-(SEQ ID NO: 85)-A;

[0617] A-(SEQ ID NO: 86)-A;

[0618] A-(SEQ ID NO: 87)-A;

[0619] A-(SEQ ID NO: 88)-A;

[0620] Ac-(SEQ ID NO: 89);

[0621] A-(SEQ ID NO: 90)-A);

[0622] A-(SEQ ID NO: 91)-A;

[0623] A-(SEQ ID NO: 91)-A-[Sar6]-[KFl];

[0624] A-(SEQ ID NO: 92)-A;

[0625] A-(SEQ ID NO: 93)-A;

[0626] A-(SEQ ID NO: 94)-A;

[0627] A-(SEQ ID NO: 95)-A;

[0628] A-(SEQ ID NO: 95)-A-[Sar6]-[KFl];

[0629] A-(SEQ ID NO: 95)-A-[K(PYA)];

[0630] Ac-(SEQ ID NO: 95);

[0631] A-(SEQ ID NO: 96)-A;

[0632] Ac-(SEQ ID NO: 96);

[0633] Ac-(SEQ ID NO: 97);

[0634] Ac-(SEQ ID NO: 98);

[0635] Ac-(SEQ ID NO: 99);

[0636] Ac-(SEQ ID NO: 100);

[0637] Ac-(SEQ ID NO: 101);

[0638] Ac-(SEQ ID NO: 102);

[0639] Ac-(SEQ ID NO: 103);

[0640] Ac-(SEQ ID NO: 104);

[0641] A-(SEQ ID NO: 105)-A;

[0642] A-(SEQ ID NO: 105)-A-[K(PYA)];

[0643] A-(SEQ ID NO: 106)-A-[K(PYA)];

[0644] A-(SEQ ID NO: 107)-A;

[0645] A-(SEQ ID NO: 107)-A-[Sar6]-[KFl];

[0646] A-(SEQ ID NO: 108)-A;

[0647] A-(SEQ ID NO: 108)-A-[K(PYA)];

[0648] Ac-(SEQ ID NO: 108)-[K(PYA)];

[0649] Ac-A-(SEQ ID NO: 108)-A-[K(PYA)];

[0650] A-(SEQ ID NO: 108)-A-[Sar6]-[(K(Ac)];

[0651] A-(SEQ ID NO: 108)-AGAAAE;

[0652] A-(SEQ ID NO: 108)-KMTHE;

[0653] A-(SEQ ID NO: 108)-NDSLN;

[0654] A-(SEQ ID NO: 108)-SVNAN;

[0655] A-(SEQ ID NO: 108)-QGHTPL;

[0656] A-(SEQ ID NO: 108)-EMEHSN;

[0657] MRQ-(SEQ ID NO: 108)-ETP;

[0658] EHM-(SEQ ID NO: 108)-TQS;

[0659] EPKRQ-(SEQ ID NO: 108)-A;

[0660] ANYAN-(SEQ ID NO: 108)-A;

[0661] DSFHQ-(SEQ ID NO: 108)-A;

[0662] MRQ-(SEQ ID NO: 108)-ETP-[K(PYA)];

[0663] EPKRQ-(SEQ ID NO: 108)-A-[K(PYA)];

[0664] Ac-(SEQ ID NO: 108)-A-[K(PYA)];

[0665] Ac-(SEQ ID NO: 108)-E-[K(PYA)];

[0666] A-(SEQ ID NO: 108)-E-[K(PYA)];

[0667] A-(SEQ ID NO: 109)-A-[K(PYA)];

[0668] A-(SEQ ID NO: 110)-A-[K(PYA)];

[0669] A-(SEQ ID NO: 111)-A-[K(PYA)];

[0670] A-(SEQ ID NO: 112)-A-[K(PYA)];

[0671] A-(SEQ ID NO: 113)-A-[K(PYA)];

[0672] A-(SEQ ID NO: 114)-A-[K(PYA)];

[0673] A-(SEQ ID NO: 115)-A-[K(PYA)];

[0674] A-(SEQ ID NO: 116)-A-[K(PYA)];

[0675] A-(SEQ ID NO: 117)-A;

[0676] A-(SEQ ID NO: 117)-A-[K(PYA)];

[0677] Ac-(SEQ ID NO: 117)-[K(PYA)];

[0678] A-(SEQ ID NO: 118)-A-[K(PYA)];

[0679] A-(SEQ ID NO: 119)-A-[K(PYA)];

[0680] MRQ-(SEQ ID NO: 119)-ETP-[K(PYA)];

[0681] EPKRQ-(SEQ ID NO: 119)-A-[K(PYA)];

[0682] MRQ-(SEQ ID NO: 119)-ETP;

[0683] EPKRQ-(SEQ ID NO: 119)-A;

[0684] Ac-(SEQ ID NO: 119)-[K(PYA)];

[0685] A-(SEQ ID NO: 120)-A-[K(PYA)];

[0686] A-(SEQ ID NO: 121)-A-[K(PYA)];

[0687] A-(SEQ ID NO: 122)-A-[K(PYA)];

[0688] A-(SEQ ID NO: 123)-A-[K(PYA)];

[0689] A-(SEQ ID NO: 124)-A-[K(PYA)];

[0690] A-(SEQ ID NO: 125)-A-[K(PYA)];

[0691] A-(SEQ ID NO: 126)-A-[K(PYA)];

[0692] [dA]-(SEQ ID NO: 127)-[dA]-[K(PYA)];

[0693] A-(SEQ ID NO: 128)-A-[K(PYA)];

[0694] A-(SEQ ID NO: 129)-A;

[0695] A-(SEQ ID NO: 129);

[0696] Ac-(SEQ ID NO: 129);

[0697] A-(SEQ ID NO: 130);

[0698] Ac-(SEQ ID NO: 130);

[0699] Ac-(SEQ ID NO: 131)-[K(PYA)];

[0700] Ac-(SEQ ID NO: 132)-[K(PYA)];

[0701] Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl];

[0702] Ac-(SEQ ID NO: 133)-[K(PYA)];

[0703] Ac-(SEQ ID NO: 134)-[K(PYA)];

[0704] Ac-(SEQ ID NO: 135)-[K(PYA)];

[0705] Ac-(SEQ ID NO: 136)-[K(PYA)];

[0706] Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl];

[0707] A-(SEQ ID NO: 137)-A;

[0708] A-(SEQ ID NO: 138)-A;

[0709] A-(SEQ ID NO: 138)-A-[Sar6]-[KFl];

[0710] A-(SEQ ID NO: 138)-A-[K(PYA)];

[0711] A-(SEQ ID NO: 139)-A;

[0712] A-(SEQ ID NO: 139)-A-[Sar6]-[KFl];

[0713] A-(SEQ ID NO: 140)-A;

[0714] A-(SEQ ID NO: 141)-A;

[0715] A-(SEQ ID NO: 141)-A-[Sar6]-[KFl];

[0716] A-(SEQ ID NO: 142)-A;

[0717] A-(SEQ ID NO: 143)-A;

[0718] A-(SEQ ID NO: 143)-A-[K(PYA)];

[0719] A-(SEQ ID NO: 144)-A;

[0720] A-(SEQ ID NO: 144)-A-[K(PYA)];

[0721] Ac-A-(SEQ ID NO: 144)-A;

[0722] Ac-(SEQ ID NO: 144);

[0723] A-(SEQ ID NO: 144);

[0724] Ac-A-(SEQ ID NO: 144);

[0725] (SEQ ID NO: 144)-A;

[0726] Ac-(SEQ ID NO: 144)-A;

[0727] AHGG-(SEQ ID NO: 144)-EVHA;

[0728] AIKP-(SEQ ID NO: 144)-QHEA;

[0729] ADST-(SEQ ID NO: 144)-QHPA;

[0730] ALNG-(SEQ ID NO: 144)-PLSA;

[0731] ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)];

[0732] A-(SEQ ID NO: 145)-A;

[0733] A-(SEQ ID NO: 146)-A;

[0734] A-(SEQ ID NO: 147)-A;

[0735] A-(SEQ ID NO: 148)-A;

[0736] A-(SEQ ID NO: 149)-A;

[0737] A-(SEQ ID NO: 150)-A;

[0738] A-(SEQ ID NO: 151)-A;

[0739] A-(SEQ ID NO: 152)-A;

[0740] A-(SEQ ID NO: 153)-A;

[0741] A-(SEQ ID NO: 154)-A;

[0742] A-(SEQ ID NO: 155)-A;

[0743] A-(SEQ ID NO: 156)-A;

[0744] A-(SEQ ID NO: 157)-A;

[0745] A-(SEQ ID NO: 158)-A;

[0746] A-(SEQ ID NO: 159)-A;

[0747] A-(SEQ ID NO: 160)-A;

[0748] A-(SEQ ID NO: 161)-A;

[0749] A-(SEQ ID NO: 162)-A;

[0750] A-(SEQ ID NO: 163)-A;

[0751] A-(SEQ ID NO: 164)-A;

[0752] A-(SEQ ID NO: 165)-A;

[0753] A-(SEQ ID NO: 166)-A;

[0754] A-(SEQ ID NO: 167)-A;

[0755] A-(SEQ ID NO: 168)-A;

[0756] A-(SEQ ID NO: 169)-A;

[0757] A-(SEQ ID NO: 170)-A;

[0758] A-(SEQ ID NO: 171)-A;

[0759] A-(SEQ ID NO: 172)-A;

[0760] A-(SEQ ID NO: 173)-A;

[0761] A-(SEQ ID NO: 174)-A;

[0762] A-(SEQ ID NO: 175)-A;

[0763] A-(SEQ ID NO: 176)-A;

[0764] A-(SEQ ID NO: 177)-A;

[0765] A-(SEQ ID NO: 178)-A;

[0766] A-(SEQ ID NO: 179)-A;

[0767] A-(SEQ ID NO: 180)-A;

[0768] A-(SEQ ID NO: 181)-A;

[0769] A-(SEQ ID NO: 182)-A;

[0770] A-(SEQ ID NO: 183)-A;

[0771] A-(SEQ ID NO: 184)-A;

[0772] A-(SEQ ID NO: 185)-A;

[0773] A-(SEQ ID NO: 186)-A;

[0774] A-(SEQ ID NO: 187)-A;

[0775] A-(SEQ ID NO: 188)-A;

[0776] A-(SEQ ID NO: 189)-A;

[0777] A-(SEQ ID NO: 190)-A;

[0778] A-(SEQ ID NO: 191)-A;

[0779] ALNG-(SEQ ID NO: 192)-PLSA;

[0780] ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)];

[0781] ALNG-(SEQ ID NO: 193)-PLSA;

[0782] ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)];

[0783] ALEQN-(SEQ ID NO: 194)-A;

[0784] ALEQN-(SEQ ID NO: 194)-A-[K(PYA)];

[0785] ALEQN-(SEQ ID NO: 195)-A;

[0786] ALEQN-(SEQ ID NO: 195)-A-[K(PYA)]; and

[0787] AHAGT-(SEQ ID NO: 196)-A;

[0788] A-(SEQ ID NO: 197)-A;

[0789] A-(SEQ ID NO: 197)-A-[K(PYA)];

[0790] A-(SEQ ID NO: 197)-A-[Sar6]-[K(Ac)];

[0791] A-(SEQ ID NO: 198)-A;

[0792] Ac-A-(SEQ ID NO: 198)-A;

[0793] A-(SEQ ID NO: 198)-NLNLK;

[0794] VNENI-(SEQ ID NO: 198)-A;

[0795] A-(SEQ ID NO: 198)-RNPHD;

[0796] A-(SEQ ID NO: 198)-IHNNG;

[0797] TNEGI-(SEQ ID NO: 198)-A;

[0798] VNENI-(SEQ ID NO: 198)-A-[K(PYA)];

[0799] A-(SEQ ID NO: 199)-A;

[0800] A-(SEQ ID NO: 200)-A;

[0801] A-(SEQ ID NO: 201)-A;

[0802] A-(SEQ ID NO: 202)-A;

[0803] A-(SEQ ID NO: 203)-A;

[0804] A-(SEQ ID NO: 204)-A;

[0805] A-(SEQ ID NO: 205)-A;

[0806] A-(SEQ ID NO: 206)-A;

[0807] A-(SEQ ID NO: 207)-A;

[0808] A-(SEQ ID NO: 208)-A;

[0809] A-(SEQ ID NO: 209)-A;

[0810] A-(SEQ ID NO: 210)-A;

[0811] A-(SEQ ID NO: 211)-A;

[0812] A-(SEQ ID NO: 212)-A;

[0813] A-(SEQ ID NO: 213)-A;

[0814] A-(SEQ ID NO: 214)-A;

[0815] A-(SEQ ID NO: 215)-A;

[0816] A-(SEQ ID NO: 216)-A;

[0817] A-(SEQ ID NO: 217)-A;

[0818] A-(SEQ ID NO: 218)-A;

[0819] A-(SEQ ID NO: 219)-A;

[0820] A-(SEQ ID NO: 220)-A;

[0821] A-(SEQ ID NO: 221)-A;

[0822] A-(SEQ ID NO: 222)-A;

[0823] A-(SEQ ID NO: 223)-A;

[0824] A-(SEQ ID NO: 224)-A;

[0825] A-(SEQ ID NO: 225)-A;

[0826] A-(SEQ ID NO: 226)-A; and

[0827] A-(SEQ ID NO: 226)-A-[K(PYA)];

[0828] A-(SEQ ID NO: 227)-A;

[0829] A-(SEQ ID NO: 228)-A;

[0830] A-(SEQ ID NO: 229)-A; and

[0831] A-(SEQ ID NO: 229)-A-[K(PYA)];

[0832] A-(SEQ ID NO: 230)-A;

[0833] A-(SEQ ID NO: 230)-A-[Sar6]-[KFl];

[0834] A-(SEQ ID NO: 231)-A;

[0835] A-(SEQ ID NO: 232)-A;

[0836] A-(SEQ ID NO: 232)-A-[Sar6]-[KFl];

[0837] A-(SEQ ID NO: 232)-A-[Sar6]-[K(Ac)];

[0838] A-(SEQ ID NO: 232)-AGAAAE;

[0839] A-(SEQ ID NO: 233)-A;

[0840] A-(SEQ ID NO: 234)-A;

[0841] A-(SEQ ID NO: 235)-A;

[0842] A-(SEQ ID NO: 236)-A;

[0843] A-(SEQ ID NO: 237)-A;

[0844] A-(SEQ ID NO: 238)-A;

[0845] A-(SEQ ID NO: 239)-A;

[0846] A-(SEQ ID NO: 240)-A;

[0847] A-(SEQ ID NO: 241)-A;

[0848] A-(SEQ ID NO: 242)-A;

[0849] A-(SEQ ID NO: 243)-A;

[0850] A-(SEQ ID NO: 244)-A;

[0851] A-(SEQ ID NO: 245)-A;

[0852] A-(SEQ ID NO: 246)-A;

[0853] A-(SEQ ID NO: 247)-A);

[0854] A-(SEQ ID NO: 248)-A;

[0855] A-(SEQ ID NO: 249)-A;

[0856] A-(SEQ ID NO: 249)-A-[Sar6]-[KFl];

[0857] Ac-A-(SEQ ID NO: 249)-A;

[0858] A-(SEQ ID NO: 250)-A;

[0859] A-(SEQ ID NO: 251)-A;

[0860] A-(SEQ ID NO: 251)-A-[K(PYA)];

[0861] A-(SEQ ID NO: 252)-A;

[0862] A-(SEQ ID NO: 253)-A;

[0863] A-(SEQ ID NO: 254)-A;

[0864] A-(SEQ ID NO: 255)-A;

[0865] A-(SEQ ID NO: 256)-A;

[0866] A-(SEQ ID NO: 257)-A;

[0867] A-(SEQ ID NO: 258)-A;

[0868] A-(SEQ ID NO: 258)-A-[Sar6]-[KFl];

[0869] A-(SEQ ID NO: 258)-A-[K(PYA)];

[0870] Ac-A-(SEQ ID NO: 258)-A;

[0871] A-(SEQ ID NO: 259)-A;

[0872] A-(SEQ ID NO: 260)-A;

[0873] A-(SEQ ID NO: 260)-A-[K(PYA)];

[0874] A-(SEQ ID NO: 261)-A;

[0875] A-(SEQ ID NO: 261)-A-[K(PYA)];

[0876] [PYA]-A-(SEQ ID NO: 261)-A;

[0877] Ac-(SEQ ID NO: 261);

[0878] A-(SEQ ID NO: 261);

[0879] Ac-A-(SEQ ID NO: 261);

[0880] [PYA]-(SEQ ID NO: 261);

[0881] [GuanAc]-(SEQ ID NO: 261)-A;

[0882] A-(SEQ ID NO: 261)-[CF3Ala];

[0883] A-(SEQ ID NO: 261)-S;

[0884] A-(SEQ ID NO: 262)-A;

[0885] A-(SEQ ID NO: 263)-A;

[0886] A-(SEQ ID NO: 264)-A;

[0887] A-(SEQ ID NO: 265)-A;

[0888] A-(SEQ ID NO: 266)-A;

[0889] A-(SEQ ID NO: 266);

[0890] A-(SEQ ID NO: 267)-A;

[0891] A-(SEQ ID NO: 267)-A-[K(PYA)];

[0892] Ac-(SEQ ID NO: 268);

[0893] A-(SEQ ID NO: 268);

[0894] [PYA]-(SEQ ID NO: 268);

[0895] A-(SEQ ID NO: 269);

[0896] Ac-(SEQ ID NO: 270);

[0897] Ac-(SEQ ID NO: 271);

[0898] A-(SEQ ID NO: 272)-A;

[0899] A-(SEQ ID NO: 273)-A;

[0900] A-(SEQ ID NO: 274)-A;

[0901] A-(SEQ ID NO: 275)-A;

[0902] A-(SEQ ID NO: 276)-A;

[0903] A-(SEQ ID NO: 277)-A;

[0904] A-(SEQ ID NO: 278)-A;

[0905] A-(SEQ ID NO: 279)-A;

[0906] A-(SEQ ID NO: 280)-A;

[0907] A-(SEQ ID NO: 281)-A;

[0908] A-(SEQ ID NO: 282)-A;

[0909] A-(SEQ ID NO: 283)-A;

[0910] A-(SEQ ID NO: 284)-A;

[0911] A-(SEQ ID NO: 285)-A;

[0912] A-(SEQ ID NO: 286)-A;

[0913] A-(SEQ ID NO: 287)-A;

[0914] A-(SEQ ID NO: 288)-A;

[0915] A-(SEQ ID NO: 289)-A;

[0916] A-(SEQ ID NO: 290)-A;

[0917] A-(SEQ ID NO: 291)-A;

[0918] A-(SEQ ID NO: 292)-A;

[0919] A-(SEQ ID NO: 293)-A;

[0920] A-(SEQ ID NO: 294)-A;

[0921] [GuanAc]-(SEQ ID NO: 295)-COOH;

[0922] [GuanAc]-(SEQ ID NO: 295);

[0923] [CIA]-[K(PYA)]-(SEQ ID NO: 295)-A;

[0924] [CIA]-[dK(PYA)]-(SEQ ID NO: 295)-A;

[0925] [GuanAc]-(SEQ ID NO: 296);

[0926] [GuanAc]-(SEQ ID NO: 297);

[0927] [GuanAc]-(SEQ ID NO: 298);

[0928] [GuanAc]-(SEQ ID NO: 299);

[0929] [GuanAc]-(SEQ ID NO: 300);

[0930] [GuanAc]-(SEQ ID NO: 301);

[0931] [GuanAc]-(SEQ ID NO: 302);

[0932] A-(SEQ ID NO: 303)-A;

[0933] A-(SEQ ID NO: 304)-A;

[0934] A-(SEQ ID NO: 305)-A-[K(PYA)];

[0935] A-(SEQ ID NO: 306)-A;

[0936] A-(SEQ ID NO: 307)-A;

[0937] A-(SEQ ID NO: 308)-A;

[0938] A-(SEQ ID NO: 309)-A;

[0939] A-(SEQ ID NO: 309)-A-[K(PYA)];

[0940] Ac-(SEQ ID NO: 309);

[0941] Ac-A-(SEQ ID NO: 309)-A;

[0942] [dA]-(SEQ ID NO: 309)-A;

[0943] A-(SEQ ID NO: 309);

[0944] Ac-A-(SEQ ID NO: 309);

[0945] (SEQ ID NO: 309)-A;

[0946] Ac-(SEQ ID NO: 309)-A;

[0947] A-(SEQ ID NO: 309)-A-[dK(PYA)];

[0948] A-(SEQ ID NO: 309)-[K(PYA)];

[0949] A-(SEQ ID NO: 309)-[dK(PYA)];

[0950] A-(SEQ ID NO: 310)-A;

[0951] A-(SEQ ID NO: 310)-A-[K(PYA)];

[0952] A-(SEQ ID NO: 311)-A;

[0953] A-(SEQ ID NO: 312)-A;

[0954] A-(SEQ ID NO: 313)-A;

[0955] A-(SEQ ID NO: 314)-A;

[0956] A-(SEQ ID NO: 315)-A;

[0957] A-(SEQ ID NO: 316)-A;

[0958] A-(SEQ ID NO: 317)-A;

[0959] A-(SEQ ID NO: 318)-A;

[0960] A-(SEQ ID NO: 319)-A;

[0961] A-(SEQ ID NO: 320)-A;

[0962] A-(SEQ ID NO: 321)-A;

[0963] A-(SEQ ID NO: 322)-A;

[0964] A-(SEQ ID NO: 323)-A;

[0965] A-(SEQ ID NO: 324)-A;

[0966] A-(SEQ ID NO: 325)-A;

[0967] A-(SEQ ID NO: 326)-A;

[0968] A-(SEQ ID NO: 327)-A;

[0969] A-(SEQ ID NO: 328)-A;

[0970] A-(SEQ ID NO: 329)-A;

[0971] A-(SEQ ID NO: 330)-A;

[0972] A-(SEQ ID NO: 331)-A;

[0973] A-(SEQ ID NO: 332)-A;

[0974] A-(SEQ ID NO: 333)-A;

[0975] A-(SEQ ID NO: 334)-A;

[0976] A-(SEQ ID NO: 335)-A;

[0977] A-(SEQ ID NO: 336)-A;

[0978] A-(SEQ ID NO: 337)-A;

[0979] A-(SEQ ID NO: 338)-A;

[0980] A-(SEQ ID NO: 339)-A;

[0981] A-(SEQ ID NO: 340)-A;

[0982] A-(SEQ ID NO: 341)-A;

[0983] A-(SEQ ID NO: 342)-A;

[0984] A-(SEQ ID NO: 343)-A;

[0985] A-(SEQ ID NO: 344)-A;

[0986] A-(SEQ ID NO: 345)-A;

[0987] A-(SEQ ID NO: 346)-A;

[0988] A-(SEQ ID NO: 347)-A;

[0989] A-(SEQ ID NO: 348)-A;

[0990] A-(SEQ ID NO: 349)-A;

[0991] A-(SEQ ID NO: 350)-A;

[0992] A-(SEQ ID NO: 351)-A;

[0993] A-(SEQ ID NO: 352)-A;

[0994] A-(SEQ ID NO: 353)-A;

[0995] A-(SEQ ID NO: 354)-A;

[0996] A-(SEQ ID NO: 355)-A;

[0997] A-(SEQ ID NO: 356)-A;

[0998] A-(SEQ ID NO: 357)-A;

[0999] A-(SEQ ID NO: 358)-A;

[1000] A-(SEQ ID NO: 359)-A;

[1001] A-(SEQ ID NO: 360)-A;

[1002] A-(SEQ ID NO: 361)-A;

[1003] A-(SEQ ID NO: 362)-A;

[1004] A-(SEQ ID NO: 363)-A;

[1005] A-(SEQ ID NO: 364)-A;

[1006] A-(SEQ ID NO: 365)-A; and

[1007] A-(SEQ ID NO: 366)-A.

[1008] In some embodiments, the peptide ligands provided herein comprise a peptide provided herein linked to a molecular scaffold. The molecular scaffold can be any molecular scaffold described in more detail herein. In some embodiments, the molecular scaffold is linked to one or more reactive groups in the peptide. In some embodiments, the molecular scaffold is linked to one or more reactive groups, such as one or more cysteine ​​or cysteamine groups in the peptide (e.g., thiol groups contained in the cysteine ​​or cysteamine side chain). In some embodiments, the peptide comprises three cysteine ​​residues (L-cysteine ​​and / or D-cysteine), and the molecular scaffold is linked to these three cysteine ​​groups.

[1009] An example of a molecule suitable as a molecular scaffold in the peptide ligands provided herein and in the complexes comprising them is TATA (1,3,5-triacryloylhexahydro-1,3,5-triazine, available from Sigma Aldrich). TATA has the following structure: .

[1010] In some embodiments, TATA reacts with the cysteine ​​thiol group of the peptide described herein to form a peptide ligand comprising a TATA derivative:

[1011]

[1012] Each Cys-S represents a cysteine ​​residue (e.g., L-cysteine ​​or D-cysteine) or a cysteamine residue.

[1013] Therefore, in one embodiment, the molecular scaffold is a derivative of TATA, having the following structure:

[1014] ,

[1015] It can also be expressed as

[1016]

[1017] in This indicates a junction of three (e.g.) cysteine ​​residues.

[1018] In another embodiment, the molecular scaffold is 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine (TATB):

[1019]

[1020] TATB.

[1021] Therefore, upon cyclization with the bicyclic peptide of the present invention at (e.g.) cysteine ​​residues, the molecular scaffold forms a trisubstituted 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine derivative of TATB having the following structure:

[1022]

[1023] It can also be expressed as

[1024]

[1025] in This indicates the junction of three cysteine ​​residues.

[1026] In another embodiment, the molecular scaffold is 2,4,6-tris(bromomethyl)-s-triazine (TBMT):

[1027]

[1028] TBMT.

[1029] Therefore, in relation to the bicyclic peptide of the present invention at C i Cii and C iii Following cyclization of the cysteine ​​residue, the molecular scaffold forms a trisubstituted 2,4,6-tris(bromomethyl)-S-triazine derivative of TBMT, which has the following structure:

[1030]

[1031] It can also be expressed as

[1032]

[1033] in This indicates, for example, the connection point of three cysteine ​​residues.

[1034] In another embodiment, the molecular scaffold is 2,4,6-tris(chloromethyl)-1,3,5-triazine (TCTZ):

[1035]

[1036] TCTZ.

[1037] Therefore, in relation to the bicyclic peptide of the present invention at C i C ii and C iii Following cyclization of the cysteine ​​residue, the molecular scaffold forms a trisubstituted 2,4,6-tris(chloromethyl)-s-triazine derivative of TCTZ, which has the following structure:

[1038]

[1039] in This indicates, for example, the connection point of three cysteine ​​residues.

[1040] It should be understood that, after the bicyclic peptide of the present invention is cyclized with TBMT or TCTZ, the TBMT and TCTZ derivatives forming the molecular scaffold have the same structure as shown above. Therefore, when a TBMT derivative is mentioned herein as a molecular scaffold, the molecular scaffold may also be a TCTZ derivative.

[1041] Therefore, according to another aspect of the invention, a bicyclic peptide ligand or a pharmaceutically acceptable salt thereof capable of binding TLR3 is provided, comprising a peptide ligand containing a polypeptide having three reactive groups, wherein the polypeptide is linked to a molecular scaffold. According to another aspect of the invention, a bicyclic peptide ligand capable of binding TLR3 is provided, comprising the peptide ligand described herein and a molecular scaffold, wherein three cysteine ​​(L-cysteine ​​or D-cysteine) or Cysam residues of the peptide ligand form covalent bonds with the molecular scaffold to form two cyclic sequences.

[1042] In one embodiment, this document provides a bicyclic peptide ligand comprising the peptide of SEQ ID NO: 1 or a modified derivative thereof (optionally extended at the N-terminus and / or C-terminus) or a pharmaceutically acceptable salt thereof, bonded at each of three reactive residues (e.g., each of three cysteine ​​residues, such as L-cysteine ​​or D-cysteine) to a molecular scaffold of a derivative of TATA, TATB, TBMT, or TCTZ described herein. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 7 to 61. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 7 to 23, and the molecular scaffold is a derivative of TATA described herein. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 24 to 37, and the molecular scaffold is a derivative of TATB described herein. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 38 to 61, and the molecular scaffold is a derivative of TBMT or TCTZ described herein.

[1043] In one embodiment, this document provides a bicyclic peptide ligand comprising the peptide of SEQ ID NO: 2 or a modified derivative thereof (optionally extended at the N-terminus and / or C-terminus) or a pharmaceutically acceptable salt thereof, bonded to a molecular scaffold of a derivative of TBMT or TCTZ described herein at each of three reactive residues (e.g., each of three cysteine ​​residues, such as L-cysteine ​​or D-cysteine). In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 62 to 64.

[1044] In one embodiment, this document provides a bicyclic peptide ligand comprising the peptide of SEQ ID NO:3 or a modified derivative thereof (optionally extended at the N-terminus and / or C-terminus) or a pharmaceutically acceptable salt thereof, bonded to a molecular scaffold of a derivative of TATA or TATB described herein at each of three reactive residues (e.g., each of three cysteine / cysteamine residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO:65 to 196. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO:65 to 141, and the molecular scaffold is a derivative of TATA described herein. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO:142 to 196, and the molecular scaffold is a derivative of TATB described herein.

[1045] In one embodiment, this document provides a bicyclic peptide ligand comprising the peptide of SEQ ID NO: 4 or a modified derivative thereof (optionally extended at the N-terminus and / or C-terminus) or a pharmaceutically acceptable salt thereof, bonded to a molecular scaffold of a derivative of TATB described herein at each of three reactive residues (e.g., each of three cysteine ​​residues, such as L-cysteine ​​or D-cysteine). In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 197 to 226.

[1046] In one embodiment, this document provides a bicyclic peptide ligand comprising the peptide of SEQ ID NO:5 or a modified derivative thereof (optionally extended at the N-terminus and / or C-terminus) or a pharmaceutically acceptable salt thereof, bonded to a molecular scaffold of a derivative of TBMT or TCTZ described herein at each of three reactive residues (e.g., each of three cysteine ​​residues, such as L-cysteine ​​or D-cysteine). In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO:227 to 229.

[1047] In one embodiment, this document provides a bicyclic peptide ligand comprising the peptide of SEQ ID NO: 6 or a modified derivative thereof (optionally extended at the N-terminus and / or C-terminus) or a pharmaceutically acceptable salt thereof, bonded at each of three reactive residues (e.g., each of three cysteine / cysteamine residues (e.g., L-cysteine ​​or D-cysteine)) to a molecular scaffold of a derivative of TATA, TBMT, or TCTZ described herein. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 230 to 366. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 230 to 259, and the molecular scaffold is a derivative of TATA described herein. In one embodiment, the bicyclic ligand comprises the peptide sequence of SEQ ID NO: 260 to 366, and the molecular scaffold is a derivative of TBMT or TCTZ described herein.

[1048] In another embodiment, the molecular scaffold is a derivative of TATA, having the following structure:

[1049]

[1050] in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1051] A-(SEQ ID NO: 7)-A-[Sar6]-[KFl] (referred to as BCY15200 in this paper);

[1052] A-(SEQ ID NO: 7)-A (referred to as BCY15212 in this document);

[1053] A-(SEQ ID NO: 8)-A (referred to as BCY15747 in this document);

[1054] A-(SEQ ID NO: 8)-A-[K(PYA)] (referred to as BCY19281 in this document);

[1055] A-(SEQ ID NO: 9)-A (referred to as BCY17064 in this document);

[1056] A-(SEQ ID NO: 10)-A (referred to as BCY17065 in this document);

[1057] A-(SEQ ID NO: 11)-A (referred to as BCY17066 in this document);

[1058] A-(SEQ ID NO: 12)-A (referred to as BCY17067 in this document);

[1059] A-(SEQ ID NO: 13)-A (referred to as BCY17068 in this document);

[1060] A-(SEQ ID NO: 14)-A (referred to as BCY17070 in this document);

[1061] A-(SEQ ID NO: 15)-A (referred to as BCY17071 in this document);

[1062] A-(SEQ ID NO: 16)-A (referred to as BCY17072 in this document);

[1063] A-(SEQ ID NO: 17)-A (referred to as BCY17079 in this document);

[1064] A-(SEQ ID NO: 18)-A (referred to as BCY17080 in this document);

[1065] A-(SEQ ID NO: 19)-A (referred to as BCY17081 in this document);

[1066] A-(SEQ ID NO: 20)-A (referred to as BCY16675 in this document);

[1067] A-(SEQ ID NO: 21)-A (referred to as BCY16676 in this document);

[1068] A-(SEQ ID NO: 22)-A (referred to herein as BCY16677); and

[1069] A-(SEQ ID NO: 23)-A (referred to as BCY16678 in this document);

[1070] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1071] In another embodiment, the molecular scaffold is a derivative of TATB, having the following structure:

[1072]

[1073] in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1074] A-(SEQ ID NO: 24)-A (referred to as BCY16997 in this document);

[1075] A-(SEQ ID NO: 25)-A (referred to as BCY18125 in this document);

[1076] A-(SEQ ID NO: 25)-A-[K(PYA)] (referred to as BCY19741 in this document);

[1077] A-(SEQ ID NO: 25) (referred to as BCY21538 in this document);

[1078] Ac-A-(SEQ ID NO: 25) (referred to as BCY21539 in this document);

[1079] (SEQ ID NO: 25)-A (referred to herein as BCY21540);

[1080] Ac-(SEQ ID NO: 25)-A (referred to as BCY21541 in this article);

[1081] Ac-(SEQ ID NO: 25) (referred to as BCY21543 in this article);

[1082] Ac-A-(SEQ ID NO: 25)-A (referred to as BCY21544 in this article);

[1083] A-(SEQ ID NO: 25)-DKTTV (referred to as BCY21769 in this document);

[1084] TVKTP-(SEQ ID NO: 25)-A (referred to as BCY21775 in this document);

[1085] A-(SEQ ID NO: 25)-DIHNN (referred to as BCY21777 in this paper);

[1086] A-(SEQ ID NO: 26)-A (referred to as BCY21550 in this document);

[1087] A-(SEQ ID NO: 27)-A (referred to as BCY21551 in this document);

[1088] A-(SEQ ID NO: 28)-A (referred to as BCY21558 in this document);

[1089] A-(SEQ ID NO: 29)-A (referred to as BCY21561 in this document);

[1090] A-(SEQ ID NO: 30)-A (referred to as BCY21562 in this document);

[1091] A-(SEQ ID NO: 31)-A (referred to as BCY21564 in this article);

[1092] A-(SEQ ID NO: 32)-A (referred to as BCY21565 in this document);

[1093] A-(SEQ ID NO: 33)-A (referred to as BCY21566 in this article);

[1094] A-(SEQ ID NO: 34)-A (referred to as BCY21567 in this article);

[1095] A-(SEQ ID NO: 35)-A (referred to as BCY21568 in this document);

[1096] A-(SEQ ID NO: 36)-A (referred to herein as BCY21569); and

[1097] A-(SEQ ID NO: 37)-A (referred to as BCY16998 in this document);

[1098] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1099] In another embodiment, the molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, having the following structure:

[1100]

[1101] in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1102] A-(SEQ ID NO: 38)-A (referred to as BCY18251 in this document);

[1103] A-(SEQ ID NO: 38)-A-[K(PYA)] (referred to as BCY19587 in this document);

[1104] A-(SEQ ID NO: 38) (referred to as BCY21493 in this article);

[1105] (SEQ ID NO: 38)-A (referred to as BCY21495 in this document);

[1106] Ac-(SEQ ID NO: 38) (referred to as BCY21498 in this article);

[1107] YYYEW-(SEQ ID NO: 38)-A (referred to as BCY21773 in this document);

[1108] A-(SEQ ID NO: 39)-A (referred to as BCY21485 in this document);

[1109] A-(SEQ ID NO: 40)-A (referred to as BCY21490 in this document);

[1110] A-(SEQ ID NO: 41)-A (referred to as BCY21500 in this document);

[1111] A-(SEQ ID NO: 42)-A (referred to as BCY21502 in this document);

[1112] A-(SEQ ID NO: 43)-A (referred to as BCY21503 in this document);

[1113] A-(SEQ ID NO: 44)-A (referred to as BCY21504 in this document);

[1114] A-(SEQ ID NO: 45)-A (referred to as BCY21505 in this document);

[1115] A-(SEQ ID NO: 46)-A (referred to as BCY21506 in this document);

[1116] A-(SEQ ID NO: 47)-A (referred to as BCY21507 in this document);

[1117] A-(SEQ ID NO: 48)-A (referred to as BCY21508 in this document);

[1118] A-(SEQ ID NO: 49)-A (referred to as BCY21510 in this document);

[1119] A-(SEQ ID NO: 50)-A (referred to as BCY21515 in this document);

[1120] A-(SEQ ID NO: 51)-A (referred to as BCY21517 in this document);

[1121] A-(SEQ ID NO: 52)-A (referred to as BCY21518 in this document);

[1122] A-(SEQ ID NO: 53)-A (referred to as BCY21519 in this article);

[1123] A-(SEQ ID NO: 54)-A (referred to as BCY21521 in this document);

[1124] A-(SEQ ID NO: 55)-A (referred to as BCY21522 in this document);

[1125] A-(SEQ ID NO: 56)-A (referred to as BCY21523 in this document);

[1126] A-(SEQ ID NO: 57)-A (referred to as BCY21527 in this document);

[1127] A-(SEQ ID NO: 58)-A (referred to as BCY21528 in this document);

[1128] A-(SEQ ID NO: 59)-A (referred to as BCY19930 in this document);

[1129] A-(SEQ ID NO: 59)-VYNVN (referred to as BCY21776 in this paper);

[1130] A-(SEQ ID NO: 60)-A (referred to herein as BCY19931); and

[1131] A-(SEQ ID NO: 61)-A (referred to as BCY19932 in this document);

[1132] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1133] In another embodiment, the molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, having the following structure:

[1134]

[1135] in This indicates the junction of three cysteine ​​residues, and CX. 10 -X 11 -YYCX 12 -QTX 13 -X 14 The peptide ligand of -FC (SEQ ID NO: 2) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1136] A-(SEQ ID NO: 62)-A (referred to as BCY17006 in this document);

[1137] A-(SEQ ID NO: 63)-A (referred to as BCY18134 in this article);

[1138] A-(SEQ ID NO: 63)-A-[K(PYA] (referred to herein as BCY19746); and

[1139] A-(SEQ ID NO: 64)-A (referred to as BCY17012 in this document);

[1140] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1141] In another embodiment, the molecular scaffold is a derivative of TATA, having the following structure:

[1142]

[1143] in This represents the junction of three cysteine ​​residues, and X. 15-X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1144] A-(SEQ ID NO: 65)-A (referred to as BCY15206 in this document);

[1145] A-(SEQ ID NO: 65)-A-[Sar6][KFl] (referred to as BCY15194 in this paper);

[1146] Ac-(SEQ ID NO: 66)-A-[K(PYA)] (referred to as BCY23135 in this paper);

[1147] Ac-(SEQ ID NO: 66)-[K(PYA)] (referred to as BCY23136 in this paper);

[1148] A-(SEQ ID NO: 66)-A-[K(PYA)] (referred to as BCY20791 in this document);

[1149] A-(SEQ ID NO: 67)-A (referred to as BCY15808 in this document);

[1150] A-(SEQ ID NO: 68)-A (referred to as BCY15810 in this document);

[1151] A-(SEQ ID NO: 69)-A (referred to as BCY16655 in this document);

[1152] A-(SEQ ID NO: 70)-A (referred to as BCY16656 in this document);

[1153] A-(SEQ ID NO: 71)-A (referred to as BCY16657 in this document);

[1154] A-(SEQ ID NO: 72)-A (referred to as BCY16658 in this document);

[1155] A-(SEQ ID NO: 73)-A (referred to as BCY16659 in this article);

[1156] A-(SEQ ID NO: 74)-A (referred to as BCY16660 in this document);

[1157] A-(SEQ ID NO: 75)-A (referred to as BCY16661 in this document);

[1158] A-(SEQ ID NO: 76)-A (referred to as BCY15207 in this document);

[1159] A-(SEQ ID NO: 76)-A-[Sar6]-[KFl] (referred to as BCY15195 in this paper);

[1160] A-(SEQ ID NO: 76)-A-[K(PYA)] (referred to as BCY15750 in this document);

[1161] A-(SEQ ID NO: 77)-A (referred to as BCY15811 in this document);

[1162] A-(SEQ ID NO: 78)-A (referred to as BCY15812 in this document);

[1163] A-(SEQ ID NO: 79)-A (referred to as BCY15813 in this article);

[1164] A-(SEQ ID NO: 80)-A (referred to as BCY15814 in this document);

[1165] A-(SEQ ID NO: 80)-A-[Sar6]-[KFl] (referred to as BCY15801 in this paper);

[1166] Ac-(SEQ ID NO: 80) (referred to as BCY17031 in this article);

[1167] A-(SEQ ID NO: 80)-A-[Sar6]-[K(Ac)] (referred to as BCY19384 in this paper);

[1168] A-(SEQ ID NO: 80)-AGAAAE (referred to as BCY19582 in this article);

[1169] A-(SEQ ID NO: 81)-A (referred to as BCY17032 in this document);

[1170] A-(SEQ ID NO: 82)-A (referred to as BCY17033 in this document);

[1171] A-(SEQ ID NO: 83)-A (referred to as BCY17035 in this document);

[1172] A-(SEQ ID NO: 84)-A (referred to as BCY17038 in this document);

[1173] A-(SEQ ID NO: 85)-A (referred to as BCY17040 in this document);

[1174] A-(SEQ ID NO: 86)-A (referred to as BCY17041 in this document);

[1175] A-(SEQ ID NO: 87)-A (referred to as BCY17042 in this document);

[1176] A-(SEQ ID NO: 88)-A (referred to as BCY17043 in this document);

[1177] Ac-(SEQ ID NO: 89) (referred to as BCY19197 in this article);

[1178] A-(SEQ ID NO: 90)-A (referred to as BCY16662 in this document);

[1179] A-(SEQ ID NO: 91)-A (referred to as BCY16663 in this document);

[1180] A-(SEQ ID NO: 91)-A-[Sar6]-[KFl] (referred to as BCY16639 in this paper);

[1181] A-(SEQ ID NO: 92)-A (referred to as BCY16664 in this article);

[1182] A-(SEQ ID NO: 93)-A (referred to as BCY16665 in this document);

[1183] A-(SEQ ID NO: 94)-A (referred to as BCY16666 in this document);

[1184] A-(SEQ ID NO: 95)-A (referred to as BCY16667 in this article);

[1185] A-(SEQ ID NO: 95)-A-[Sar6]-[KFl] (referred to as BCY16643 in this paper);

[1186] A-(SEQ ID NO: 95)-A-[K(PYA)] (referred to as BCY17238 in this document);

[1187] Ac-(SEQ ID NO: 95) (referred to as BCY19193 in this article);

[1188] A-(SEQ ID NO: 96)-A (referred to as BCY19192 in this article);

[1189] Ac-(SEQ ID NO: 96) (referred to as BCY19196 in this article);

[1190] Ac-(SEQ ID NO: 97) (referred to as BCY19194 in this article);

[1191] Ac-(SEQ ID NO: 98) (referred to as BCY19195 in this article);

[1192] Ac-(SEQ ID NO: 99) (referred to as BCY19198 in this article);

[1193] Ac-(SEQ ID NO: 100) (referred to as BCY19199 in this article);

[1194] Ac-(SEQ ID NO: 101) (referred to as BCY19200 in this article);

[1195] Ac-(SEQ ID NO: 102) (referred to as BCY19203 in this article);

[1196] Ac-(SEQ ID NO: 103) (referred to as BCY19205 in this article);

[1197] Ac-(SEQ ID NO: 104) (referred to as BCY19206 in this article);

[1198] A-(SEQ ID NO: 105)-A (referred to as BCY15208 in this document);

[1199] A-(SEQ ID NO: 105)-A-[K(PYA)] (referred to as BCY15751 in this document);

[1200] A-(SEQ ID NO: 106)-A-[K(PYA)] (referred to as BCY21608 in this document);

[1201] A-(SEQ ID NO: 107)-A (referred to as BCY15209 in this document);

[1202] A-(SEQ ID NO: 107)-A-[Sar6]-[KFl] (referred to as BCY15197 in this paper);

[1203] A-(SEQ ID NO: 108)-A (referred to as BCY15727 in this document);

[1204] A-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY17452 in this document);

[1205] Ac-(SEQ ID NO: 108)-[K(PYA)] (referred to as BCY19157 in this paper);

[1206] Ac-A-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY19158 in this document);

[1207] A-(SEQ ID NO: 108)-A-[Sar6]-[(K(Ac)] (referred to as BCY19385 in this paper);

[1208] A-(SEQ ID NO: 108)-AGAAAE (referred to as BCY19580 in this article);

[1209] A-(SEQ ID NO: 108)-KMTHE (referred to as BCY21192 in this article);

[1210] A-(SEQ ID NO: 108)-NDSLN (referred to as BCY21193 in this document);

[1211] A-(SEQ ID NO: 108)-SVNAN (referred to as BCY21194 in this paper);

[1212] A-(SEQ ID NO: 108)-QGHTPL (referred to as BCY21195 in this paper);

[1213] A-(SEQ ID NO: 108)-EMEHSN (referred to as BCY21196 in this document);

[1214] MRQ-(SEQ ID NO: 108)-ETP (referred to as BCY21197 in this document);

[1215] EHM-(SEQ ID NO: 108)-TQS (referred to as BCY21198 in this article);

[1216] EPKRQ-(SEQ ID NO: 108)-A (referred to as BCY21199 in this document);

[1217] ANYAN-(SEQ ID NO: 108)-A (referred to as BCY21200 in this document);

[1218] DSFHQ-(SEQ ID NO: 108)-A (referred to as BCY21201 in this document);

[1219] MRQ-(SEQ ID NO: 108)-ETP-[K(PYA)] (referred to as BCY21993 in this document);

[1220] EPKRQ-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY21994 in this paper);

[1221] Ac-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY23137 in this article);

[1222] Ac-(SEQ ID NO: 108)-E-[K(PYA)] (referred to as BCY23174 in this paper);

[1223] A-(SEQ ID NO: 108)-E-[K(PYA)] (referred to as BCY23179 in this document);

[1224] A-(SEQ ID NO: 109)-A-[K(PYA)] (referred to as BCY19159 in this document);

[1225] A-(SEQ ID NO: 110)-A-[K(PYA)] (referred to as BCY19161 in this document);

[1226] A-(SEQ ID NO: 111)-A-[K(PYA)] (referred to as BCY19162 in this paper);

[1227] A-(SEQ ID NO: 112)-A-[K(PYA)] (referred to as BCY19163 in this document);

[1228] A-(SEQ ID NO: 113)-A-[K(PYA)] (referred to as BCY19164 in this paper);

[1229] A-(SEQ ID NO: 114)-A-[K(PYA)] (referred to as BCY19165 in this document);

[1230] A-(SEQ ID NO: 115)-A-[K(PYA)] (referred to as BCY19166 in this document);

[1231] A-(SEQ ID NO: 116)-A-[K(PYA)] (referred to as BCY19167 in this document);

[1232] A-(SEQ ID NO: 117)-A (referred to as BCY19170 in this document);

[1233] A-(SEQ ID NO: 117)-A-[K(PYA)] (referred to as BCY19284 in this document);

[1234] Ac-(SEQ ID NO: 117)-[K(PYA)] (referred to as BCY19995 in this paper);

[1235] A-(SEQ ID NO: 118)-A-[K(PYA)] (referred to as BCY19171 in this document);

[1236] A-(SEQ ID NO: 119)-A-[K(PYA)] (referred to as BCY19177 in this document);

[1237] MRQ-(SEQ ID NO: 119)-ETP-[K(PYA)] (referred to as BCY21995 in this document);

[1238] EPKRQ-(SEQ ID NO: 119)-A-[K(PYA)] (referred to as BCY21996 in this document);

[1239] MRQ-(SEQ ID NO: 119)-ETP (referred to as BCY21997 in this document);

[1240] EPKRQ-(SEQ ID NO: 119)-A (referred to as BCY21998 in this document);

[1241] Ac-(SEQ ID NO: 119)-[K(PYA)] (referred to as BCY22499 in this paper);

[1242] A-(SEQ ID NO: 120)-A-[K(PYA)] (referred to as BCY19179 in this document);

[1243] A-(SEQ ID NO: 121)-A-[K(PYA)] (referred to as BCY19181 in this document);

[1244] A-(SEQ ID NO: 122)-A-[K(PYA)] (referred to as BCY19184 in this document);

[1245] A-(SEQ ID NO: 123)-A-[K(PYA)] (referred to as BCY19185 in this document);

[1246] A-(SEQ ID NO: 124)-A-[K(PYA)] (referred to as BCY19187 in this document);

[1247] A-(SEQ ID NO: 125)-A-[K(PYA)] (referred to as BCY19188 in this document);

[1248] A-(SEQ ID NO: 126)-A-[K(PYA)] (referred to as BCY19189 in this document);

[1249] [dA]-(SEQ ID NO: 127)-[dA]-[K(PYA)] (referred to as BCY20840 in this document);

[1250] A-(SEQ ID NO: 128)-A-[K(PYA)] (referred to as BCY21040 in this document);

[1251] A-(SEQ ID NO: 129)-A (referred to as BCY21631 in this document);

[1252] A-(SEQ ID NO: 129) (referred to as BCY21633 in this article);

[1253] Ac-(SEQ ID NO: 129) (referred to as BCY21634 in this article);

[1254] A-(SEQ ID NO: 130) (referred to as BCY21635 in this document);

[1255] Ac-(SEQ ID NO: 130) (referred to as BCY21636 in this article);

[1256] Ac-(SEQ ID NO: 131)-[K(PYA)] (referred to as BCY23702 in this paper);

[1257] Ac-(SEQ ID NO: 132)-[K(PYA)] (referred to as BCY23703 in this paper);

[1258] Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl] (referred to herein as BCY25601);

[1259] Ac-(SEQ ID NO: 133)-[K(PYA)] (referred to as BCY23704 in this paper);

[1260] Ac-(SEQ ID NO: 134)-[K(PYA)] (referred to as BCY23705 in this paper);

[1261] Ac-(SEQ ID NO: 135)-[K(PYA)] (referred to as BCY23706 in this paper);

[1262] Ac-(SEQ ID NO: 136)-[K(PYA)] (referred to as BCY23707 in this paper);

[1263] Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl] (referred to herein as BCY25602);

[1264] A-(SEQ ID NO: 137)-A (referred to as BCY15729 in this article);

[1265] A-(SEQ ID NO: 138)-A (referred to as BCY15210 in this document);

[1266] A-(SEQ ID NO: 138)-A-[Sar6]-[KFl] (referred to as BCY15198 in this paper);

[1267] A-(SEQ ID NO: 138)-A-[K(PYA)] (referred to as BCY15752 in this document);

[1268] A-(SEQ ID NO: 139)-A (referred to as BCY15731 in this article);

[1269] A-(SEQ ID NO: 139)-A-[Sar6]-[KFl] (referred to as BCY15730 in this article);

[1270] A-(SEQ ID NO: 140)-A (referred to as BCY15733 in this article);

[1271] A-(SEQ ID NO: 141)-A (referred to herein as BCY15735); and

[1272] A-(SEQ ID NO: 141)-A-[Sar6]-[KFl] (referred to as BCY15734 in this paper);

[1273] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1274] In another embodiment, the molecular scaffold is a derivative of TATB, having the following structure:

[1275]

[1276] in This represents the junction of three cysteine ​​residues, and X. 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1277] A-(SEQ ID NO: 142)-A (referred to as BCY17001 in this document);

[1278] A-(SEQ ID NO: 143)-A (referred to as BCY18128 in this document);

[1279] A-(SEQ ID NO: 143)-A-[K(PYA)] (referred to as BCY19743 in this document);

[1280] A-(SEQ ID NO: 144)-A (referred to as BCY18129 in this article);

[1281] A-(SEQ ID NO: 144)-A-[K(PYA)] (referred to as BCY19744 in this document);

[1282] Ac-A-(SEQ ID NO: 144)-A (referred to as BCY24131 in this article);

[1283] Ac-(SEQ ID NO: 144) (referred to as BCY24135 in this article);

[1284] A-(SEQ ID NO: 144) (referred to as BCY24450 in this document);

[1285] Ac-A-(SEQ ID NO: 144) (referred to as BCY24451 in this article);

[1286] (SEQ ID NO: 144)-A (referred to as BCY24452 in this document);

[1287] Ac-(SEQ ID NO: 144)-A (referred to as BCY24453 in this article);

[1288] AHGG-(SEQ ID NO: 144)-EVHA (referred to as BCY25863 in this article);

[1289] AIKP-(SEQ ID NO: 144)-QHEA (referred to as BCY25864 in this article);

[1290] ADST-(SEQ ID NO: 144)-QHPA (referred to as BCY25865 in this document);

[1291] ALNG-(SEQ ID NO: 144)-PLSA (referred to as BCY25866 in this document);

[1292] ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)] (referred to as BCY28840 in this document);

[1293] A-(SEQ ID NO: 145)-A (referred to as BCY24442 in this document);

[1294] A-(SEQ ID NO: 146)-A (referred to as BCY24443 in this article);

[1295] A-(SEQ ID NO: 147)-A (referred to as BCY24444 in this article);

[1296] A-(SEQ ID NO: 148)-A (referred to as BCY24445 in this document);

[1297] A-(SEQ ID NO: 149)-A (referred to as BCY24456 in this document);

[1298] A-(SEQ ID NO: 150)-A (referred to as BCY24457 in this document);

[1299] A-(SEQ ID NO: 151)-A (referred to as BCY24458 in this document);

[1300] A-(SEQ ID NO: 152)-A (referred to as BCY24459 in this article);

[1301] A-(SEQ ID NO: 153)-A (referred to as BCY24462 in this document);

[1302] A-(SEQ ID NO: 154)-A (referred to as BCY24466 in this document);

[1303] A-(SEQ ID NO: 155)-A (referred to as BCY24467 in this document);

[1304] A-(SEQ ID NO: 156)-A (referred to as BCY24468 in this document);

[1305] A-(SEQ ID NO: 157)-A (referred to as BCY24469 in this article);

[1306] A-(SEQ ID NO: 158)-A (referred to as BCY24471 in this document);

[1307] A-(SEQ ID NO: 159)-A (referred to as BCY24472 in this article);

[1308] A-(SEQ ID NO: 160)-A (referred to as BCY24473 in this document);

[1309] A-(SEQ ID NO: 161)-A (referred to as BCY24474 in this document);

[1310] A-(SEQ ID NO: 162)-A (referred to as BCY24475 in this document);

[1311] A-(SEQ ID NO: 163)-A (referred to as BCY24477 in this article);

[1312] A-(SEQ ID NO: 164)-A (referred to as BCY24478 in this document);

[1313] A-(SEQ ID NO: 165)-A (referred to as BCY24479 in this article);

[1314] A-(SEQ ID NO: 166)-A (referred to as BCY24480 in this document);

[1315] A-(SEQ ID NO: 167)-A (referred to as BCY24481 in this document);

[1316] A-(SEQ ID NO: 168)-A (referred to as BCY24482 in this document);

[1317] A-(SEQ ID NO: 169)-A (referred to as BCY24483 in this article);

[1318] A-(SEQ ID NO: 170)-A (referred to as BCY24484 in this document);

[1319] A-(SEQ ID NO: 171)-A (referred to as BCY24485 in this document);

[1320] A-(SEQ ID NO: 172)-A (referred to as BCY24486 in this document);

[1321] A-(SEQ ID NO: 173)-A (referred to as BCY24487 in this article);

[1322] A-(SEQ ID NO: 174)-A (referred to as BCY24488 in this document);

[1323] A-(SEQ ID NO: 175)-A (referred to as BCY24489 in this document);

[1324] A-(SEQ ID NO: 176)-A (referred to as BCY24490 in this document);

[1325] A-(SEQ ID NO: 177)-A (referred to as BCY24491 in this document);

[1326] A-(SEQ ID NO: 178)-A (referred to as BCY24492 in this article);

[1327] A-(SEQ ID NO: 179)-A (referred to as BCY24493 in this article);

[1328] A-(SEQ ID NO: 180)-A (referred to as BCY24495 in this document);

[1329] A-(SEQ ID NO: 181)-A (referred to as BCY24496 in this document);

[1330] A-(SEQ ID NO: 182)-A (referred to as BCY24497 in this document);

[1331] A-(SEQ ID NO: 183)-A (referred to as BCY24498 in this document);

[1332] A-(SEQ ID NO: 184)-A (referred to as BCY24499 in this article);

[1333] A-(SEQ ID NO: 185)-A (referred to as BCY24500 in this document);

[1334] A-(SEQ ID NO: 186)-A (referred to as BCY24501 in this document);

[1335] A-(SEQ ID NO: 187)-A (referred to as BCY24503 in this document);

[1336] A-(SEQ ID NO: 188)-A (referred to as BCY24504 in this document);

[1337] A-(SEQ ID NO: 189)-A (referred to as BCY24505 in this document);

[1338] A-(SEQ ID NO: 190)-A (referred to as BCY24506 in this document);

[1339] A-(SEQ ID NO: 191)-A (referred to as BCY24509 in this document);

[1340] ALNG-(SEQ ID NO: 192)-PLSA (referred to herein as BCY28838);

[1341] ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)] (referred to as BCY28841 in this document);

[1342] ALNG-(SEQ ID NO: 193)-PLSA (referred to as BCY28839 in this article);

[1343] ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)] (referred to as BCY28842 in this document);

[1344] ALEQN-(SEQ ID NO: 194)-A (referred to as BCY25861 in this document);

[1345] ALEQN-(SEQ ID NO: 194)-A-[K(PYA)] (referred to as BCY28843 in this document);

[1346] ALEQN-(SEQ ID NO: 195)-A (referred to as BCY28844 in this document);

[1347] ALEQN-(SEQ ID NO: 195)-A-[K(PYA)] (referred to herein as BCY28845); and

[1348] AHAGT-(SEQ ID NO: 196)-A (referred to as BCY25859 in this document);

[1349] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1350] In another embodiment, the molecular scaffold is a derivative of TATB, having the following structure:

[1351]

[1352] in This indicates the junction of three cysteine ​​residues, and CQPTX. 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 The peptide ligand of -C (SEQ ID NO: 4) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1353] A-(SEQ ID NO: 197)-A (referred to as BCY16999 in this document);

[1354] A-(SEQ ID NO: 197)-A-[K(PYA)] (referred to as BCY17693 in this paper);

[1355] A-(SEQ ID NO: 197)-A-[Sar6]-[K(Ac)] (referred to as BCY19387 in this paper);

[1356] A-(SEQ ID NO: 198)-A (referred to as BCY18126 in this document);

[1357] Ac-A-(SEQ ID NO: 198)-A (referred to as BCY20725 in this document);

[1358] A-(SEQ ID NO: 198)-NLNLK (referred to as BCY21770 in this article);

[1359] VNENI-(SEQ ID NO: 198)-A (referred to as BCY21771 in this article);

[1360] A-(SEQ ID NO: 198)-RNPHD (referred to as BCY21772 in this paper);

[1361] A-(SEQ ID NO: 198)-IHNNG (referred to as BCY21774 in this paper);

[1362] TNEGI-(SEQ ID NO: 198)-A (referred to as BCY21778 in this article);

[1363] VNENI-(SEQ ID NO: 198)-A-[K(PYA)] (referred to as BCY23767 in this document);

[1364] A-(SEQ ID NO: 199)-A (referred to as BCY20731 in this document);

[1365] A-(SEQ ID NO: 200)-A (referred to as BCY20732 in this document);

[1366] A-(SEQ ID NO: 201)-A (referred to as BCY20734 in this document);

[1367] A-(SEQ ID NO: 202)-A (referred to herein as BCY20735);

[1368] A-(SEQ ID NO: 203)-A (referred to as BCY20736 in this document);

[1369] A-(SEQ ID NO: 204)-A (referred to as BCY20737 in this document);

[1370] A-(SEQ ID NO: 205)-A (referred to as BCY20738 in this document);

[1371] A-(SEQ ID NO: 206)-A (referred to as BCY20741 in this document);

[1372] A-(SEQ ID NO: 207)-A (referred to as BCY20742 in this document);

[1373] A-(SEQ ID NO: 208)-A (referred to as BCY20743 in this document);

[1374] A-(SEQ ID NO: 209)-A (referred to as BCY20746 in this document);

[1375] A-(SEQ ID NO: 210)-A (referred to as BCY20747 in this document);

[1376] A-(SEQ ID NO: 211)-A (referred to as BCY20748 in this document);

[1377] A-(SEQ ID NO: 212)-A (referred to as BCY20749 in this document);

[1378] A-(SEQ ID NO: 213)-A (referred to as BCY20751 in this document);

[1379] A-(SEQ ID NO: 214)-A (referred to as BCY20752 in this document);

[1380] A-(SEQ ID NO: 215)-A (referred to as BCY20756 in this document);

[1381] A-(SEQ ID NO: 216)-A (referred to as BCY20757 in this document);

[1382] A-(SEQ ID NO: 217)-A (referred to as BCY20758 in this document);

[1383] A-(SEQ ID NO: 218)-A (referred to as BCY20759 in this document);

[1384] A-(SEQ ID NO: 219)-A (referred to as BCY20760 in this document);

[1385] A-(SEQ ID NO: 220)-A (referred to as BCY20761 in this document);

[1386] A-(SEQ ID NO: 221)-A (referred to as BCY20762 in this document);

[1387] A-(SEQ ID NO: 222)-A (referred to as BCY20763 in this document);

[1388] A-(SEQ ID NO: 223)-A (referred to as BCY20764 in this document);

[1389] A-(SEQ ID NO: 224)-A (referred to as BCY20765 in this document);

[1390] A-(SEQ ID NO: 225)-A (referred to as BCY20766 in this document);

[1391] A-(SEQ ID NO: 226)-A (referred to herein as BCY18127); and

[1392] A-(SEQ ID NO: 226)-A-[K(PYA)] (referred to as BCY19742 in this paper);

[1393] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1394] In another embodiment, the molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, having the following structure:

[1395]

[1396] in This indicates the junction of three cysteine ​​residues, and CYYX. 38 -X 39 -X 40 The peptide ligand of -YACLDC (SEQ ID NO: 5) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1397] A-(SEQ ID NO: 227)-A (referred to as BCY17007 in this document);

[1398] A-(SEQ ID NO: 228)-A (referred to as BCY18135 in this document);

[1399] A-(SEQ ID NO: 229)-A (referred to herein as BCY18136); and

[1400] A-(SEQ ID NO: 229)-A-[K(PYA)] (referred to as BCY19747 in this document);

[1401] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1402] In another embodiment, the molecular scaffold is a derivative of TATA, having the following structure:

[1403]

[1404] in This represents the junction of three cysteine ​​residues, and X. 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1405] A-(SEQ ID NO: 230)-A (referred to as BCY15211 in this document);

[1406] A-(SEQ ID NO: 230)-A-[Sar6]-[KFl] (referred to as BCY15199 in this paper);

[1407] A-(SEQ ID NO: 231)-A (referred to as BCY15737 in this document);

[1408] A-(SEQ ID NO: 232)-A (referred to as BCY15739 in this article);

[1409] A-(SEQ ID NO: 232)-A-[Sar6]-[KFl] (referred to as BCY15738 in this paper);

[1410] A-(SEQ ID NO: 232)-A-[Sar6]-[K(Ac)] (referred to as BCY19386 in this paper);

[1411] A-(SEQ ID NO: 232)-AGAAAE (referred to as BCY19581 in this article);

[1412] A-(SEQ ID NO: 233)-A (referred to as BCY17047 in this document);

[1413] A-(SEQ ID NO: 234)-A (referred to as BCY17049 in this article);

[1414] A-(SEQ ID NO: 235)-A (referred to as BCY17051 in this document);

[1415] A-(SEQ ID NO: 236)-A (referred to as BCY17055 in this document);

[1416] A-(SEQ ID NO: 237)-A (referred to as BCY17056 in this document);

[1417] A-(SEQ ID NO: 238)-A (referred to as BCY17057 in this document);

[1418] A-(SEQ ID NO: 239)-A (referred to as BCY17058 in this document);

[1419] A-(SEQ ID NO: 240)-A (referred to as BCY17059 in this document);

[1420] A-(SEQ ID NO: 241)-A (referred to as BCY17061 in this document);

[1421] A-(SEQ ID NO: 242)-A (referred to as BCY17656 in this document);

[1422] A-(SEQ ID NO: 243)-A (referred to as BCY15741 in this article);

[1423] A-(SEQ ID NO: 244)-A (referred to as BCY15743 in this article);

[1424] A-(SEQ ID NO: 245)-A (referred to as BCY15745 in this document);

[1425] A-(SEQ ID NO: 246)-A (referred to as BCY16668 in this document);

[1426] A-(SEQ ID NO: 247)-A (referred to as BCY16669 in this document);

[1427] A-(SEQ ID NO: 248)-A (referred to as BCY16670 in this document);

[1428] A-(SEQ ID NO: 249)-A (referred to as BCY16671 in this article);

[1429] A-(SEQ ID NO: 249)-A-[Sar6]-[KFl] (referred to as BCY16647 in this paper);

[1430] Ac-A-(SEQ ID NO: 249)-A (referred to as BCY19586 in this article);

[1431] A-(SEQ ID NO: 250)-A (referred to as BCY18510 in this document);

[1432] A-(SEQ ID NO: 251)-A (referred to as BCY18511 in this document);

[1433] A-(SEQ ID NO: 251)-A-[K(PYA)] (referred to as BCY25826 in this document);

[1434] A-(SEQ ID NO: 252)-A (referred to as BCY18514 in this document);

[1435] A-(SEQ ID NO: 253)-A (referred to as BCY18515 in this document);

[1436] A-(SEQ ID NO: 254)-A (referred to as BCY18518 in this document);

[1437] A-(SEQ ID NO: 255)-A (referred to as BCY18519 in this document);

[1438] A-(SEQ ID NO: 256)-A (referred to as BCY18520 in this document);

[1439] A-(SEQ ID NO: 257)-A (referred to as BCY16672 in this document);

[1440] A-(SEQ ID NO: 258)-A (referred to as BCY16673 in this article);

[1441] A-(SEQ ID NO: 258)-A-[Sar6]-[KFl] (referred to as BCY16649 in this paper);

[1442] A-(SEQ ID NO: 258)-A-[K(PYA)] (referred to as BCY17237 in this document);

[1443] Ac-A-(SEQ ID NO: 258)-A (referred to herein as BCY19585); and

[1444] A-(SEQ ID NO: 259)-A (referred to as BCY16674 in this article);

[1445] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1446] In another embodiment, the molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, having the following structure:

[1447]

[1448] in This represents the junction of three cysteine ​​residues, and X. 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[1449] A-(SEQ ID NO: 260)-A (referred to as BCY17002 in this document);

[1450] A-(SEQ ID NO: 260)-A-[K(PYA)] (referred to as BCY19745 in this document);

[1451] A-(SEQ ID NO: 261)-A (referred to as BCY18130 in this document);

[1452] A-(SEQ ID NO: 261)-A-[K(PYA)] (referred to as BCY20847 in this document);

[1453] [PYA]-A-(SEQ ID NO: 261)-A (referred to herein as BCY20852);

[1454] Ac-(SEQ ID NO: 261) (referred to as BCY21616 in this article);

[1455] A-(SEQ ID NO: 261) (referred to as BCY21617 in this document);

[1456] Ac-A-(SEQ ID NO: 261) (referred to as BCY21618 in this document);

[1457] [PYA]-(SEQ ID NO: 261) (referred to herein as BCY21619);

[1458] [GuanAc]-(SEQ ID NO: 261)-A (referred to as BCY23043 in this document);

[1459] A-(SEQ ID NO: 261)-[CF3Ala] (referred to as BCY23080 in this article);

[1460] A-(SEQ ID NO: 261)-S (referred to as BCY23081 in this document);

[1461] A-(SEQ ID NO: 262)-A (referred to as BCY20848 in this document);

[1462] A-(SEQ ID NO: 263)-A (referred to as BCY20849 in this document);

[1463] A-(SEQ ID NO: 264)-A (referred to as BCY20850 in this document);

[1464] A-(SEQ ID NO: 265)-A (referred to as BCY20851 in this document);

[1465] A-(SEQ ID NO: 266)-A (referred to as BCY20853 in this document);

[1466] A-(SEQ ID NO: 266) (referred to as BCY21620 in this document);

[1467] A-(SEQ ID NO: 267)-A (referred to as BCY21622 in this document);

[1468] A-(SEQ ID NO: 267)-A-[K(PYA)] (referred to as BCY21607 in this document);

[1469] Ac-(SEQ ID NO: 268) (referred to as BCY21624 in this article);

[1470] A-(SEQ ID NO: 268) (referred to as BCY21625 in this document);

[1471] [PYA]-(SEQ ID NO: 268) (referred to herein as BCY21626);

[1472] A-(SEQ ID NO: 269) (referred to as BCY21627 in this document);

[1473] Ac-(SEQ ID NO: 270) (referred to as BCY22879 in this article);

[1474] Ac-(SEQ ID NO: 271) (referred to as BCY22880 in this article);

[1475] A-(SEQ ID NO: 272)-A (referred to as BCY23044 in this document);

[1476] A-(SEQ ID NO: 273)-A (referred to as BCY23045 in this document);

[1477] A-(SEQ ID NO: 274)-A (referred to as BCY23046 in this document);

[1478] A-(SEQ ID NO: 275)-A (referred to as BCY23047 in this document);

[1479] A-(SEQ ID NO: 276)-A (referred to as BCY23050 in this document);

[1480] A-(SEQ ID NO: 277)-A (referred to as BCY23051 in this document);

[1481] A-(SEQ ID NO: 278)-A (referred to as BCY23052 in this document);

[1482] A-(SEQ ID NO: 279)-A (referred to as BCY23053 in this document);

[1483] A-(SEQ ID NO: 280)-A (referred to as BCY23054 in this document);

[1484] A-(SEQ ID NO: 281)-A (referred to as BCY23058 in this document);

[1485] A-(SEQ ID NO: 282)-A (referred to as BCY23059 in this document);

[1486] A-(SEQ ID NO: 283)-A (referred to as BCY23062 in this document);

[1487] A-(SEQ ID NO: 284)-A (referred to as BCY23063 in this document);

[1488] A-(SEQ ID NO: 285)-A (referred to as BCY23064 in this document);

[1489] A-(SEQ ID NO: 286)-A (referred to as BCY23066 in this document);

[1490] A-(SEQ ID NO: 287)-A (referred to as BCY23067 in this document);

[1491] A-(SEQ ID NO: 288)-A (referred to as BCY23068 in this document);

[1492] A-(SEQ ID NO: 289)-A (referred to as BCY23071 in this document);

[1493] A-(SEQ ID NO: 290)-A (referred to as BCY23072 in this document);

[1494] A-(SEQ ID NO: 291)-A (referred to as BCY23073 in this document);

[1495] A-(SEQ ID NO: 292)-A (referred to as BCY23074 in this document);

[1496] A-(SEQ ID NO: 293)-A (referred to as BCY23075 in this document);

[1497] A-(SEQ ID NO: 294)-A (referred to as BCY23079 in this document);

[1498] [GuanAc]-(SEQ ID NO: 295)-COOH (referred to as BCY27058 in this paper);

[1499] [GuanAc]-(SEQ ID NO: 295) (referred to as BCY27059 in this document);

[1500] [CIA]-[K(PYA)]-(SEQ ID NO: 295)-A (referred to as BCY27064 in this article);

[1501] [CIA]-[dK(PYA)]-(SEQ ID NO: 295)-A (referred to as BCY27065 in this document);

[1502] [GuanAc]-(SEQ ID NO: 296) (referred to as BCY27060 in this document);

[1503] [GuanAc]-(SEQ ID NO: 297) (referred to as BCY27061 in this document);

[1504] [GuanAc]-(SEQ ID NO: 298) (referred to as BCY27062 in this document);

[1505] [GuanAc]-(SEQ ID NO: 299) (referred to as BCY27063 in this document);

[1506] [GuanAc]-(SEQ ID NO: 300) (referred to as BCY27066 in this document);

[1507] [GuanAc]-(SEQ ID NO: 301) (referred to as BCY27067 in this document);

[1508] [GuanAc]-(SEQ ID NO: 302) (referred to as BCY27068 in this document);

[1509] A-(SEQ ID NO: 303)-A (referred to as BCY18131 in this document);

[1510] A-(SEQ ID NO: 304)-A (referred to as BCY18132 in this article);

[1511] A-(SEQ ID NO: 305)-A-[K(PYA)] (referred to as BCY19588 in this document);

[1512] A-(SEQ ID NO: 306)-A (referred to as BCY19933 in this document);

[1513] A-(SEQ ID NO: 307)-A (referred to as BCY19934 in this document);

[1514] A-(SEQ ID NO: 308)-A (referred to as BCY19935 in this document);

[1515] A-(SEQ ID NO: 309)-A (referred to as BCY19936 in this document);

[1516] A-(SEQ ID NO: 309)-A-[K(PYA)] (referred to as BCY21606 in this document);

[1517] Ac-(SEQ ID NO: 309) (referred to as BCY23139 in this article);

[1518] Ac-A-(SEQ ID NO: 309)-A (referred to as BCY23140 in this article);

[1519] [dA]-(SEQ ID NO: 309)-A (referred to herein as BCY32061);

[1520] A-(SEQ ID NO: 309) (referred to as BCY32074 in this document);

[1521] Ac-A-(SEQ ID NO: 309) (referred to as BCY32075 in this article);

[1522] (SEQ ID NO: 309)-A (referred to as BCY32076 in this document);

[1523] Ac-(SEQ ID NO: 309)-A (referred to as BCY32077 in this article);

[1524] A-(SEQ ID NO: 309)-A-[dK(PYA)] (referred to as BCY32126 in this paper);

[1525] A-(SEQ ID NO: 309)-[K(PYA)] (referred to as BCY32127 in this document);

[1526] A-(SEQ ID NO: 309)-[dK(PYA)] (referred to as BCY32128 in this paper);

[1527] A-(SEQ ID NO: 310)-A (referred to as BCY23138 in this document);

[1528] A-(SEQ ID NO: 310)-A-[K(PYA)] (referred to as BCY24613 in this document);

[1529] A-(SEQ ID NO: 311)-A (referred to as BCY32062 in this document);

[1530] A-(SEQ ID NO: 312)-A (referred to as BCY32065 in this document);

[1531] A-(SEQ ID NO: 313)-A (referred to as BCY32066 in this document);

[1532] A-(SEQ ID NO: 314)-A (referred to as BCY32069 in this document);

[1533] A-(SEQ ID NO: 315)-A (referred to as BCY32071 in this document);

[1534] A-(SEQ ID NO: 316)-A (referred to as BCY32072 in this document);

[1535] A-(SEQ ID NO: 317)-A (referred to as BCY32078 in this document);

[1536] A-(SEQ ID NO: 318)-A (referred to as BCY32079 in this document);

[1537] A-(SEQ ID NO: 319)-A (referred to as BCY32080 in this document);

[1538] A-(SEQ ID NO: 320)-A (referred to as BCY32081 in this document);

[1539] A-(SEQ ID NO: 321)-A (referred to as BCY32082 in this document);

[1540] A-(SEQ ID NO: 322)-A (referred to as BCY32083 in this document);

[1541] A-(SEQ ID NO: 323)-A (referred to as BCY32084 in this document);

[1542] A-(SEQ ID NO: 324)-A (referred to as BCY32085 in this document);

[1543] A-(SEQ ID NO: 325)-A (referred to as BCY32086 in this document);

[1544] A-(SEQ ID NO: 326)-A (referred to as BCY32087 in this document);

[1545] A-(SEQ ID NO: 327)-A (referred to as BCY32088 in this document);

[1546] A-(SEQ ID NO: 328)-A (referred to as BCY32089 in this document);

[1547] A-(SEQ ID NO: 329)-A (referred to as BCY32090 in this document);

[1548] A-(SEQ ID NO: 330)-A (referred to as BCY32091 in this document);

[1549] A-(SEQ ID NO: 331)-A (referred to as BCY32092 in this document);

[1550] A-(SEQ ID NO: 332)-A (referred to as BCY32093 in this document);

[1551] A-(SEQ ID NO: 333)-A (referred to as BCY32095 in this article);

[1552] A-(SEQ ID NO: 334)-A (referred to as BCY32096 in this document);

[1553] A-(SEQ ID NO: 335)-A (referred to as BCY32098 in this document);

[1554] A-(SEQ ID NO: 336)-A (referred to as BCY32099 in this document);

[1555] A-(SEQ ID NO: 337)-A (referred to as BCY32100 in this document);

[1556] A-(SEQ ID NO: 338)-A (referred to as BCY32101 in this document);

[1557] A-(SEQ ID NO: 339)-A (referred to as BCY32103 in this article);

[1558] A-(SEQ ID NO: 340)-A (referred to as BCY32104 in this document);

[1559] A-(SEQ ID NO: 341)-A (referred to as BCY32105 in this document);

[1560] A-(SEQ ID NO: 342)-A (referred to as BCY32106 in this document);

[1561] A-(SEQ ID NO: 343)-A (referred to as BCY32107 in this document);

[1562] A-(SEQ ID NO: 344)-A (referred to as BCY32108 in this document);

[1563] A-(SEQ ID NO: 345)-A (referred to as BCY32109 in this document);

[1564] A-(SEQ ID NO: 346)-A (referred to as BCY32110 in this document);

[1565] A-(SEQ ID NO: 347)-A (referred to as BCY32112 in this article);

[1566] A-(SEQ ID NO: 348)-A (referred to as BCY32113 in this document);

[1567] A-(SEQ ID NO: 349)-A (referred to as BCY32114 in this document);

[1568] A-(SEQ ID NO: 350)-A (referred to as BCY32115 in this document);

[1569] A-(SEQ ID NO: 351)-A (referred to as BCY32116 in this document);

[1570] A-(SEQ ID NO: 352)-A (referred to as BCY32117 in this document);

[1571] A-(SEQ ID NO: 353)-A (referred to as BCY32120 in this document);

[1572] A-(SEQ ID NO: 354)-A (referred to as BCY32121 in this document);

[1573] A-(SEQ ID NO: 355)-A (referred to as BCY32122 in this document);

[1574] A-(SEQ ID NO: 356)-A (referred to as BCY32123 in this document);

[1575] A-(SEQ ID NO: 357)-A (referred to as BCY32124 in this article);

[1576] A-(SEQ ID NO: 358)-A (referred to as BCY32125 in this document);

[1577] A-(SEQ ID NO: 359)-A (referred to as BCY19937 in this article);

[1578] A-(SEQ ID NO: 360)-A (referred to as BCY19938 in this document);

[1579] A-(SEQ ID NO: 361)-A (referred to as BCY19939 in this article);

[1580] A-(SEQ ID NO: 362)-A (referred to as BCY19940 in this document);

[1581] A-(SEQ ID NO: 363)-A (referred to as BCY19941 in this article);

[1582] A-(SEQ ID NO: 364)-A (referred to as BCY19942 in this article);

[1583] A-(SEQ ID NO: 365)-A (referred to herein as BCY19943); and

[1584] A-(SEQ ID NO: 366)-A (referred to as BCY18253 in this article);

[1585] Or its modified derivatives and / or pharmaceutically acceptable salts.

[1586] Polymerized complex

[1587] According to another aspect of the invention, a polymeric binding complex is provided comprising at least two bicyclic peptide ligands (e.g., 2, 3, or 4 bicyclic peptide ligands), said bicyclic peptide ligands may be the same or different, wherein at least one bicyclic peptide ligand is a peptide ligand as defined herein, or a pharmaceutically acceptable salt thereof. According to another aspect of the invention, a polymeric binding complex is provided comprising at least two bicyclic peptide ligands as defined herein, said peptide ligands may be the same or different, or a pharmaceutically acceptable salt thereof. In some embodiments, the polymeric binding complex comprises, for example, 2, 3, or 4 bicyclic peptide ligands as defined herein, said peptide ligands may be the same or different.

[1588] In one embodiment, the polymer-binding complex comprises more than one identical bicyclic peptide (i.e., homomeric). In an alternative embodiment, the polymer-binding complex comprises different bicyclic peptides (i.e., heteromeric). In one embodiment, the polymer-binding complex comprises at least two identical bicyclic peptide ligands and at least one different bicyclic peptide. In some embodiments, the polymer-binding complex comprises (a) two identical bicyclic peptide ligands and (b) one or two other bicyclic peptide ligands that may be the same or different, and the two other bicyclic peptide ligands in (b) may be the same or different from the two bicyclic peptide ligands in (a).

[1589] In one embodiment, the polymeric conjugating complex further comprises one or more effector groups and / or functional groups, such as one or more cytotoxic agents, radiochelates, or chromophores. The effector groups and / or functional groups may also be groups capable of generating a detectable signal in the presence of a second intermediate (e.g., biotin and various protein antigens). For biotin, the second intermediate may comprise a streptavidin-enzyme conjugate or a streptavidin-dye conjugate. In one embodiment, the polymeric conjugating complex further comprises a fluorophore.

[1590] spacer base

[1591] In one embodiment, the polymeric binding complex further comprises a spacer or hinge portion, or one or more spacer or hinge portions. Such spacer or hinge portions are configured to maintain a plurality of bicyclic peptide ligands in an optimal alignment for delivery to a target.

[1592] It is understood that bicyclic peptide ligands in heteropolymer-bound complexes can be coupled to each other via any suitable linker. In this document, the terms linker and spacer / hinge moiety are used interchangeably. The properties of the linker can be tuned to increase length, rigidity, or solubility, thereby optimizing the desired functional outcome. Increasing the valence state of either binding peptide can enhance the affinity of the heteropolymer for the target.

[1593] In one embodiment, the linker is a linear linker or a branched linker. In some embodiments, the linker is a branched linker and includes three or four branches. In some embodiments, the linker is capable of binding three or four bicyclic peptide ligands. In some embodiments, the linker includes three branches and is capable of binding three bicyclic peptide ligands. In some embodiments, the linker includes four branches and is capable of binding four bicyclic peptide ligands. In some embodiments, the linker includes one or more repeating monomeric groups.

[1594] In some embodiments, the connector is a bidentate or multidentate group with a length of about 0.3 nm to about 300 nm. In some embodiments, the connector length is about 0.5 nm to about 200 nm, for example, about 1 nm to about 100 nm, such as about 1.5 nm to about 50 nm, such as about 2 nm to about 20 nm, such as about 3 nm to about 10 nm. In some embodiments, the connector length is a persistent length. In some embodiments, the length is determined in an aqueous solution under physiological conditions (e.g., phosphate-buffered saline at pH 7.4 and 37°C), and in some embodiments, it can be determined using atomic force microscopy.

[1595] In some embodiments, the connector includes one or more connecting portions, such as one or more poly(alkylene glycol) groups, like poly(ethylene glycol) or poly(propylene glycol). In some embodiments, the connector may include one or more groups, such as amino, amide, alkylene, urethane, ether, ester, disulfide, hydrazone, sulfonamide, thioether, or cyclic groups, preferably 4-12 membered carbocyclic or heterocyclic groups, 5-12 membered heteroaryl groups, or C6 groups. 6-12 Aryl groups; wherein the alkylene, alkenylene, ynylene, poly(alkylene glycol), amino, and cyclic groups are each optionally substituted independently.

[1596] In some embodiments, the linker comprises one or more amino acids or amino acid analogs. In some embodiments, the linker comprises about 1 to about 5 amino acids or amino acid analogs. In some embodiments, the side chains of two amino acids or amino acid analogs in the linker are linked together. In some embodiments, the linker comprises a portion of the following form:

[1597]

[1598] Each R 1 For H or C 1-4 Alkyl; each R 2 Side chains selected from amino acids (e.g., typical amino acids), or those that can be reacted with, for example, OH, SH, SC. 1-4 Alkyl, aryl (which can be substituted by OH), heteroaryl, C(O)OH, C(O)NH2, N + H3, NH (C=N) + H2)NH2-substituted C 1-4 Alkyl, for example, R 2 It may contain arginine or high-arginine side chains; wherein the linker is a adapter, and the linker may be C-type. 2-8 A alkyl diene (e.g., alkylene) linker, optionally capped or substituted by one or more groups such as amino, amide, alkylene, urethane, ether, ester, disulfide, hydrazone, sulfonamide, thioether, or a cyclic group as defined herein; for example, the linker may contain a C-terminated or interrupted C-terminus. 3-6 Alkylene groups; for example, linkers may contain portions of the form: -C 1-4 Alkylene-NHC(O)-C 1-4 Alkylene, for example -C4 alkylene-NHC(O)-C1 alkylene-. In some embodiments, the portion is linked to a polypeptide contained in a peptide ligand or bicyclic peptide ligand as defined herein, for example, to the N-terminus or C-terminus of a polypeptide contained in a peptide ligand or bicyclic peptide ligand as defined herein.

[1599] In some embodiments, the linker comprises one or more reactive groups for reacting with the bicyclic peptide ligands described herein. Exemplary reactive groups include an azide group (which can react with an alkynyl group on the bicyclic peptide ligands described herein, for example, under suitable conditions, such as in the presence of an azide-alkynyl cycloaddition catalyst, thereby forming a 1,2,3-triazole group); carboxylic acids and their activated derivatives (such as NHS esters) (which can react with an amino group on the bicyclic peptide ligands described herein, for example, under suitable conditions, thereby forming an amide bond), etc. In the bicyclic peptide ligands described herein, the terms "azido" and "triazole" are sometimes used interchangeably to describe the same structure, wherein "azido" refers to the structure in the linker before coupling with the bicyclic peptide ligand, and "triazole" refers to the structure in the linker after reaction with an alkynyl group on the bicyclic peptide ligand.

[1600] In some embodiments, when the connector comprises a poly(alkylene glycol), the poly(alkylene glycol) is poly(ethylene glycol) (PEG) or poly(propylene glycol) (PPG). In some embodiments, the connector comprises one or more PEGs. n The PEG group, wherein n represents the number of consecutive ethylene glycol units in each PEG group. In some embodiments, n is an integer from about 1 to about 30, for example from about 2 to about 25, or from about 3 to about 10. In some embodiments, the connector comprises one or more branches, such as three branches, and each branch contains PEG. n Group.

[1601] In some embodiments, when the linker comprises an amide group, the amide group is of the formula -NHC(O)- or -C(O)NH-. In some embodiments, when the linker comprises an amino group, the amino group is of the formula N(R)3, wherein each R may be the same or different. In some embodiments, each R comprises a bicyclic peptide ligand as described herein, for example by comprising one or more PEGs as described herein. n The linker group is attached to the amine nitrogen. In some embodiments, when the linker contains a cyclic group, the cyclic group is a C6 aryl group. In some embodiments, when the linker contains an alkylene group, the alkylene group is a C6 aryl group. 1-3 Alkylene group.

[1602] The aforementioned linkers can also be used to couple bicyclic peptide ligands to effector groups and / or functional groups as defined herein. Typically, linkers for coupling effector groups and / or functional groups to bicyclic peptide ligands contain or are composed of one or more PEGs. n The group composition, wherein n represents the number of consecutive ethylene glycol units in each of the PEG groups. In some embodiments, n is an integer from about 1 to about 30, for example from about 2 to about 25, or from about 3 to about 10. In some embodiments, the linker that couples the effector group and / or functional group to the bicyclic peptide ligand is a covalent bond.

[1603] Dimer

[1604] In one embodiment, the polymeric binding complex comprises two identical (i.e., homodimers) or different (i.e., heterodimers) bicyclic peptides. In one embodiment, the polymeric binding complex comprises two identical bicyclic peptides (i.e., homodimers). In another embodiment, the polymeric binding complex comprises two different bicyclic peptides (i.e., heterodimers).

[1605] When a polycyclic complex contains two bicyclic peptides, it is understandable that the spacer group will require two connection points.

[1606] In some dimer implementations, the linker is a group of the following formula: N3-(Alk1) m -PEG n -(Alk1) m -NHC(O)(Alk2)C(O)NH-(Alk1) m -PEG n -(Alk1) m -N3

[1607] Each Alk1 is independently C 1-3 alkylene groups; Alk2 is C 1-6 Alk2 is an alkylene group; each m is independently 0 or 1; n is an integer from about 1 to about 30; and wherein Alk2 is optionally substituted with a functional group capable of forming a linker with an effect group and / or functional group as defined herein, such as a fluorophore. In some embodiments, Alk2 is a C5 alkylene group. In some embodiments, Alk2 is -CH2CH2CH(N H)CH2CH2- ， in For the connection point with the effector and / or functional group as defined herein, optionally Alk2 is coupled to the effector and / or functional group via a linker. In some embodiments, Alk2 is -CH2CH2CH(NH(fluorophore))CH2CH2-, where the fluorophore is a fluorophore as defined herein, such as AlexaFluor488. An example of such a linker is "AHDA-(PEG)". 10 "-N3)" refers to compound 4 from Example 2.

[1608] In some dimer implementations, the linker is a group of the following formula: N3-(Alk1) m -PEG n -(Alk1) m -NHC(O)(Alk2)C(O)NH-(Alk1) m-PEG n -(Alk1) m -N3

[1609] Each Alk1 is independently C 1-3 alkylene groups; Alk2 is C 1-6 Alk2 is an alkylene group; each m is independently 0 or 1; n is an integer from about 1 to about 30. In some embodiments, Alk2 is a propylene group. In some embodiments, when Alk2 is a propylene group, such a connector may be referred to as "GTA-Peg". n "-N3", such as "GTA-PEG10-N3" shown in Examples 5 and 6, describes the synthesis of BCY26427 and BCY26435.

[1610] In some implementations of the dimer, the linker is a group of the following formula:

[1611] [N3—(Alk) m —PEG n —(Alk) m -]2-N-[-(Alk) m —PEG n —(Alk) m —Z]

[1612] Each Alk is independently C 1-3 An alkylene group, independently optionally terminated with an amide or -O- group; each m independently being 0, 1, or 2; each n independently being an integer from about 1 to about 30; and Z comprising an effector group and / or a functional group as defined herein. In some embodiments, Z is or comprises biotin. In some embodiments, Z is or comprises a fluorophore as defined herein, such as Bodipy558. For the avoidance of doubt, each group [N3—(Alk)] m —PEG n —(Alk) m -] can be the same or different.

[1613] In some implementations of the dimer, the linker is a group of the following formula:

[1614] N3—(Alk) m —PEG n —(Alk) m —Q

[1615] Each Alk is independently C 1-3 The alkylene group is independently optionally capped with an amide group or an -O- group; each m is independently 0 or 1; n is an integer from about 1 to about 30; and Q is a carboxylic acid (C(O)OH) or an activated derivative thereof (e.g., an NHS-ester group).

[1616] In one embodiment, the polymer-binding complex comprises two bicyclic peptides, and the polymer-binding complex is a motif of formula (A) or (B):

[1617]

[1618] (A)

[1619]

[1620] (B)

[1621] Wherein BCY stands for “bicyclic peptide ligand”. As will be understood by those skilled in the art as described above, the triazole group shown in the above structure originates from the reaction between the azide group in the linker and the alkynyl group on the bicyclic peptide ligand (e.g., the reaction with the alkynyl group contained in the K(PYA) portion described herein).

[1622] In one embodiment, the polymeric conjugate complex comprises the dimeric conjugate complexes described in Table 1 below:

[1623] Table 1: Exemplary dimerized complexes of the present invention

[1624]

[1625] Wherein AF488 represents AlexaFluor488; AHDA is derived from the name of compound AHDA-[Peg10-N3]2 (compound 4 in Example 2), GTA refers to glutaric anhydride (but when used as a linker, it forms a ring-opening -C(O)(CH2)5C(O)- moiety), BDP558 represents Bodipy558, and BDP558-N3SC2 and BDP558-N3SC1 are shown below:

[1626] .

[1627] For example, the structure of BCY26427 is as follows:

[1628]

[1629] In some embodiments, the polymeric conjugate is selected from BCY28218, BCY28219, BCY28220, BCY28885, BCY28887, or a pharmaceutically acceptable salt thereof. In some embodiments, the polymeric conjugate is BCY26435, or a pharmaceutically acceptable salt thereof.

[1630] Trimer

[1631] In one embodiment, the polymeric binding complex comprises three identical (i.e., homotrimers) or different (i.e., heterotrimers) bicyclic peptides. In a further embodiment, the heterotrimer comprises a bicyclic peptide with a first sequence and two bicyclic peptides with second sequences. In one embodiment, the polymeric binding complex comprises three identical bicyclic peptides.

[1632] In some implementations of the trimer, the linker is a group of the following formula:

[1633] [N3—(Alk) m —PEG n —(Alk) m -]3-N

[1634] Each Alk is independently C 1-3 Alkylene groups, independently optionally terminated with amide or -O- groups; each m independently is 0, 1, or 2; each n independently is an integer from about 1 to about 30. For the avoidance of ambiguity, each [N3—(Alk)]... m —PEG n —(Alk) m -] can be the same or different.

[1635] When a polypolymer conjugating complex comprises three bicyclic peptides, it is understood that three connection sites will be required for the spacer group. Therefore, in one embodiment, the polypolymer conjugating complex comprises three bicyclic peptides, and the polypolymer conjugating complex is a motif of formula (C) or formula (D):

[1636]

[1637] (C),

[1638]

[1639] (D),

[1640] BCY stands for bicyclic peptide ligand.

[1641] In one embodiment, the polymeric conjugate complex comprises the trimeric conjugate complexes described in Table 2 below:

[1642] Table 2: Exemplary trimer-binding complexes of the present invention

[1643]

[1644] TCA is N((CH2)2O(CH2)2CONH)3.

[1645] Tetramer

[1646] In one embodiment, the polycyclic complex comprises four identical (i.e., homotetramers) or different (i.e., heterotetramers) bicyclic peptides. In a further embodiment, the heterotetramer comprises one bicyclic peptide with a first sequence and three bicyclic peptides with second sequences. In an alternative embodiment, the heterotetramer comprises two bicyclic peptides with first sequences and two bicyclic peptides with second sequences. In one embodiment, the polycyclic complex comprises four identical bicyclic peptides.

[1647] In some tetramer implementations, the linker is a group of the following formula:

[1648] [N3—(Alk) m —PEG n —(Alk) m -]4-C

[1649] Each Alk is independently C 1-3 Alkylene groups, independently optionally terminated with amide or -O- groups; each m independently is 0, 1, or 2; each n independently is an integer from about 1 to about 30. For the avoidance of ambiguity, each [N3—(Alk)]... m —PEG n —(Alk) m -] can be the same or different.

[1650] When a polypolymer conjugating complex comprises four bicyclic peptides, it is understood that four linker sites will be required. Therefore, in one embodiment, the polypolymer conjugating complex comprises four bicyclic peptides, and the polypolymer conjugating complex is a motif of formula (E):

[1651]

[1652] (E),

[1653] BCY stands for bicyclic peptide ligand.

[1654] In one embodiment, the polymeric complex comprises the tetrameric complexes described in Table 3 below:

[1655] Table 3: Exemplary tetrameric complexes of the present invention

[1656]

[1657] TET is C((CH2)O(CH2)2CONH)4.

[1658] As will be understood by those skilled in the art as described above, when coupled with the bicyclic peptide ligands described herein, the azide group or each azide group typically reacts with an alkynyl group on a bicyclic peptide ligand (e.g., with the alkynyl group contained in the K(PYA) moiety described herein to form a triazole group).

[1659] All of the above compounds are available in the form of their pharmaceutically acceptable salts, which are also included herein.

[1660] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, such as in the fields of peptide chemistry, cell culture and phage display, nucleic acid chemistry, and biochemistry. Molecular biology, genetics, and biochemistry methods use standard techniques (see Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Ausubel et al., Short Protocols in Molecular Biology (1999), 4th ed., John Wiley & Sons, Inc.), the contents of which are incorporated herein by reference.

[1661] serial number

[1662] When referring to the positions of amino acid residues in the peptides of the present invention, invariant residues are omitted from the numbering. Therefore, the numbering of amino acid residues in the peptides of the present invention is as follows:

[1663] C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1).

[1664] Molecular format

[1665] The N-terminus or C-terminus of the double-loop core sequence is added to the left or right side of the sequence, separated by a hyphen. For example, the N-terminal βAla-Sar10-Ala tail chain is represented as:

[1666] βAla-Sar10-A-(SEQ ID NO: X).

[1667] Sar represents sarcosine, and βAla represents β-alanine.

[1668] It is understood that, unless otherwise stated, all bicyclic peptides have a C-terminal CONH2 group, except for those containing a C-terminal Cysam group (i.e., SEQ ID NO: 130), which lacks the C-terminal CONH2 group. Furthermore, in some bicyclic peptides, the C-terminal CONH2 group may be replaced by a COOH group, as shown in BCY27058 herein.

[1669] Reverse peptide sequence

[1670] Given the disclosure in Nair et al. (2003) J Immunol 170(3), 1362-1373, it is conceivable that the peptide sequences disclosed herein will also be useful in their reverse-inverted forms. For example, the sequence is reversed (i.e., the N-terminus becomes the C-terminus, and vice versa), and its stereochemistry is also reversed (i.e., the D-amino acid becomes the L-amino acid, and vice versa).

[1671] Bicyclic peptide ligand

[1672] The term "bicyclic peptide ligand" as used herein refers to a peptide ligand that is covalently bound to a molecular scaffold. Typically, such bicyclic peptides comprise a polypeptide having natural or non-natural amino acids, two or more reactive groups capable of forming covalent bonds with the scaffold (e.g., cysteine, homocysteine ​​(hCys, (S)-2-amino-4-thiobutyric acid), βCys ((R)-3-amino-3-mercaptopropionic acid), cysteamine (Cystam), or penicillamine (Pen, (R)-2-amino-3-mercapto-3-methylbutyric acid), Dap ((S)-2,3-diaminopropionic acid), or N-alkyl-Dap (e.g., N-methyl-Dap, (S)-2-amino-3-(methylamino)propionic acid)), and a sequence located between the reactive groups, referred to as a ring sequence because it forms a ring when the peptide binds to the scaffold. In this case, the peptide typically contains at least three cysteine ​​residues (e.g., three cysteine ​​residues), or two cysteine ​​residues and one cystam residue, and forms at least two loops on the scaffold, most typically two loops.

[1673] Therefore, in some embodiments, this disclosure provides peptides, peptide ligands, or bicyclic peptide ligands provided herein, wherein one or more cysteine ​​or cysteamine residues of one or more polypeptides contained in the peptide, peptide ligand, or bicyclic peptide ligand are replaced by homocysteine ​​(hCys), βCys, penicillamine (Pen), Dap, or N-methyl-Dap. For the avoidance of doubt, in the complexes provided herein comprising two or more peptide ligands (e.g., two or more bicyclic peptide ligands), each ligand is optionally modified independently in such a manner that different ligands may be modified or not modified, and different modified ligands may contain different modifications.

[1674] peptide specificity

[1675] As described above, in some embodiments, the provided peptide and ligand containing such peptide (described in more detail herein) are specific for TLR3. In some embodiments, the provided complex (e.g., a polymeric binding complex) comprises a peptide specific for TLR3 and a ligand containing such peptide (described in more detail herein).

[1676] As used herein, the term "specificity" ("specific binding," etc.) refers most broadly to the binding of a peptide or peptide ligand to its biological target. In some embodiments, the peptide or peptide ligand binds to its biological target in a specific manner; that is, the binding to the biological target is not nonspecific. In some embodiments, peptides exhibiting nonspecific binding are heterogeneous; that is, the peptide is capable of binding to a variety of different biological species, typically including both the target of interest and off-target binding sites, such as binding sites on cell types other than the target cell type. Therefore, in some embodiments, peptides or peptide ligands selected or designed to bind specifically to their intended target do not exhibit heterogeneous binding to off-target binding sites.

[1677] In some embodiments, binding to a target is binding to a specific epitope on the target. The peptide or peptide ligand can be engineered to be specific to a specific epitope, or can be identified by suitable screening methods (such as display techniques, e.g., phage display) that can be used to develop high-affinity binders to a given target (e.g., epitope). Alternatively, peptides or peptide ligands that specifically bind to biological targets (e.g., cellular targets) can be identified without knowing the specific epitope to which they bind. In some embodiments, peptides or peptide ligands that specifically bind to a target or epitope have high affinity for the target or epitope. In some embodiments, the binding affinity of a peptide or peptide ligand to its epitope can be determined by its dissociation constant (K0). D Also written as Kd). Typically, the K-value of a peptide or peptide ligand that specifically binds to a biological target is the K-value of that target. D Less than 10 µM, for example, less than 1 µM. Typically, the Kt of a peptide or peptide ligand that specifically binds to a biological target is related to the target's Kt. D The binding affinity is in the nanomolar range, for example, less than 500 nM, less than 250 nM, less than 100 nM, less than 20 nM, less than 10 nM, or even less than 1 nM. Binding affinity can be determined by methods known in the art, such as SPR and competitive assays. Some suitable assays are described in the examples.

[1678] In some implementations, the peptide or peptide ligand that specifically binds to the biological target has a lower affinity (K0) for the specific biological target. DThe affinity for a target-specific peptide or peptide ligand is higher than that for other biological epitopes. For example, peptides or peptide ligands that specifically bind to TLR3 typically have a higher affinity for TLR3 than for other epitopes (e.g., other Toll-like receptors). In some embodiments, the binding affinity of a target-specific peptide or peptide ligand to the target is at least twice, for example at least 5 times, at least 10 times, at least 20 times, at least 50 times, at least 100 times, at least 1000 times, or more than that of any other off-target binding chaperone.

[1679] Advantages of bicyclic peptide ligands

[1680] Certain bicyclic peptides of the present invention possess numerous advantageous properties, making them suitable as pharmaceutically analogous molecules for injection, inhalation, nasal administration, ocular administration, oral administration, or topical administration. These advantageous properties include:

[1681] - Species cross-reactivity. This is a typical requirement for preclinical pharmacodynamic and pharmacokinetic assessments;

[1682] - Protease stability. Ideally, bicyclic peptide ligands should exhibit stability against plasma proteases, epithelial ("membrane-anchored") proteases, gastric and intestinal proteases, lung surface proteases, intracellular proteases, etc. Protease stability should be consistent across different species so that bicyclic lead candidates can be developed in animal models and confidently applied to humans;

[1683] - Ideal solubility characteristics. This is a function of the ratio of charged residues and hydrophilic residues to hydrophobic residues, as well as intramolecular / intermolecular H bonds, and is important for formulation and absorption purposes;

[1684] - Optimal plasma half-life in circulation. Depending on the clinical indication and treatment regimen, there may be a need to develop bicyclic peptides for short-term exposure in acute disease management settings, or bicyclic peptides with enhanced retention in circulation, which are therefore more suitable for managing more chronic disease states. Other factors leading to an ideal plasma half-life include the requirements between sustained exposure to achieve maximum therapeutic efficacy and the toxicological requirements associated with sustained exposure to the agent; and

[1685] -Selectivity.

[1686] abbreviation

[1687] The peptide ligands of this invention use many non-natural amino acids, which are referred to herein as abbreviations for clarity, and their full definitions are as follows:

[1688] Agb: 2-Amino-4-guanidinobutyric acid

[1689] Aib: Aminoisobutyric acid

[1690] AlloIle: AlloIleucine

[1691] Arg(Me): dN-methylarginine

[1692] AzaTrp: Aza-tryptophan

[1693] Aze: Azacyclobutane

[1694] Cba: β-Cyclobutylalanine

[1695] Cbg: Cyclobutylglycine

[1696] CF3Ala: β-Trifluoromethylalanine

[1697] CF3Nva: 5,5,5-trifluorovaline (or (S)-2-amino-5,5,5-trifluorovaleric acid)

[1698] 4CF3Phe: 4-Trifluoromethylphenylalanine

[1699] C5g: Cyclopentylglycine

[1700] CIA: Carboximidamide

[1701] cis-HyP: cis-L-4-hydroxyproline

[1702] Cit: Citrulline

[1703] 6ClTrp: 6-Chloro-tryptophan

[1704] Cysam: Cysteine

[1705] Dap: Diaminopropionic acid

[1706] 44DFP: 4,4-Difluoroproline

[1707] 26DiMeTyr: 2,6-Dimethyltyrosine

[1708] DOPA: 3,4-Dihydroxyphenylalanine

[1709] EPA: 2-Amino-3-ethylpentanoic acid

[1710] 4FlPro: 4-Fluoro-proline

[1711] 2FPhe: 2-Fluoro-phenylalanine

[1712] 3FPhe: 3-Fluoro-phenylalanine

[1713] 4FPhe: 4-Fluoro-phenylalanine

[1714] 4FTrp: 4-Fluoro-L-Tryptophan

[1715] 5FTrp: 5-Fluoro-L-Tryptophan

[1716] 6FTrp: 6-Fluoro-L-Tryptophan

[1717] 7FTrp: 7-Fluoro-L-Tryptophan

[1718] 2FTyr: 2-Fluoro-tyrosine

[1719] 3FTyr: 3-Fluoro-tyrosine

[1720] Gla: L-γ-carboxyglutamic acid

[1721] HArg: High Arginine

[1722] His1Me: N1-methyl-L-histidine

[1723] His3Me: N3-methyl-L-histidine

[1724] HLeu: High Leucine

[1725] HSer: Homoserine

[1726] HyP: Hydroxyproline

[1727] 3HyV: 3-Hydroxy-L-valine

[1728] KFl: Lysine-fluorescein

[1729] K(PYA): Lysine, ε-4-pentynyl group

[1730] 4MeOTrp: 4-Methoxy-tryptophan

[1731] 5MeOTrp: 5-Methoxy-tryptophan

[1732] 2MePhe: 2-Methyl-phenylalanine

[1733] 3MePhe: 3-Methyl-phenylalanine

[1734] 4MePhe: 4-Methyl-phenylalanine

[1735] 2MeTrp: 2-Methyl-Tryptophan

[1736] 4MeTrp: 4-Methyl-Tryptophan

[1737] 5MeTrp: 5-Methyl-Tryptophan

[1738] 6MeTrp: 6-Methyl-Tryptophan

[1739] 7MeTrp: 7-Methyl-Tryptophan

[1740] 1Nal: 1-Naphthylalanine

[1741] 2Nal: 2-Naphthylalanine

[1742] Nle: Ortholeucine

[1743] Nva: n-valine

[1744] Orn: Ornithine

[1745] PG: Acrylaminoglycine

[1746] Pip: Piperidinic acid

[1747] PYA: Pentynoic acid

[1748] R-aMeLys(PYA): ( R α-methyllysine, ε-4-pentyneyl

[1749] S-aMeLys(PYA): ( S α-methyllysine, ε-4-pentyneyl

[1750] tBuAla: tert-butyl-alanine

[1751] tBuGly: tert-butyl-glycine

[1752] 4tBuPhe: 4-tert-butyl-phenylalanine

[1753] 3tBuTyr: 3-tert-butyl-tyrosine

[1754] TfNle: 6,6,6-Trifluoroleucine

[1755] trans-4FlPro: trans-4-fluoro-pyrrolidine-2-carboxylic acid

[1756] Trp(Me): Methyl-tryptophan

[1757] Trp(S): α-amino-benzo[b]thiophene-3-propionic acid

[1758] Pharmaceutically acceptable salts

[1759] It is understood that, within the scope of this invention, reference to peptide ligands includes the salt form of the ligand.

[1760] The salts of this invention can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties, such as... Pharmaceutical Salts: Properties, Selection, and UseP. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002, as described in the article. Typically, such salts can be prepared by reacting the free acid or free base form of these compounds with a suitable base or acid in water, in an organic solvent, or in a mixture of both.

[1761] Acid addition salts (monosal or diosal) can be formed from a variety of inorganic and organic acids. Examples of acid addition salts include monosal or diosal salts formed with acids selected from the group consisting of: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, butyric acid, (+) camphor, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutarate. Glycolic acid, hippuric acid, hydrohalic acids (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), hydroxyethanesulfonic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthyl acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid, undecenoic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[1762] A specific group of salts consists of the following: acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, hydroxyethanesulfonic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, mesylate, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, propionic acid, butyric acid, malonic acid, glucuronic acid, and lactobionic acid. One specific salt is a hydrochloride salt. Another specific salt is an acetate salt.

[1763] If the compound is anionic, or has a functional group that can be anionic (e.g., -COOH can be -COO), - Then, it can form salts with organic or inorganic bases to generate suitable cations. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li⁻. + Na+ and K + Alkaline earth metal cations such as Ca 2+ and Mg 2+ and other cations such as Al 3+ or Zn 2+ Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4+). + ) and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Examples of suitable substituted ammonium ions derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4. + .

[1764] When the peptides of the present invention contain amine functional groups, these can, for example, be reacted with an alkylating agent to form a quaternary ammonium salt according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the peptides of the present invention.

[1765] The peptides (including peptide ligands and their complexes) of the present invention can exist as zwitterions. Such compounds can also be provided in the form of pharmaceutically acceptable salts. Suitable salts include those formed with pharmaceutically acceptable acids, said acids being negatively charged groups such as COO. - The zwitterion provides a proton and a counterion to a positively charged group, such as a quaternary nitrogen atom, to balance the positive charge. Suitable pharmaceutically acceptable acids include hydrochloric acid, sulfonic acids (including methanesulfonic acid and toluenesulfonic acid), ascorbic acid, and citric acid. Hydrochloric acid and sulfonic acids are preferred, especially hydrochloric acid. Alternatively, the zwitterion can be combined with a pharmaceutically acceptable base, such as alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides.

[1766] Modified derivatives

[1767] It is understood that the modified derivatives of peptide ligands defined herein are within the scope of this invention.

[1768] In some implementations, the modified derivatives include functional fragments, derivatives, and variants of the sequences provided herein.

[1769] As those skilled in the art will understand, fragments of amino acid sequences include deletion variants of such sequences, wherein one or more amino acids, such as at least 1, 2, 3, 4, or 5 amino acids, are missing. Deletions may occur at the C-terminus or N-terminus of the reference sequence, or within the reference sequence.

[1770] Derivatives of amino acid sequences include modified sequences, including sequences modified in vivo or in vitro. Many different protein modifications are known to those skilled in the art, including modifications that modify amino acid residues to introduce new functions, modifications that protect reactive amino acid residues, or modifications that couple amino acid residues to chemical moieties, such as reactive functional groups for attachment to such amino acid residues. Exemplary modifications that may be made to the provided peptides, ligands, and related complexes are described in more detail herein.

[1771] Derivatives of the amino acid sequence include addition variants of such sequences, wherein one or more amino acids, such as at least 1, 2, 3, 4, or 5 amino acids, are added to or introduced into the reference sequence. Addition may occur at the C-terminus or N-terminus of the reference sequence, or within the reference sequence.

[1772] Variations of the amino acid sequence include sequences in which one or more amino acids (e.g., at least 1, 2, 3, 4, or 5 amino acid residues in the reference sequence) are exchanged for one or more substitute residues. Variations of the amino acid sequence include sequences carrying naturally occurring amino acids and / or non-natural amino acids.

[1773] Variants, derivatives, and fragments of the above-described amino acid sequence generally retain at least some of the activity / function of the reference sequence. In a preferred embodiment, the variants, derivatives, and fragments substantially retain the biological functions described herein. Thus, in one embodiment, the variants, derivatives, and fragments retain the binding specificity of the reference sequence, i.e., the ability to specifically bind TLR3. In one such embodiment, the variants, derivatives, and fragments bind the same epitopes as the reference sequence. In another embodiment, the variants, derivatives, and fragments retain the binding affinity of the reference sequence. Preferably, the variants, derivatives, and fragments of the reference sequence have increased / improved activity / function compared to the reference sequence.

[1774] In some implementations, variants, derivatives, or fragments of the amino acid sequence are represented by their percentage identity with a reference sequence. Determining percentage identity is a conventional procedure within the scope of those skilled in the art. Suitable methods include CLUSTAL W (Thompson et al., Nucleic Acids Research, 22(22) 4673-4680(1994)) and iterative optimization (Gotoh, J. Mol. Biol. 264(4) 823-838(1996)); and the methods described in Altschul et al., Bull. Math. Bio. 48: 603-16, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA89:10915-19, 1992. In the exemplary method, two amino acid sequences are aligned using a vacancy opening penalty of 10, a vacancy extension penalty of 1, and a Henikoff to Henikoff (same as above) “blosum 62” scoring matrix to optimize the alignment score. The percentage identity is then calculated as: [100 × (T / L)]; where T = the total number of identical matches and L = the length of the longer sequence plus the number of vacancy numbers introduced in the longer sequence to align the two sequences.

[1775] In some implementations, variants, derivatives, or fragments of the reference sequence have at least 60% identity with the reference sequence, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or higher identity.

[1776] Examples of suitable modified derivatives include one or more modifications selected from: N-terminal and / or C-terminal modifications; substitution of one or more amino acid residues with one or more non-natural amino acid residues, or vice versa; substitution of one or more amino acids (e.g., one or more natural amino acids) with one or more isosteric amino acids and / or isoelectronic amino acids, substitution of one or more natural amino acids with one or more isosteric non-natural amino acids and / or isoelectronic non-natural amino acids, or vice versa (e.g., substitution of one or more polar amino acid residues with one or more isosteric or isoelectronic amino acids; substitution of one or more nonpolar amino acid residues with one or more other non-natural isosteric or non-natural isoelectronic amino acids); addition of a spacer group; and substitution of one or more antioxidant amino acids. The following methods are employed: replacing one or more oxidation-sensitive amino acid residues with an amino acid residue; replacing one or more amino acid residues with one or more alanine residues; replacing one or more L-amino acid residues with one or more D-amino acid residues; N-alkylation of one or more amide bonds in a bicyclic peptide ligand; replacing one or more peptide bonds with one or more alternative bonds; modifying the peptide backbone length; replacing the hydrogen on the α-carbon of one or more amino acid residues with one or more other chemical groups; functionalizing amino acids such as cysteine, lysine, glutamic acid / aspartic acid, and tyrosine with suitable amino, thiol, carboxylic acid, and phenolic reactive agents; and introducing or replacing amino acids with orthogonal reactivity suitable for functionalization, for example, azide-containing or alkynyl-containing amino acids that allow functionalization with alkynyl-containing or azido-containing moieties, respectively.

[1777] Amino acid residues are typically replaced with other amino acid residues having similar chemical structures, similar chemical properties, or similar side chain volumes (“conservative substitutions”). The introduced amino acid may have similar polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality, or charge as the substituted amino acid. Alternatively, a conservative substitution may introduce another aromatic or aliphatic amino acid at a pre-existing aromatic or aliphatic amino acid position. Variations in conservative amino acids are well known in the art and can be selected based on the properties of the 20 principal amino acids defined in Table A above. When amino acids have similar polarity, this can also be determined by referring to a hydrophilicity scale of amino acid side chains well known to those skilled in the art.

[1778] In one embodiment, the modified derivative includes N-terminal and / or C-terminal modifications. In a further embodiment, the modified derivative includes N-terminal modification using a suitable amino-reactive chemistry and / or C-terminal modification using a suitable carboxyl-reactive chemistry. In a further embodiment, the N-terminal or C-terminal modification includes the addition of an effector group, which includes, but is not limited to, cytotoxic agents, radiochelates, or chromophores.

[1779] In a further embodiment, the modified derivative includes an N-terminal modification. In a further embodiment, the N-terminal modification includes an N-terminal acetyl group. In this embodiment, the N-terminal cysteine ​​group is capped with acetic anhydride or other suitable reagent during peptide synthesis, resulting in N-terminal acetylation of the molecule. This embodiment provides the advantage of removing potential aminopeptidase recognition sites and avoiding potential degradation of the bicyclic peptide.

[1780] In an alternative embodiment, N-terminal modification includes adding a molecular spacer group that promotes coupling of effector groups and maintains the efficacy of the bicyclic peptide on its target.

[1781] In a further embodiment, the modified derivative includes a C-terminal modification. In a further embodiment, the C-terminal modification includes an amide group. In this embodiment, the C-terminal cysteine ​​group is synthesized as an amide during peptide synthesis, resulting in C-terminal amidation of the molecule. This embodiment provides the advantage of removing potential carboxypeptidase recognition sites and reducing the hydrolytic degradation potential of bicyclic peptides.

[1782] In one embodiment, the modified derivative comprises replacing one or more amino acid residues with one or more non-natural amino acid residues. In this embodiment, non-natural amino acids having isosteric / isoelectronic side chains may be selected, wherein the amino acids are neither recognized by degrading proteases nor have any adverse effect on target efficacy.

[1783] Alternatively, non-natural amino acids with restricted amino acid side chains can be used, thereby hindering proteolysis of nearby peptide bonds both conformally and spatially. In particular, these involve proline analogs, large side chains, Cα-disubstituted derivatives (e.g., aminoisobutyric acid, Aib), and cyclic amino acids; a simple derivative is aminocyclopropylcarboxylic acid.

[1784] In one embodiment, the modified derivative includes adding a spacer group. In a further embodiment, the modified derivative includes adding a spacer group to the N-terminal cysteine ​​and / or the C-terminal cysteine.

[1785] In one embodiment, the modified derivative includes replacing one or more oxidation-sensitive amino acid residues with one or more antioxidant amino acid residues.

[1786] In one embodiment, the modified derivative comprises replacing one or more charged amino acid residues with one or more hydrophobic amino acid residues. In an alternative embodiment, the modified derivative comprises replacing one or more hydrophobic amino acid residues with one or more charged amino acid residues. The proper balance between charged and hydrophobic amino acid residues is an important characteristic of bicyclic peptide ligands. For example, hydrophobic amino acid residues affect the degree of binding to plasma proteins, thereby affecting the concentration of the free available fraction in plasma, while charged amino acid residues (especially arginine) can affect the interaction of the peptide with the cell surface phospholipid membrane. The combination of both can affect the half-life, volume of distribution, and exposure of the peptide drug, and can be adjusted according to clinical endpoints. Furthermore, the correct combination and amount of charged and hydrophobic amino acid residues can reduce injection site irritation (if the peptide drug has been administered subcutaneously).

[1787] In one embodiment, the modified derivative comprises replacing one or more L-amino acid residues with one or more D-amino acid residues. This embodiment is believed to increase proteolytic stability through steric hindrance and the tendency of D-amino acids to stabilize the β-turn conformation (Tugyi et al. (2005) PNAS, 102(2), 413-418).

[1788] In one embodiment, the modified derivative comprises removing any amino acid residues and replacing them with alanine. This embodiment offers the advantage of removing potential proteolytic attack sites.

[1789] It should be noted that each of the above modifications is intended to intentionally improve the potency or stability of the peptide. Further potency improvements based on modifications can be achieved through the following mechanisms:

[1790] - Introducing a hydrophobic component, which utilizes the hydrophobic effect to result in a lower dissociation rate, thereby achieving higher affinity;

[1791] - Introducing charged groups, which utilize long-range ion interactions, leads to faster binding rates and higher affinities (see, for example, Schreiber et al.). Rapid, electrostatically assisted association of proteins (1996), Nature Struct. Biol. 3, 427-31); and

[1792] - Introducing additional constraints to peptides, such as by properly restricting the side chains of amino acids to minimize entropy loss during target binding, restricting the torsion angle of the backbone to minimize entropy loss during target binding, and introducing additional cyclization into the molecule for the same reason.

[1793] (For reviews, see Gentilucci et al., Curr. Pharmaceutical Design, (2010), 16, 3185-203, and Nestor et al., Curr. Medicinal Chem (2009), 16, 4399-418).

[1794] Isotope variants

[1795] This invention includes all pharmaceutically acceptable (radioactive) isotope-labeled peptide ligands of this invention, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those commonly found in nature; peptide ligands of this invention wherein a metal chelating group (referred to as an "effect group") capable of accommodating the relevant (radioactive) isotope is attached; and peptide ligands of this invention wherein certain functional groups are covalently replaced by relevant (radioactive) isotope or isotope-labeled functional groups.

[1796] Suitable examples of isotopes included in the peptide ligands of the present invention include isotopes of hydrogen, such as... 2 H(D) and 3 H(T); isotopes of carbon, such as 11 C 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; Isotopes of iodine, such as 123 I, 125 I and 131 I; Isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O、 17 O and 18 O; isotopes of phosphorus, such as 32 P; isotopes of sulfur, such as 35 S; isotopes of copper, such as 64 Cu; isotopes of gallium, such as 67 Ga or 68 Ga; isotopes of yttrium, such as 90 Y; isotopes of lutetium, such as 177 Lu; and bismuth isotopes, such as 213 Bi.

[1797] Certain isotope-labeled peptide ligands of the present invention, for example, those incorporating radioactive isotopes, are useful in tissue distribution studies of drugs and / or substrates. The peptide ligands of the present invention may also possess valuable diagnostic properties because they can be used to detect or identify the formation of complexes between labeled compounds and other molecules, peptides, proteins, enzymes, or receptors. Methods for detection or identification may use compounds labeled with labeling agents such as radioactive isotopes, enzymes, fluorescent substances, luminescent substances (e.g., luminol, luminol derivatives, luciferin, jellyfish luminescent protein, and luciferase). The radioactive isotope tritium, i.e. 3 H(T), and carbon-14, i.e. 14 C, given its ease of incorporation and detection, is particularly useful for this purpose.

[1798] Using heavier isotopes such as deuterium, i.e. 2 H(D) substitution can offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in certain situations.

[1799] Using positron emission isotopes, such as 11 C 18 F, 15 O and 13 N substitution can be used to examine target occupancy in positron emission tomography (PET) studies.

[1800] The isotope-labeled compounds of the peptide ligands of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by a process similar to that described in the examples, using a suitable isotope-labeling reagent instead of the previously used unlabeled reagent.

[1801] Molecular scaffold

[1802] In some embodiments, the peptides disclosed herein are linked to a molecular scaffold. In one embodiment, the molecular scaffold comprises a non-aromatic molecular scaffold. The reference herein to "non-aromatic molecular scaffold" refers to any molecular scaffold as defined herein that does not contain aromatic (i.e., unsaturated) carbocyclic or heterocyclic ring systems. Therefore, in some embodiments, the peptide is linked to a non-aromatic molecular scaffold. In other embodiments, the peptide is linked to an aromatic molecular scaffold. Molecular scaffolds are described, for example, in WO 2009 / 098450 and its cited references, particularly WO 2004 / 077062 and WO 2006 / 078161.

[1803] As described in the aforementioned document, the molecular scaffold can be a small molecule, such as a small organic molecule.

[1804] In one embodiment, the molecular scaffold can be a macromolecule. In one embodiment, the molecular scaffold is a macromolecule composed of amino acids, nucleotides, or carbohydrates.

[1805] In one embodiment, the molecular scaffold includes reactive groups capable of reacting with functional groups of a polypeptide to form covalent bonds.

[1806] Molecular scaffolds may contain chemical groups that are linked to peptides, such as amino, mercapto, hydroxyl, ketone, aldehyde, nitrile, carboxylic acid, ester, alkenyl, alkynyl, azide, acid anhydride, succinimide, maleimide, alkyl halide, and acyl halide.

[1807] The molecular scaffold of the present invention contains chemical groups that allow functional groups of peptides encoding the library of the present invention to form covalently linked chemical groups with the molecular scaffold. These chemical groups are selected from a wide range of functional groups, including amino, mercapto, hydroxyl, ketone, aldehyde, nitrile, carboxylic acid, ester, alkenyl, alkynyl, acid anhydride, succinimide, maleimide, azide, alkyl halide, and acyl halide.

[1808] The scaffold reactive groups that can be used to react with the thiol group of cysteine ​​on the molecular scaffold are alkyl halides (or also called haloalkanes or haloalkanes).

[1809] Examples include bromomethylbenzene or iodoacetamide. Other scaffold reactive groups used for selectively coupling compounds to cysteine ​​residues in proteins are maleimides, compounds containing α,β-unsaturated carbonyl groups, and compounds containing α-halomethyl carbonyl groups. Examples of maleimides that can be used as molecular scaffolds in this invention include tris-(2-maleimide ethyl)amine, tris-(2-maleimide ethyl)benzene, and tris-(maleimide)benzene.

[1810] In one embodiment, the molecular scaffold is selected from 1,1',1''-(1,3,5-triazine-1,3,5-triyl)tripropyl-2-en-1-one (also known as triacryloylhexahydro-s-triazine; TATA), 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine (TATB), 2,4,6-tris(bromomethyl)-s-triazine (TBMT), and 2,4,6-tris(chloromethyl)-1,3,5-triazine (TCTZ).

[1811] In a further embodiment, the molecular scaffold is 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (also known as triacryloylhexahydro-s-triazine (TATA)):

[1812]

[1813] TATA.

[1814] Therefore, upon cyclization of the bicyclic peptide of the present invention (e.g., on a cysteine ​​residue), the molecular scaffold forms a trisubstituted 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tripropyl-1-one derivative of TATA having the following structure:

[1815] ,

[1816] It can also be expressed as

[1817] ,

[1818] in This indicates the junction of three cysteine ​​residues.

[1819] In another embodiment, the molecular scaffold is 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine (TATB):

[1820]

[1821] TATB.

[1822] Therefore, upon cyclization of the bicyclic peptide of the present invention (e.g., on a cysteine ​​residue), the molecular scaffold forms a trisubstituted 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine derivative of TATB having the following structure:

[1823]

[1824] It can also be expressed as

[1825]

[1826] in This indicates the junction of three cysteine ​​residues.

[1827] In another embodiment, the molecular scaffold is 2,4,6-tris(bromomethyl)-s-triazine (TBMT):

[1828]

[1829] TBMT.

[1830] Therefore, in relation to the bicyclic peptide of the present invention at C i C ii and C iii Following cyclization of cysteine ​​residues, the molecular scaffold forms a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT with the following structure:

[1831]

[1832] It can also be expressed as

[1833]

[1834] in This indicates, for example, the connection point of three cysteine ​​residues.

[1835] A complete description of TBMT and its use in the derivatization of cyclic peptides is found in van de Langemheen et al. (2016). ChemBioChem 10.1002 / cbic.201600612 (https: / / onlinelibrary.wiley.com / doi / abs / 10.1002 / cbic.201600612).

[1836] In another embodiment, the molecular scaffold is 2,4,6-tris(chloromethyl)-1,3,5-triazine (TCTZ):

[1837]

[1838] TCTZ.

[1839] Therefore, in relation to the bicyclic peptide of the present invention at C i C ii and C iii Following cyclization of the cysteine ​​residues, the molecular scaffold forms a trisubstituted 2,4,6-tris(chloromethyl)-s-triazine derivative of TCTZ with the following structure:

[1840]

[1841] in This indicates, for example, the connection point of three cysteine ​​residues.

[1842] It is understood that after the bicyclic peptide of the present invention is cyclized with TBMT or TCTZ, the TBMT derivative and the TCTZ derivative forming the molecular scaffold have the same structure, as shown above. Therefore, when a molecular scaffold of a TBMT derivative is mentioned herein, the molecular scaffold can also be a TCTZ derivative.

[1843] reactive groups

[1844] The molecular scaffold of the present invention can be bound to the polypeptide via functional groups or reactive groups on the polypeptide. These are typically formed from side chains of specific amino acids found in the polypeptide polymer. Such reactive groups can be cysteine ​​side chains, homocysteine ​​side chains (hCys, (S)-2-amino-4-thiobutyric acid), βCys side chains ((R)-3-amino-3-mercaptopropionic acid), cysteamine side chains (Cysam, 2-aminoethanethiol), penicillamine side chains (Pen, (R)-2-amino-3-mercapto-3-methylbutyric acid), Dap groups ((S)-2,3-diaminopropionic acid), N-alkyl-Dap groups (e.g., N-methyl-Dap, (S)-2-amino-3-(methylamino)propionic acid, [Dap(Me)] group), lysine side chains, or N-terminal amino groups, or any other suitable reactive groups. Details can be found in WO 2009 / 098450. In one implementation, the reactive groups are all cysteine ​​residues.

[1845] Examples of reactive groups in natural amino acids include the thiol group of cysteine, the amino group of lysine, the carboxyl group of aspartic acid or glutamic acid, the guanidinium group of arginine, the phenolic group of tyrosine, or the hydroxyl group of serine. Non-natural amino acids can provide a wide range of reactive groups, including azide, ketone carbonyl, alkynyl, vinyl, or aryl halide groups. The amino and carboxyl groups at the ends of peptides can also serve as reactive groups to form covalent bonds with the molecular scaffold / core.

[1846] The polypeptide of the present invention contains at least three reactive groups. The polypeptide may also contain four or more reactive groups. The more reactive groups used, the more rings can be formed on the molecular scaffold.

[1847] In a preferred embodiment, a polypeptide with three reactive groups is generated. The polypeptide reacts with a molecular scaffold / core having triplet rotational symmetry to generate a single product isomer. There are several advantages to generating a single product isomer. The nucleic acids in the compound library encode only the primary sequence of the polypeptide, not the isomeric state of the molecule formed after the polypeptide reacts with the molecular core. If only one product isomer can be formed, the allocation of nucleic acids to the product isomers is well-defined. If multiple product isomers are formed, the nucleic acids cannot provide information about the properties of the product isomers isolated during screening or selection. It is also advantageous to form a single product isomer if a specific member of the present invention's library is to be synthesized. In this case, the chemical reaction of the polypeptide with the molecular scaffold produces a single product isomer, rather than a mixture of isomers.

[1848] In another embodiment of the invention, a polypeptide having four reactive groups is generated. The polypeptide reacts with a molecular scaffold / core having tetrahedral symmetry to generate two product isomers. Although the two different product isomers are encoded by the same nucleic acid, the isomeric properties of the isolated isomers can be determined by chemically synthesizing the two isomers, isolating the two isomers, and testing the binding of the two isomers to a target ligand.

[1849] In one embodiment of the invention, at least one reactive group of the polypeptide is orthogonal to the remaining reactive groups. The use of orthogonal reactive groups allows the orthogonal reactive groups to be directed to specific sites on the molecular core. Linkage strategies involving orthogonal reactive groups can be used to limit the number of product isomers formed. In other words, by selecting unique or different reactive groups for one or more of at least three bonds compared to those selected for the remaining at least three bonds, a specific bond sequence or the direction of specific reactive groups of the polypeptide to specific positions on the molecular scaffold can be effectively achieved.

[1850] In another embodiment, the reactive groups of the polypeptide of the present invention react with a molecular linker, wherein the linker is capable of reacting with a molecular scaffold such that the linker is situated between the molecular scaffold and the polypeptide in the final bonded state.

[1851] In some embodiments, the amino acids of the library members or the collection of peptides can be replaced by any natural or non-natural amino acids. Excluded from these exchangeable amino acids are those carrying functional groups for crosslinking the peptide to the molecular core, such that only the ring sequence is exchangeable. The exchangeable peptide sequences can be random sequences, constant sequences, or sequences with both random and constant amino acids. Amino acids with reactive groups are located at specific positions within the peptide, as the positions of these amino acids determine the ring size.

[1852] In one embodiment, the polypeptide having three reactive groups has sequence (X). l Y(X) m Y(X) n Y(X) o In this denot, Y represents an amino acid with a reactive group, X represents a random amino acid, m and n are numbers between 2 and 8 that define the length of the inserted polypeptide fragment, which can be the same or different, and l and o are numbers between 0 and 20 that define the length of the flanking polypeptide fragment.

[1853] Alternative methods to thiol-mediated coupling can be used to attach molecular scaffolds to peptides via covalent interactions. Alternatively, these techniques can be used to modify or attach other parts (e.g., small molecules of interest different from the molecular scaffold) to the peptide after selection or isolation according to the invention—in this embodiment, the attachment obviously does not have to be covalent and may include non-covalent linkages. These methods can be used in combination with small molecules having complementary reactive groups by generating phages displaying proteins and peptides with non-natural amino acids exhibiting desired chemically reactive groups, or by incorporating non-natural amino acids into chemically synthesized or recombinantly synthesized peptides in a molecular preparation stage after the selection / isolation stage, as an alternative to (or in combination with) thiol-mediated methods. Further details can be found in WO 2009 / 098450 or Heinis et al. Nat Chem Biol Found in 2009, 5(7), 502-7.

[1854] Effector groups and functional groups

[1855] According to another aspect of the invention, a pharmaceutical conjugate is provided comprising a peptide ligand, a bicyclic peptide ligand, or a polymeric conjugate as described herein, coupled to one or more effector groups and / or functional groups.

[1856] Effector groups and / or functional groups can be linked, for example, to the N-terminus and / or C-terminus of the polypeptide, to amino acids within the polypeptide, or to a molecular scaffold.

[1857] Suitable effector groups include antibodies and portions or fragments thereof. For example, in addition to one or more constant regions, effector groups may include the antibody light chain constant region (CL), the antibody CH1 heavy chain domain, the antibody CH2 heavy chain domain, the antibody CH3 heavy chain domain, or any combination thereof. Effector groups may also include the antibody hinge region (which is typically located between the CH1 and CH2 domains of the IgG molecule).

[1858] In a further embodiment of this aspect of the invention, the effector group is the Fc region of an IgG molecule. Advantageously, the peptide ligand-effector group according to the invention comprises or consists of a peptide ligand Fc fusion having a tβ half-life of one day or longer, two days or longer, three days or longer, four days or longer, five days or longer, six days or longer, or seven days or longer. Most advantageously, the peptide ligand according to the invention comprises or consists of a peptide ligand Fc fusion having a tβ half-life of one day or longer.

[1859] Functional groups typically include binding groups, drugs, reactive groups used to connect to other entities, and functional groups that help macrocyclic peptides enter cells.

[1860] The ability of a peptide to penetrate cells makes it effective against intracellular targets. Targets accessible through peptides with cell-penetrating capabilities include transcription factors, intracellular signaling molecules such as tyrosine kinases, and molecules involved in apoptosis pathways. Functional groups that enable cell penetration include peptides or chemical groups added to the peptide or molecular scaffold. Such peptides include those derived from peptides such as VP22, HIV-Tat, and Drosophila homeobox proteins (antennaepopoproteins), as described by Chen and Harrison in Biochemical Society Transactions (2007), Vol. 35, Part 4, p. 821; and by Gupta et al. in Advanced Drug Discovery Reviews (2004), Vol. 57, p. 9637. Examples of short peptides proven to be highly efficient in transmembrane translocation include a 16-amino acid penetrating peptide from Drosophila antennal foot proteins (Derossi et al. (1994) J Biol. Chem. Vol. 269, p. 10444), an 18-amino acid “model amphiphilic peptide” (Oehlke et al. (1998) Biochim Biophys Acts Vol. 1414, p. 127), and the arginine-rich region of the HIV TAT protein. Non-peptide approaches include the use of small molecule mimics or SMOCs that are readily linked to biomolecules (Okuyama et al. (2007) Nature Methods Vol. 4, p. 153). Other chemical strategies, such as adding guanidine groups to molecules, also enhance cell penetration (Elson-Scwab et al. (2007) J Biol. Chem. Vol. 282, p. 13585). Small molecular weight molecules, such as steroids, can be added to molecular scaffolds to enhance cellular uptake.

[1861] One class of functional groups that can be linked to peptide ligands includes antibodies and their binding fragments, such as Fab, Fv, or single-domain fragments. In particular, antibodies that bind to proteins that can increase the half-life of peptide ligands in vivo can be used.

[1862] In one embodiment, the peptide ligand-effect group according to the invention has a tβ half-life selected from the group consisting of: 12 hours or longer, 24 hours or longer, 2 days or longer, 3 days or longer, 4 days or longer, 5 days or longer, 6 days or longer, 7 days or longer, 8 days or longer, 9 days or longer, 10 days or longer, 11 days or longer, 12 days or longer, 13 days or longer, 14 days or longer, 15 days or longer, or 20 days or longer. Advantageously, the peptide ligand-effect group or composition according to the invention will have a tβ half-life in the range of 12 to 60 hours. In a further embodiment, it will have a tβ half-life of one day or longer. In a still further embodiment, it will be in the range of 12 to 26 hours.

[1863] In one particular embodiment of the invention, the functional group is selected from metal chelators suitable for chelating medically relevant radioactive metal isotopes.

[1864] Suitable effector groups and / or functional groups also include chromophores and / or fluorophores. Suitable fluorophores are well known to those skilled in the art and include, for example, AlexaFluor compounds (such as AlexaFluor488) and Bodipy compounds (such as Bodipy558). Effector groups and / or functional groups can also be groups that generate a detectable signal in the presence of a second intermediate (e.g., biotin and various protein antigens). For biotin, the second intermediate may include streptavidin-enzyme conjugates or streptavidin-dye conjugates.

[1865] Possible effector groups also include enzymes, such as carboxypeptidase G2 used for enzyme therapy / prodrug therapy, in which the peptide ligand replaces the antibody in ADEPT.

[1866] In a particular embodiment of the invention, the functional group is selected from pharmaceuticals, such as cytotoxic agents used for cancer treatment. Suitable examples include: alkylating agents such as cisplatin and carboplatin, as well as oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, and ifosfamide; antimetabolites including purine analogs such as azathioprine and mercaptopurine or pyrimidine analogs; plant alkaloids and terpenoids including vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine; podophyllotoxin and its derivatives such as etoposide and teniposide; taxanes, including paclitaxel, originally known as Taxol; topoisomerase inhibitors including camptothecins: irinotecan and topotecan, and type II inhibitors including acridine, etoposide, etoposide phosphate, and teniposide. Other pharmaceuticals may include antitumor antibiotics, including immunosuppressants such as actinomycin D (used in kidney transplantation), doxorubicin, epirubicin, bleomycin, spirochetes, etc.

[1867] In a further specific embodiment of the invention, the cytotoxic agent is selected from maytansine compounds (such as DM1) or monomethyl olrithatine (such as MMAE).

[1868] In one embodiment, the cytotoxic agent is linked to the bicyclic peptide via a cleavable bond such as a disulfide bond or a protease-sensitive bond. In a further embodiment, the groups adjacent to the disulfide bond are modified to control the steric hindrance of the disulfide bond, thereby controlling the cleavage rate and the associated release of the cytotoxic agent.

[1869] Published work has established the potential to modify the reduction sensitivity of disulfide bonds by introducing steric hindrance on either side (Kellogg et al. (2011) Bioconjugate Chemistry, 22, 717). Greater steric hindrance reduces the rate of reduction of intracellular glutathione and extracellular (systemic) reducing agents, thereby reducing the ease of toxin release, both intracellularly and extracellularly. Therefore, by carefully selecting the degree of steric hindrance on either side of the disulfide bond, a balance can be achieved between optimal disulfide bond stability in circulation (minimizing adverse side effects of toxins) and efficient release from the intracellular environment (maximizing therapeutic efficacy).

[1870] Steric hindrance on either side of the disulfide bond can be modulated by introducing one or more methyl groups on the toxin side of the target entity (here, a bicyclic peptide) or molecular construct.

[1871] synthesis

[1872] The peptides of this invention can be synthesized using standard techniques and then reacted in vitro with a molecular scaffold. Standard chemical methods can be used in performing this operation. This enables the rapid, large-scale preparation of soluble materials for further downstream experiments or validation. Such methods can be accomplished using conventional chemical approaches, as disclosed by Timmerman et al. (ibid.).

[1873] Therefore, the present invention also relates to the preparation of peptides selected as described herein, wherein the preparation includes optional further steps as described below. In one embodiment, these steps are performed on a chemically synthesized final product peptide.

[1874] Peptides can also be extended to, for example, introduce another ring, thereby introducing multiple specificities.

[1875] To extend peptides, extension can be achieved simply by using orthogonally protected lysine residues (and analogues) at their N-terminus or C-terminus or within the ring via standard solid-phase or liquid-phase chemistry. Activated or activatable N-termini or C-termini can be introduced using standard (bio)conjugation techniques. Alternatively, they can be added via fragment condensation or native chemical ligation, as described by Dawson et al. (1994), Synthesis of Proteins by Native Chemical Ligation. Science 266:776-779, or via enzymes, such as those described by Chang et al. in Proc Natl Acad Sci USA, Dec 20, 1994; 91(26):12544-8, or by Hikari et al. in Bioorganic & Medicinal Chemistry Letters, Vol. 18, No. 22, Nov 15, 2008, pp. 6000-6003.

[1876] Alternatively, the peptide can be further extended or modified via disulfide coupling. This has the added advantage of allowing the first and second peptides to dissociate from each other in a reducing environment within the cell. In this case, a molecular scaffold (e.g., TATA, TATB, or TBMT) can be added during the chemical synthesis of the first peptide to react with the three cysteine ​​groups; then, additional cysteine ​​or thiol groups can be attached to the N-terminus or C-terminus of the first peptide such that the cysteine ​​or thiol group reacts only with the free cysteine ​​or thiol group of the second peptide, forming a disulfide-linked bicyclic peptide-peptide conjugate.

[1877] Similar techniques are also applicable to the synthesis / coupling of two bicyclic and bispecific macrocycles, potentially producing tetraspecific molecules.

[1878] Furthermore, the addition of other functional groups or effector groups can be accomplished in the same manner, using suitable chemical methods, by coupling at the N-terminus or C-terminus or via side chains. In one embodiment, the coupling is carried out in a manner that does not inhibit the activity of either entity.

[1879] In some embodiments, the synthesis of the peptide ligands provided herein may include solid-phase synthesis of peptides as described herein. In some embodiments, solid-phase synthesis includes Fmoc solid-phase peptide synthesis (e.g., as described in more detail herein). In some embodiments, the synthesized peptide is cyclized with the molecular scaffold described herein. In some embodiments, the cyclized ligand is purified by, for example, freeze-drying. In some embodiments, the synthesis of the complex described herein includes the reaction of the cyclized peptide with a linker as described herein. In some embodiments, the reaction of the cyclized peptide with the linker involves the reaction of an azide group (e.g., on the linker) with an alkynyl group (e.g., on the peptide). In some embodiments, the reaction of the azide group with the alkynyl group is carried out in the presence of a suitable azide-alkynyl cycloaddition catalyst. In some embodiments, a suitable catalyst includes CuSO4. In some embodiments, the reaction of the azide group with the alkynyl group is carried out under an inert atmosphere (e.g., N2). In some embodiments, the reaction of the cyclized peptide with the linker involves the reaction of an amino group (e.g., on the peptide) with a carboxylic acid group or its activated derivative (e.g., an NHS ester group) (e.g., on the linker). In some embodiments, the reaction between the amino group and the carboxylic acid group or its activated derivative is carried out in the presence of a suitable coupling agent. In some embodiments, a suitable coupling agent includes a base.

[1880] Pharmaceutical Composition

[1881] According to another aspect of the invention, a pharmaceutical composition is provided comprising a peptide ligand or polymeric binding complex as defined herein, in combination with one or more pharmaceutically acceptable excipients.

[1882] Typically, the peptide ligands of the present invention are used in purified form with pharmacologically suitable excipients or carriers. These excipients or carriers typically include aqueous or alcohol / aqueous solutions, emulsions, or suspensions, including saline and / or buffer media. Parenteral media include sodium chloride solutions, Ringer's glucose solutions, glucose and sodium chloride, and lactated Ringer's solutions. If it is necessary to keep the peptide complex in suspension, suitable physiologically acceptable adjuvants may be selected from thickeners such as carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, and alginate.

[1883] Intravenous mediators include fluid and nutritional supplements, as well as electrolyte supplements, such as Ringer's glucose-based supplements. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, and inert gases, may also be present (Mack (1982) Remington's Pharmaceutical Sciences, 16th edition).

[1884] The compounds of the present invention can be used alone or in combination with another or more pharmaceutical agents.

[1885] The compounds of the present invention can also be used in combination with biotherapies such as nucleic acid-based therapies, antibodies, bacteriophages or bacteriophage lysins.

[1886] The routes of administration of the pharmaceutical compositions according to the invention can be any route commonly known to those skilled in the art. When used for treatment, the peptide ligands of the invention can be administered to any patient according to standard techniques. Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, by aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrathecal, intraspinous, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or reservoir, for example, subcutaneous or intramuscular. Preferably, the pharmaceutical composition according to the invention is administered parenterally. The dosage and frequency of administration will depend on the patient's age, sex, and condition, as well as other medications administered concurrently, contraindications, and other parameters that the clinician needs to consider.

[1887] The peptide ligands of this invention can be freeze-dried for storage and reconstituted in a suitable carrier before use. This technique has proven effective and can be employed using freeze-drying and reconstitution techniques known in the art. Those skilled in the art will understand that freeze-drying and reconstitution can lead to varying degrees of activity loss, thus requiring upward adjustments to compensate for this.

[1888] Compositions containing the peptide ligands of the present invention or mixtures thereof may be administered for therapeutic purposes. In certain therapeutic applications, an amount sufficient to achieve at least partial inhibition, blockade, regulation, killing, or some other measurable parameter against a selected cell population is defined as a “therapeutic effective dose.” The amount required to achieve this dose will depend on the severity of the disease and the overall state of the patient’s immune system, but typically ranges from 10 µg to 250 mg of the selected peptide ligand per kilogram of body weight, with more commonly used doses ranging from 100 µg to 25 mg / kg / dose.

[1889] The peptide ligand-containing compositions of the present invention can be used in therapeutic settings to treat microbial infections or to provide prophylaxis for subjects at risk of infection, such as those undergoing surgery, chemotherapy, mechanical ventilation, or other conditions or planned interventions. Furthermore, the peptide ligands described herein can selectively kill, deplete, or otherwise effectively remove target cell populations from heterogeneous cell populations in vitro or ex vivo. Mammalian blood can be combined in vitro with selected peptide ligands to kill or otherwise remove unwanted cells from the blood, and then returned to the mammal according to standard techniques.

[1890] Therapeutic uses

[1891] According to another aspect of the invention, peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymeric binding complexes or pharmaceutical conjugates as described herein are provided for the prevention, inhibition or treatment of diseases or conditions mediated by TLR3.

[1892] According to another aspect of the invention, a method for preventing, inhibiting, or treating diseases or conditions mediated by TLR3 is provided, comprising administering to a patient in need a peptide ligand, bicyclic peptide ligand, pharmaceutical composition, polymeric conjugate, or pharmaceutical conjugate as described herein. According to another aspect of the invention, the use of peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymeric conjugates, or pharmaceutical conjugates as described herein in the preparation of medicaments for the prevention, inhibition, or treatment of diseases or conditions mediated by TLR3 is provided.

[1893] Examples of diseases or conditions mediated by TLR3 include autoimmune diseases, inflammatory conditions, and cancer.

[1894] According to a further aspect, peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymeric conjugates, or pharmaceutical conjugates as defined herein are provided for the prevention, inhibition, or treatment of diseases or conditions selected from autoimmune diseases, inflammatory conditions, and cancer. According to a further aspect, methods for the prevention, inhibition, or treatment of diseases or conditions selected from autoimmune diseases, inflammatory conditions, and cancer are provided, comprising administering a peptide ligand, bicyclic peptide ligand, pharmaceutical composition, polymeric conjugate, or pharmaceutical conjugate as defined herein to a patient in need. According to a further aspect, use of peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymeric conjugates, or pharmaceutical conjugates as defined herein in the preparation of medicaments for the prevention, inhibition, or treatment of diseases or conditions selected from autoimmune diseases, inflammatory conditions, and cancer is provided.

[1895] Examples of suitable autoimmune diseases include, but are not limited to: rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, celiac disease, Sjögren's syndrome, ankylosing spondylitis, vasculitis (e.g., giant cell arteritis, Wegener's granulomatosis, polymyalgia rheumatica, myasthenia gravis, pernicious anemia, Addison's disease, autoimmune hepatitis, Goodpassuia syndrome, dermatomyositis, and sarcoidosis).

[1896] Examples of suitable inflammatory conditions include, but are not limited to: acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, colitis, diverticulitis, familial Mediterranean fever, glomerulonephritis, hidradenitis suppurativa, hypersensitivity reactions, inflammatory bowel disease, interstitial cystitis, lichen planus, mast cell activation syndrome, mastocytosis, otitis media, pelvic inflammatory disease, peripheral ulcerative keratitis, pneumonia, reperfusion injury, rheumatic fever, rheumatoid arthritis, rhinitis, sarcoidosis, transplant rejection, and vasculitis.

[1897] Examples of treatable (or suppressable) cancers (and their benign counterparts) include, but are not limited to: tumors of epithelial origin (adenomas and various types of carcinoma, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and others), such as bladder and urinary tract cancers, breast cancers, gastrointestinal cancers (including cancers of the esophagus, stomach, small intestine, colon, rectum, and anus), liver cancer (hepatocellular carcinoma), gallbladder and biliary system cancers, pancreatic exocrine carcinomas, kidney cancers, lung cancers (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, and mesothelioma), head and neck cancers (e.g., tongue cancer, buccal carcinoma, laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, tonsil cancer, salivary gland cancer, nasal cavity cancer, and paranasal sinus cancer), ovarian cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, vulvar cancer, penile cancer, and cervical cancer. Cancer, including myometrial cancer, endometrial cancer, thyroid cancer (e.g., follicular thyroid carcinoma), adrenal cancer, prostate cancer, and skin and adnexal cancers (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, corneal acanthoma, hyperplastic nevus); hematologic malignancies (i.e., leukemia, lymphoma) and precancerous and marginal malignancies of the hematologic system, including lymphoid hematologic malignancies and related conditions (e.g., acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, T-cell lymphoma and leukemia, natural killer [NK] cell lymphoma, Hodgkin's lymphoma, and hairy cell leukemia). Diseases of unknown significance, monoclonal gammopathy, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders; and myelopathic hematologic malignancies and related conditions (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilia, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and essential myelofibrosis, myelodysplastic syndrome, myelodysplastic syndrome and promyelocytic leukemia); mesenchymal tumors, such as soft tissue, bone or chondrosarcomas, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, etc. Ingersoll sarcoma, synovial sarcoma, epithelioid sarcoma, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (e.g., astrocytoma, glioma and glioblastoma, meningioma, ependymoma, pineal tumor and schwannoma); endocrine tumors (e.g., pituitary adenoma, adrenal adenoma, islet cell tumor, parathyroid adenoma, carcinoid tumor and medullary thyroid carcinoma); tumors of the eye and adnexa (e.g., retinoblastoma); germ cell and trophoblastic cell tumors (e.g., teratoma, seminoma, dysgerminoma, hydatidiform mole and choriocarcinoma); and pediatric tumors and embryonic tumors (e.g., medulloblastoma, neuroblastoma, nephroblastoma and primitive neuroectodermal tumors);Or it may be a congenital condition or other syndrome that makes the patient susceptible to malignant tumors (e.g., xeroderma pigmentosum).

[1898] In this document, the term "prevention" refers to the application of a protective composition prior to the onset of disease. "Inhibition" refers to the application of a composition after an precipitating event but before the clinical manifestation of disease. "Treatment" refers to the application of a protective composition after the onset of disease symptoms.

[1899] Animal model systems are currently available for screening the effectiveness of peptide ligands in protecting against or treating diseases. This invention facilitates the use of animal model systems that allow for the development of peptide ligands that cross-react with targets in humans and animals, thereby enabling the use of animal models.

[1900] The present invention is further described below through the following embodiments.

[1901] Example

[1902] Materials and methods

[1903] Preparation of bicyclic peptide ligands (general method)

[1904] Bicyclic peptides were synthesized on Rink amide resin using standard Fmoc (9-fluorenylmethoxycarbonyl) solid-phase peptide synthesis, either by manual coupling (large-scale) or using a Biotage SyroII automated peptide synthesizer (small-scale). After TFA-based cleavage from the resin, the peptide was precipitated with diethyl ether and dissolved in 50:50 acetonitrile / water. The crude peptide (approximately 1 mM concentration) was then cyclized with 1.3 equivalents of a scaffold using ammonium bicarbonate (100 mM) as the base. Cyclization completion was confirmed by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF) or LC-MS. Once complete, the cyclization reaction was quenched with N-acetylcysteine ​​(10 equivalents relative to the peptide), and the solution was lyophilized. The residues were dissolved in a suitable solvent and purified by RP-HPLC. Peptide fractions with sufficient purity and correct molecular weight (verified by MALDI-TOF and HPLC or LC-MS) were combined and lyophilized. Concentration was determined by UV absorption using the extinction coefficient at 280 nm, which is based on the extinction coefficient of aromatic amino acids at 280 nm. Examples include Trp and Tyr, as well as non-natural amino acids such as 5FTrp.

[1905] Unless otherwise stated, all amino acids are referred to in the L-configuration. References to amino acids with the prefix "d" (i.e., dC or dA) in this document refer to amino acids in the D-configuration.

[1906] Preparation of polymeric complex

[1907] Example 1: Preparation process of BCY15926

[1908]

[1909] A mixture of compound 1 (20.0 mg, 4.21 µmol, 1.0 equivalent), compound 2 (42.6 mg, 18.5 µmol, 4.4 equivalent), and THPTA (7.30 mg, 16.8 µmol, 4.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 1.0 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 21.0 µL, 2.0 equivalent) and VcNa (3.30 mg, 16.8 µmol, 4.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction was stirred at 25–30 °C for 1 hour under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 13904, observed m / z: 1391.3 [M+10H]). 10+ The reaction mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY15926 (13.2 mg, 9.27 µmol, yield 29.3%, purity 97.6%) as a white solid.

[1910] Example 2: Preparation process of BCY16282

[1911]

[1912] A mixture of compound 4 (15.0 mg, 23.8 µmol, 1.0 equivalent), compound 5 (39.7 mg, 33.3 µmol, 1.4 equivalent), and DIEA (12.4 µL, 71.3 µmol, 4.0 equivalent) was dissolved in DMF (0.5 mL). The reaction mixture was stirred at 25–30 °C for 1 h. LC-MS showed complete consumption of compound 4 and detected a main peak with the desired m / z (molecular weight: 1708.85, observed m / z: 854.9 ([M+2H]2+)). The reaction mixture was filtered to remove undissolved residues. The crude product was then purified by preparative HPLC (TFA conditions). Compound 6 (18.0 mg, 10.0 µmol, yield 42.2%, purity 95.3%) was given as an orange solid.

[1913]

[1914] A mixture of compound 6 (3.00 mg, 1.76 µmol, 1.0 equivalent), BCY15751 (8.80 mg, 3.86 µmol, 2.2 equivalent), and THPTA (1.60 mg, 3.69 µmol, 2.1 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.2 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 8.80 µL, 2.0 equivalent) and VcNa (1.40 mg, 3.51 µmol, 4.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned yellow-green. The reaction was stirred at 25–30 °C for 1 hour under N2 atmosphere. LC-MS showed complete consumption of compound 6 and detected a main peak with the desired m / z (calculated molecular weight: 6286.09, observed m / z: 1257.9 [M+5H]). 5+ ), 1048.6 ([M+6H]) 6+ The reaction mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY16282 (3.40 mg, 0.54 µmol, yield 28.7%, purity 93.2%) as an orange solid.

[1915] Example 3: Preparation process of BCY25831

[1916]

[1917] A mixture of compound 1 (5.0 mg, 2.03 µmol, 1.0 equivalent), compound 2 (22.1 mg, 9.15 µmol, 4.5 equivalent), and THPTA (3.50 mg, 8.13 µmol, 4.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.2 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 20.3 µL, 4.0 equivalent) and VcNa (3.20 mg, 16.3 µmol, 8.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction was stirred at 0 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 12137.87, observed m / z: 1349.4 [M+9H]). 9+The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY25831 (5.70 mg, 0.45 µmol, yield 22.3%, purity 96.3%) as a white solid.

[1918] Example 4: Preparation process of BCY25832

[1919]

[1920] A mixture of compound 1 (5.0 mg, 2.64 µmol, 1.0 equivalent), compound 2 (21.1 mg, 8.72 µmol, 3.3 equivalent), and THPTA (3.50 mg, 7.93 µmol, 3.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.2 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 19.8 µL, 3.0 equivalent) and VcNa (3.10 mg, 15.9 µmol, 6.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction was stirred at 0 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 9150.48, observed m / z: 1307.2 [M+7H]). 7+ The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY25832 (7.50 mg, 0.80 µmol, yield 30.3%, purity 97.9%) as a white solid.

[1921] Example 5: Preparation process of BCY26427

[1922]

[1923] A mixture of compound 1 (6.0 mg, 5.22 µmol, 1.0 equivalent), compound 2 (27.7 mg, 11.5 µmol, 2.2 equivalent), and THPTA (4.5 mg, 10.4 µmol, 2.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.3 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 26.1 µL, 2.0 equivalent) and VcNa (4.1 mg, 20.88 µmol, 4.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned deep blue. The reaction was stirred at 0 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 5988.8, observed m / z: 1198.5 [M+5H]). 5+ The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY26427 (13.8 mg, 2.26 µmol, yield 43.4%, purity 98.2%) as a white solid.

[1924] Example 6: Preparation process of BCY26435

[1925]

[1926] A mixture of compound 1 (10.0 mg, 8.70 µmol, 1.0 equivalent), compound 2 (43.5 mg, 19.1 µmol, 2.2 equivalent), and THPTA (7.56 mg, 17.4 µmol, 2.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.6 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 43.5 µL, 2.0 equivalent) and VcNa (6.89 mg, 34.8 µmol, 4.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned deep blue. The reaction was stirred at 25 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 5694.57, observed m / z: 949.9 [M+6H]). 6+The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY26435 (20.2 mg, 3.41 µmol, yield 39.2%, purity 96.2%) as a white solid.

[1927] Example 7: Preparation process of BCY26437

[1928]

[1929] A mixture of compound 1 (11.0 mg, 5.82 µmol, 1.0 equivalent), compound 2 (43.6 mg, 19.2 µmol, 3.3 equivalent), and THPTA (7.58 mg, 17.5 µmol, 3.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.6 mL, pre-degassed by purging three times with N2). Then, an aqueous solution of CuSO4 (0.4 M, 43.6 µL, 3.0 equivalent) and VcNa (6.91 mg, 34.9 µmol, 6.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned deep blue. The reaction was stirred at 25 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 8709.05, observed m / z: 1244.9 [M+7H]). 7+ The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY26437 (19.0 mg, 2.06 µmol, yield 35.5%, purity 94.6%) as a white solid.

[1930] Example 8: Preparation process of BCY26438

[1931]

[1932] A mixture of compound 1 (5.00 mg, 3.17 µmol, 1.0 equivalent), compound 2 (32.4 mg, 14.3 µmol, 4.5 equivalent), and THPTA (5.50 mg, 12.7 µmol, 4.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.4 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 31.7 µL, 4.0 equivalent) and VcNa (5.00 mg, 25.4 µmol, 8.0 equivalent) was added under N2 atmosphere. The pH of the solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), and the solution turned deep blue. The reaction was stirred at 0 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 10668.3, observed m / z: 1334.4 [M+8H]). 8+ The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY26438 (3.40 mg, 0.29 µmol, yield 9.1%, purity 90.2%) as a white solid.

[1933] Example 9: Preparation process of BCY26439

[1934]

[1935] A mixture of compound 1 (5.0 mg, 2.03 µmol, 1.0 equivalent), compound 2 (20.8 mg, 9.15 µmol, 4.5 equivalent), and THPTA (3.50 mg, 8.13 µmol, 4.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.2 mL, pre-degassed by purging three times with N2). Then, an aqueous solution of CuSO4 (0.4 M, 20.3 µL, 4.0 equivalent) and VcNa (3.20 mg, 16.3 µmol, 8.0 equivalent) was added under N2 atmosphere. The pH of this solution was adjusted to 8 by dropwise addition of 0.2 M NH4HCO3 (dissolved in 1:1 t-BuOH / H2O), resulting in a pale yellow solution. The reaction was stirred at 0 °C for 0.5 h under N2 atmosphere. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 11549.45, observed m / z: 1444.4 [M+8H]). 8+The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY26439 (4.0 mg, 0.30 µmol, yield 15.8%, purity 92.8%) as a white solid.

[1936] Example 10: Preparation process of BCY28218 (biotinylated dimer)

[1937]

[1938] A mixture of compound 1 (6.00 mg, 3.53 µmol, 1.0 equivalent), compound 2 (17.6 mg, 7.76 µmol, 2.2 equivalent), and THPTA (3.06 mg, 7.05 µmol, 2.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.3 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 17.6 µL, 2.0 equivalent) and VcNa (2.79 mg, 14.1 µmol, 4.0 equivalent) was added under N2 atmosphere with stirring at 0 °C for 0.5 h. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 6247.29, observed m / z: 1042.0 [M+6H]). 6+ The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY28218 (8.50 mg, 1.35 µmol, yield 38.2%, purity 98.9%) as a white solid.

[1939] Example 11: Preparation process of BCY28224 (biotinylated dimer)

[1940]

[1941] A mixture of compound 1 (6.00 mg, 3.44 µmol, 1.0 equivalent), compound 2 (22.1 mg, 7.56 µmol, 2.2 equivalent), and THPTA (2.99 mg, 6.87 µmol, 2.0 equivalent) was dissolved in t-BuOH / H2O (1:1, 0.3 mL, pre-degassed by purging with N2 three times). Then, an aqueous solution of CuSO4 (0.4 M, 17.2 µL, 2.0 equivalent) and VcNa (2.72 mg, 13.7 µmol, 4.0 equivalent) was added under N2 atmosphere with stirring at 0 °C for 0.5 h. LC-MS showed complete consumption of compound 1 and detected a main peak with the desired m / z (calculated molecular weight: 7604.74, observed m / z: 1087.3 [M+7H]). 7+ The mixture was filtered to remove undissolved residues. The crude product was purified by preparative HPLC (TFA conditions) to give BCY28224 (7.20 mg, 0.907 µmol, yield 26.4%, purity 95.8%) as a white solid.

[1942] Biological data

[1943] SPR combined experiment

[1944] TLR3 monomeric SPR: Surface plasmon resonance (SPR) was performed using a Biacore T200 or 8K+ to determine the kJ / kJ level at which the peptide binds to the TLR3 target. a (M-1 s-1), k d (s-1) and K D(M) values. Recombinant human TLR3-Avi[bt]-Fc-Flag-his protein was custom-produced in Hi5 insect cells by the Charles River laboratory. The protein was captured on a CM5 chip (GE Healthcare) using goat anti-human IgG at a surface density ranging from ~1100 to 1800 RU. Standard SPR screening assays were performed in acidic run buffer 25 mM MES, 100 mM NaCl, 0.05% Tween 20 at pH 5.5, as the binding of dsRNA to TLR3 is known to be pH sensitive (Leonard et al. (2008) PNAS 105(1), 258-265). In some experiments, binding was also confirmed in a neutral pH range using 25 mM MES, 100 mM NaCl, 0.05% Tween 20 buffer at pH 7.4. Eightfold dilutions of the peptide were prepared in run buffer at a maximum test concentration of 30 mM peptide, with a final dimethyl sulfoxide (DMSO) concentration of 0.5%. Data were corrected for volume effects to exclude DMSO. The peptide was injected into the chip at 25 °C at a flow rate of 90 μL / min. All data were processed using standard procedures with dual references for blank injection and reference surfaces. Data were fitted to a 1:1 binding model (in Biacore evaluation software) using steady-state or kinetic methods, depending on the situation.

[1945] Acknowledgments

[1946] Thanks to Charles River Laboratory (Harlow and Chesterford campuses) for the SPR analysis.

[1947] The selected monomeric bicyclic peptide of this invention was tested in the above SPR binding experiment, and the results are shown in Table 4A:

[1948] Table 4A

[1949]

[1950]

[1951]

[1952]

[1953]

[1954]

[1955]

[1956]

[1957]

[1958]

[1959]

[1960]

[1961] The selected polymeric binding complex of the present invention was tested in the above SPR binding experiment, and the results are shown in Table 4B:

[1962] Table 4B

[1963]

[1964] TLR3 reporter assay method

[1965] Null cells or TLR3 cells (Invivogen, hkd-htlr3ni) were added to 96-well plates (5e4 / well) and incubated with BCY at 37°C for 48 hours. The supernatant was collected, mixed with QUANTI-Blue solution (rep-qbs), and the absorbance was read on a microplate reader (Clariostar) (Dobashi et al. (2022) Experimental Biology and Medicine 247(21), 917-922).

[1966] The selected peptides of this invention were tested in the reporter assay described above, and the results are shown in Table 5:

[1967] Table 5

[1968]

[1969] MoMac cell binding assay

[1970] 1. MoMac Generation

[1971] Human PBMCs were isolated from healthy blood donors (data presented in Table 6 are from a single donor, referred to as donor 1875 (230110)) by density gradient centrifugation using Ficoll-Pacque (GE Healthcare 1714403) and Leukosep tubes (Greiner Bio One 227290) and frozen at 5e7 cells / mL. Thawed PBMCs were attached to T175cm culture flasks in RPMI (Gibco 11875-093) 10% FBS (Corning 35-011-CV) and incubated at 37°C for at least two hours. The culture medium and unattached cells were then aspirated. Remaining cells (attached monocytes) were supplemented with 20 mL RPMI + 10% FBS + 100 ng / mL M-CSF (Peprotech 300-25) and incubated at 37°C for 7 days to differentiate into monocyte-derived macrophages. On day 5, the cells were replenished with RPMI + 10% FBS + 100 ng / mL M-CSF. Between days 7 and 10, the cells were washed with cold PBS and gently scraped with a sponge cell scraper to harvest monocyte-derived macrophages (moMac). Cells were seeded at 100,000 cells per well in 96-well round-bottom plates, with 100 µL of RPMI + 10% FBS added to each well. The plates were incubated for at least one hour in preparation for binding or activation assays.

[1972] 2. MoMac cell binding

[1973] Differentiated moMac cells were seeded at 100,000 cells per well in 96-well round-bottom plates, with 100 µL of RPMI + 10% FBS medium added to each well. Cells were stained with reactive dyes, incubated at room temperature for 10 min, and washed. A biotin-labeled bicyclic multimer compound was pre-incubated with an equimolar concentration of phycoerythrin-labeled streptavidin at room temperature for 30 min. After pre-incubation, the multimer complex, surface expression antibodies (CD206, TLR3), and antibody control staining agents were added to the seeded moMac cells, and the cells were incubated on ice for 90 min to prevent internalization. The supernatant was aspirated by tapping, and the cells were resuspended in 200 µL / well FACS buffer (PBS + 2% FBS, 0.5 MEDTA) and analyzed immediately on an Attune Nxt flow cytometer without fixation.

[1974] The selected peptides of this invention were tested in the above-mentioned MoMac cell binding assay, and the results are shown in Table 6:

[1975] Table 6

[1976]

[1977] The results presented in Table 6 indicate that an increase in the maximum gMFI relative to the untreated gMFI indicates that the polymer-binding complex has been bound. For example, a higher signal indicates a greater amount of polymer-binding complex bound. It should be noted that the untreated gMFI values ​​are all the same because all polymer-binding complexes are bound to this single sample. BCY28217 and BCY28221 are non-binding controls.

[1978] Imaging analysis of macrophages derived from monocytes

[1979] Monocyte-derived macrophages, derived from human PBMCs and differentiated via M-CSF, were enriched using negative magnetic beads. The macrophages were incubated at 37°C for 90 min in the absence of (mediator (BCY), DMSO 0.01%; mediator (LPS / Poly-IC), 1% dH2O) or in the presence of LPS (100 ng / mL), HMW Vaccigrade Poly I:C (10 μg / mL), or unconjugated bicyclic peptide (1000 nM), and in the absence or presence of latex beads. Subsequently, the cells were fixed / permeabilized, labeled overnight at 4°C with phosphorylated NF-κB antibody, and then labeled with AF647-conjugated secondary antibody and Hoechst. Images were acquired using confocal microscopy. The images are presented in this paper as follows: Figure 1 Presented.

[1980] The NF-κB transposition is known to be an important step in downstream signal transduction of TLR3. Figure 1 The data presented indicate that for the bicyclic peptide BCY26435, NF-κB translocation levels increased relative to background, while crucially, no such increase was observed in the unbound bicyclic peptide control. Therefore, this data provides evidence that BCY26435 not only binds to TLR3 but also participates in TLR3 signaling. This confirms the biological function of BCY26435, and consequently, other TLR3-binding bicyclic peptides described herein, in primary cells.

[1981] The following are aspects of the invention numbered:

[1982] 1. A peptide ligand capable of binding TLR3, wherein the peptide ligand comprises an amino acid sequence selected from the following:

[1983] C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1);

[1984] CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC (SEQ ID NO: 2);

[1985] X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 (SEQ ID NO: 3);

[1986] CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4);

[1987] CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5); and

[1988] X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 (SEQ ID NO: 6);

[1989] in:

[1990] X1 represents D, N, P, Y, 26DiMeTyr, 2FTyr, 3FTyr, or 4FPhe;

[1991] X2 represents A, I, N, P, S, T, Aze, Cba, cis-HyP, tBuAla, or tBuGly;

[1992] X3 represents A, G, N, P, Q, R, Aib, Aze, cis-HyP, dA, HyP, or Pip;

[1993] X4 represents L, S, or Cba;

[1994] X5 represents K, P, R, W, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me) or Trp(S);

[1995] X6 represents M, R, or HArg;

[1996] X7 represents A, F, Q, Y, 2FTyr, 3FTyr, 3tBuTyr, or 4FPhe;

[1997] X8 represents H, I, N, V, Cbg, His1Me, His3Me, or tBuGly;

[1998] X9 represents D, F, L, 1Nal, 2Nal, 4tBuPhe, Cba, or tBuAla;

[1999] X 10 Represents S or T;

[2000] X 11 Represents K or S;

[2001] X 12 Represents E or Q;

[2002] X 13 Represents R or V;

[2003] X 14 Represents H or R;

[2004] X 15 Represents C or dC;

[2005] X 16 Represents A, D, H, I, L, M, N, P, S, T, W, CF3Nva, dP, HyP, Nle, Nva, or TfNle;

[2006] X 17 Represents E, L, N, P, Q, S, T, Y, 26DiMeTyr, Cba, dL, or tBuAla;

[2007] X 18 Represents D, E, L, P, R, T, Agb, Cba, Cit, dD, HArg, or tBuAla;

[2008] X 19Represents A, E, I, L, M, Q, V, AlloIle, Cba, CF3Ala, dL, HLeu, Nle or tBuAla;

[2009] X 20 Represents C or dC;

[2010] X 21 Represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe or dE;

[2011] X 22 Represents A, R, V, Y, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, DOPA, or dY;

[2012] X 23 Represents A, D, W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, dW, Gla, or Trp(S);

[2013] X 24 Represents A, D, E, H, M, Q, S, Y, dS, K (PYA) or Nle;

[2014] X 25 Represents E, F, L, N, S, T, V, Cba, or dS;

[2015] X 26 Represents R, W, Y, 1Nal, 2FTyr, 2MeTrp, 2Nal, 3FTyr, 4FTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, Cit, dR, HArg or Trp(Me);

[2016] X 27 Represents G, R, S, Agb, Cit, dA, dE, or HArg;

[2017] X 28 Represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro;

[2018] X 29 Represents C, dC, or Cysam;

[2019] X 30 Represents P, cis-HyP, HyP, or Pip;

[2020] X 31 Represents E, Q, or R;

[2021] X 32 Represents P, Aze, cis-HyP, or HyP;

[2022] X 33 Represents F, Y, 2FTyr, 2Nal, 3FTyr, 4FPhe, or 4tBuPhe;

[2023] X 34 Represents N, S, or Dap;

[2024] X 35 Represents T or Dap;

[2025] X 36 Represents W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, 5MeoTrp, 6ClTrp, 6FTrp, AzaTrp, or Trp(S);

[2026] X 37 Represents P, Aze, cis-HyP, HyP, or Pip;

[2027] X 38 Represents E or P;

[2028] X 39 Represents D or N;

[2029] X 40 Represents W or Y;

[2030] X 41 Represents C or dC;

[2031] X 42 Represents A, D, E, G, K, N, P, S, T, V, Y, 3HyV, Aib, CF3Ala, dA, Dap, dK(PYA), dS, HSe or K(PYA);

[2032] X 43 Represents N, T, or 3HyV;

[2033] X 44 Represents D, E, P, 4FlPro, cis-HyP, HyP, or trans-4FlPro;

[2034] X 45 Represents A, H, M, Q, S, V, Y, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, or HSe;

[2035] X 46Represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, or TfNle;

[2036] X 47 Represents A, E, S, T, W, 1Nal, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, AzaTrp, CF3Ala or Dap;

[2037] X 48 Represents K, R, Y, 2FTyr, 3FTyr, Agb, DOPA, HArg, or Orn;

[2038] X 49 Represents A, D, L, V, W, 1Nal, 2Nal, 3HyV, 4FTrp, 5FTrp, 5MeoTrp, 6FTrp, AzaTrp, C5g, Cbg, tBuGly, or Trp(S);

[2039] X 50 Represents E, M, Q, R, S, T, Arg(Me), Dap, HArg, or PG;

[2040] X 51 Represents A, E, K, M, R, S, T, 3HyV, Cit, HArg, or Orn;

[2041] X 52 Represents A, G, L, M, N, P, Q, Cba, dA, dK(PYA), K(PYA), Nle, Nva, R-aMeLys(PYA), S-aMeLys(PYA) or tBuAla;

[2042] X 53 Represents D, I, L, M, V, EPA, Nle, Nva, or tBuGly; and

[2043] X 54 Represents C, dC, or Cysam.

[2044] Or its modified derivatives and / or pharmaceutically acceptable salts.

[2045] 2. A bicyclic peptide ligand comprising a peptide ligand according to aspect 1 and a molecular scaffold, wherein three cysteine ​​or Cysam residues of the peptide ligand are covalently bonded to the molecular scaffold to form two cyclic sequences.

[2046] 3. The bicyclic peptide ligand according to aspect 2, wherein the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) comprises an amino acid sequence selected from:

[2047] CDIACLKMYNFC (SEQ ID NO: 7);

[2048] CDIGCLRMYNFC (SEQ ID NO: 8);

[2049] CD[tBuAla]GCLRMYNFC (SEQ ID NO: 9);

[2050] CD[tBuGly]GCLRMYNFC (SEQ ID NO: 10);

[2051] CD[Cba]GCLRMYNFC (SEQ ID NO: 11);

[2052] CDI[dA]CLRMYNFC (SEQ ID NO: 12);

[2053] CDI[Aib]CLRMYNFC (SEQ ID NO: 13);

[2054] CDIGC[Cba]RMYNFC (SEQ ID NO: 14):

[2055] CDIGCL[HArg]MYNFC (SEQ ID NO: 15):

[2056] CDIGCL[Agb]MYNFC (SEQ ID NO: 16);

[2057] CDIGCLRMYN[1Nal]C (SEQ ID NO: 17);

[2058] CDIGCLRMYN[2Nal]C (SEQ ID NO: 18);

[2059] CDIGCLRMYN[4tBuPhe]C (SEQ ID NO: 19);

[2060] CDIQCLRMYNFC (SEQ ID NO: 20);

[2061] CNIQCLRMYNFC (SEQ ID NO: 21);

[2062] CDIRCLRMYNFC (SEQ ID NO: 22);

[2063] CDINCLRMYNFC (SEQ ID NO: 23);

[2064] CPPGCSPRFHLC (SEQ ID NO: 24);

[2065] CPPGCSPRYHLC (SEQ ID NO: 25; when complexed with a derivative of TATB having the following structure, it is referred to herein as BCY21542:

[2066]

[2067] in (Indicates the junction of three cysteine ​​residues);

[2068] CP[cis-HyP]GCSPRYHLC (SEQ ID NO: 26);

[2069] CP[Aze]GCSPRYHLC (SEQ ID NO: 27);

[2070] CPPGCSP[HArg]YHLC (SEQ ID NO: 28);

[2071] CPPGCSPR[4FPhe]HLC (SEQ ID NO: 29);

[2072] CPPGCSPR[3tBuTyr]HLC (SEQ ID NO: 30):

[2073] CPPGCSPR[3FTyr]HLC (SEQ ID NO: 31);

[2074] CPPGCSPR[2FTyr]HLC (SEQ ID NO: 32);

[2075] CPPGCSPRY[His1Me]LC (SEQ ID NO: 33);

[2076] CPPGCSPRY[His3Me]LC (SEQ ID NO: 34);

[2077] CPPGCSPRYH[tBuAla]C (SEQ ID NO: 35);

[2078] CPPGCSPRYH[Cba]C (SEQ ID NO: 36);

[2079] CPPGCSPRYNLC (SEQ ID NO: 37);

[2080] CYNPCLWRQVDC (SEQ ID NO: 38; referred to herein as BCY21497 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure):

[2081]

[2082] in (Indicates the junction of three cysteine ​​residues);

[2083] CYAPCLWRQVDC (SEQ ID NO: 39);

[2084] CYNPCLWRAVDC (SEQ ID NO: 40);

[2085] C[4FPhe]NPCLWRQVDC (SEQ ID NO: 41);

[2086] C[26DiMeTyr]NPCLWRQVDC (SEQ ID NO: 42);

[2087] C[3FTyr]NPCLWRQVDC (SEQ ID NO: 43);

[2088] C[2FTyr]NPCLWRQVDC (SEQ ID NO: 44);

[2089] CYN[HyP]CLWRQVDC (SEQ ID NO: 45);

[2090] CYN[cis-HyP]CLWRQVDC (SEQ ID NO: 46);

[2091] CYN[Aze]CLWRQVDC (SEQ ID NO: 47);

[2092] CYN[Pip]CLWRQVDC (SEQ ID NO: 48);

[2093] CYNPC[Cba]WRQVDC (SEQ ID NO: 49);

[2094] CYNPCL[6MeTrp]RQVDC (SEQ ID NO: 50);

[2095] CYNPCL[6FTrp]RQVDC (SEQ ID NO: 51);

[2096] CYNPCL[5FTrp]RQVDC (SEQ ID NO: 52);

[2097] CYNPCL[6ClTrp]RQVDC (SEQ ID NO: 53);

[2098] CYNPCL[5MeoTrp]RQVDC (SEQ ID NO: 54);

[2099] CYNPCL[Trp(S)]RQVDC (SEQ ID NO: 55);

[2100] CYNPCL[Trp(Me)]RQVDC (SEQ ID NO: 56);

[2101] CYNPCLWRQ[tBuGly]DC (SEQ ID NO: 57);

[2102] CYNPCLWRQ[Cbg]DC (SEQ ID NO: 58);

[2103] CYNPCLWRQIDC (SEQ ID NO: 59);

[2104] CYSPCLWRQVDC (SEQ ID NO: 60); and

[2105] CYTPCLWRQVDC (SEQ ID NO: 61), for example:

[2106] The molecular scaffold is a derivative of TATA and has the following structure:

[2107]

[2108] in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2109] A-(SEQ ID NO: 7)-A-[Sar6]-[KFl] (referred to as BCY15200 in this paper);

[2110] A-(SEQ ID NO: 7)-A (referred to as BCY15212 in this document);

[2111] A-(SEQ ID NO: 8)-A (referred to as BCY15747 in this document);

[2112] A-(SEQ ID NO: 8)-A-[K(PYA)] (referred to as BCY19281 in this document);

[2113] A-(SEQ ID NO: 9)-A (referred to as BCY17064 in this document);

[2114] A-(SEQ ID NO: 10)-A (referred to as BCY17065 in this document);

[2115] A-(SEQ ID NO: 11)-A (referred to as BCY17066 in this document);

[2116] A-(SEQ ID NO: 12)-A (referred to as BCY17067 in this document);

[2117] A-(SEQ ID NO: 13)-A (referred to as BCY17068 in this document);

[2118] A-(SEQ ID NO: 14)-A (referred to as BCY17070 in this document);

[2119] A-(SEQ ID NO: 15)-A (referred to as BCY17071 in this document);

[2120] A-(SEQ ID NO: 16)-A (referred to as BCY17072 in this document);

[2121] A-(SEQ ID NO: 17)-A (referred to as BCY17079 in this document);

[2122] A-(SEQ ID NO: 18)-A (referred to as BCY17080 in this document);

[2123] A-(SEQ ID NO: 19)-A (referred to as BCY17081 in this document);

[2124] A-(SEQ ID NO: 20)-A (referred to as BCY16675 in this document);

[2125] A-(SEQ ID NO: 21)-A (referred to as BCY16676 in this document);

[2126] A-(SEQ ID NO: 22)-A (referred to herein as BCY16677); and

[2127] A-(SEQ ID NO: 23)-A (referred to as BCY16678 in this document);

[2128] or its modified derivatives and / or pharmaceutically acceptable salts, or

[2129] The molecular scaffold is a derivative of TATB and has the following structure:

[2130]

[2131] in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2132] A-(SEQ ID NO: 24)-A (referred to as BCY16997 in this document);

[2133] A-(SEQ ID NO: 25)-A (referred to as BCY18125 in this document);

[2134] A-(SEQ ID NO: 25)-A-[K(PYA)] (referred to as BCY19741 in this document);

[2135] A-(SEQ ID NO: 25) (referred to as BCY21538 in this document);

[2136] Ac-A-(SEQ ID NO: 25) (referred to as BCY21539 in this document);

[2137] (SEQ ID NO: 25)-A (referred to herein as BCY21540);

[2138] Ac-(SEQ ID NO: 25)-A (referred to as BCY21541 in this article);

[2139] Ac-(SEQ ID NO: 25) (referred to as BCY21543 in this article);

[2140] Ac-A-(SEQ ID NO: 25)-A (referred to as BCY21544 in this article);

[2141] A-(SEQ ID NO: 25)-DKTTV (referred to as BCY21769 in this document);

[2142] TVKTP-(SEQ ID NO: 25)-A (referred to as BCY21775 in this document);

[2143] A-(SEQ ID NO: 25)-DIHNN (referred to as BCY21777 in this paper);

[2144] A-(SEQ ID NO: 26)-A (referred to as BCY21550 in this document);

[2145] A-(SEQ ID NO: 27)-A (referred to as BCY21551 in this document);

[2146] A-(SEQ ID NO: 28)-A (referred to as BCY21558 in this document);

[2147] A-(SEQ ID NO: 29)-A (referred to as BCY21561 in this document);

[2148] A-(SEQ ID NO: 30)-A (referred to as BCY21562 in this document);

[2149] A-(SEQ ID NO: 31)-A (referred to as BCY21564 in this article);

[2150] A-(SEQ ID NO: 32)-A (referred to as BCY21565 in this document);

[2151] A-(SEQ ID NO: 33)-A (referred to as BCY21566 in this article);

[2152] A-(SEQ ID NO: 34)-A (referred to as BCY21567 in this article);

[2153] A-(SEQ ID NO: 35)-A (referred to as BCY21568 in this document);

[2154] A-(SEQ ID NO: 36)-A (referred to herein as BCY21569); and

[2155] A-(SEQ ID NO: 37)-A (referred to as BCY16998 in this document);

[2156] or its modified derivatives and / or pharmaceutically acceptable salts, or

[2157] The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-S-triazine derivative of TBMT, which has the following structure:

[2158]

[2159] in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2160] A-(SEQ ID NO: 38)-A (referred to as BCY18251 in this document);

[2161] A-(SEQ ID NO: 38)-A-[K(PYA)] (referred to as BCY19587 in this document);

[2162] A-(SEQ ID NO: 38) (referred to as BCY21493 in this article);

[2163] (SEQ ID NO: 38)-A (referred to as BCY21495 in this document);

[2164] Ac-(SEQ ID NO: 38) (referred to as BCY21498 in this article);

[2165] YYYEW-(SEQ ID NO: 38)-A (referred to as BCY21773 in this document);

[2166] A-(SEQ ID NO: 39)-A (referred to as BCY21485 in this document);

[2167] A-(SEQ ID NO: 40)-A (referred to as BCY21490 in this document);

[2168] A-(SEQ ID NO: 41)-A (referred to as BCY21500 in this document);

[2169] A-(SEQ ID NO: 42)-A (referred to as BCY21502 in this document);

[2170] A-(SEQ ID NO: 43)-A (referred to as BCY21503 in this document);

[2171] A-(SEQ ID NO: 44)-A (referred to as BCY21504 in this document);

[2172] A-(SEQ ID NO: 45)-A (referred to as BCY21505 in this document);

[2173] A-(SEQ ID NO: 46)-A (referred to as BCY21506 in this document);

[2174] A-(SEQ ID NO: 47)-A (referred to as BCY21507 in this document);

[2175] A-(SEQ ID NO: 48)-A (referred to as BCY21508 in this document);

[2176] A-(SEQ ID NO: 49)-A (referred to as BCY21510 in this document);

[2177] A-(SEQ ID NO: 50)-A (referred to as BCY21515 in this document);

[2178] A-(SEQ ID NO: 51)-A (referred to as BCY21517 in this document);

[2179] A-(SEQ ID NO: 52)-A (referred to as BCY21518 in this document);

[2180] A-(SEQ ID NO: 53)-A (referred to as BCY21519 in this article);

[2181] A-(SEQ ID NO: 54)-A (referred to as BCY21521 in this document);

[2182] A-(SEQ ID NO: 55)-A (referred to as BCY21522 in this document);

[2183] A-(SEQ ID NO: 56)-A (referred to as BCY21523 in this document);

[2184] A-(SEQ ID NO: 57)-A (referred to as BCY21527 in this document);

[2185] A-(SEQ ID NO: 58)-A (referred to as BCY21528 in this document);

[2186] A-(SEQ ID NO: 59)-A (referred to as BCY19930 in this document);

[2187] A-(SEQ ID NO: 59)-VYNVN (referred to as BCY21776 in this paper);

[2188] A-(SEQ ID NO: 60)-A (referred to herein as BCY19931); and

[2189] A-(SEQ ID NO: 61)-A (referred to as BCY19932 in this document);

[2190] Or its modified derivatives and / or pharmaceutically acceptable salts.

[2191] 4. The bicyclic peptide ligand according to aspect 2, wherein CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 The peptide ligand of -FC (SEQ ID NO: 2) contains an amino acid sequence selected from the following:

[2192] CTSYYCEQTRHFC (SEQ ID NO: 62);

[2193] CTKYYCEQTRHFC (SEQ ID NO: 63); and

[2194] CSKYYCQQTVRFC (SEQ ID NO: 64), for example:

[2195] The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-S-triazine derivative of TBMT, which has the following structure:

[2196]

[2197] in This indicates the junction of three cysteine ​​residues, and CX. 10 -X 11 -YYCX 12 -QTX 13 -X 14 The peptide ligand of -FC (SEQ ID NO: 2) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2198] A-(SEQ ID NO: 62)-A (referred to as BCY17006 in this document);

[2199] A-(SEQ ID NO: 63)-A (referred to as BCY18134 in this article);

[2200] A-(SEQ ID NO: 63)-A-[K(PYA] (referred to herein as BCY19746); and

[2201] A-(SEQ ID NO: 64)-A (referred to as BCY17012 in this document);

[2202] Or its modified derivatives and / or pharmaceutically acceptable salts.

[2203] 5. The bicyclic peptide ligand according to aspect 2, wherein X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) comprises an amino acid sequence selected from the following:

[2204] CTNEVCTYWYNRGLC (SEQ ID NO: 65);

[2205] CANEVCEYWYNRGLC (SEQ ID NO: 66);

[2206] CPLDLCEYWSFRGLC (SEQ ID NO: 67);

[2207] CTNEVCRYWYNRGLC (SEQ ID NO: 68);

[2208] CDSPVCEYWSFRGLC (SEQ ID NO: 69);

[2209] CHNEVCEYWSFRGLC (SEQ ID NO: 70);

[2210] CSNEVCEYWSFRGLC (SEQ ID NO: 71);

[2211] CSNPVCEYWSFRGLC (SEQ ID NO: 72);

[2212] CNNPVCEYWSFRGLC (SEQ ID NO: 73);

[2213] CDNEVCEYWSFRGLC (SEQ ID NO: 74);

[2214] CTSEVCEYWSFRGLC (SEQ ID NO: 75);

[2215] CSTLVCQRDQLYSLC (SEQ ID NO: 76);

[2216] CHNEVCLYWYNRGLC (SEQ ID NO: 77);

[2217] CWNPVCEYWYNRGLC (SEQ ID NO: 78);

[2218] CATLQCQRDMLYGLC (SEQ ID NO: 79);

[2219] CSTLVCQRDQLYGLC (SEQ ID NO: 80);

[2220] CST[tBuAla]VCQRDQLYGLC (SEQ ID NO: 81);

[2221] CST[Cba]VCQRDQLYGLC (SEQ ID NO: 82);

[2222] CSTL[tBuAla]CQRDQLYGLC (SEQ ID NO: 83);

[2223] CSTLVCQRD[Nle]LYGLC (SEQ ID NO: 84);

[2224] CSTLVCQRDQ[Cba]YGLC (SEQ ID NO: 85);

[2225] CSTLVCQRDQLY[dA]LC (SEQ ID NO: 86);

[2226] CSTLVCQRDQLYG[tBuAla]C (SEQ ID NO: 87);

[2227] CSTLVCQRDQLYG[Cba]C (SEQ ID NO: 88);

[2228] CST[tBuAla]VCQRDQLY[dA]LC (SEQ ID NO: 89);

[2229] CNPLICQRDQLYGLC (SEQ ID NO: 90);

[2230] CISLACQRDQLYGLC (SEQ ID NO: 91);

[2231] CSTLECQRDQLYGLC (SEQ ID NO: 92);

[2232] CNTLVCQRDQLYGLC (SEQ ID NO: 93);

[2233] CTQLMCQRDQLYGLC (SEQ ID NO: 94);

[2234] CTELMCQRDQLYGLC (SEQ ID NO: 95);

[2235] CTE[tBuAla]MCQRDQLY[dA]LC (SEQ ID NO: 96);

[2236] CTELMCQRDQLY[dA]LC (SEQ ID NO: 97);

[2237] CTE[tBuAla]MCQRDQLYGLC (SEQ ID NO: 98);

[2238] CTELACQRDQLYGLC (SEQ ID NO: 99);

[2239] CTEL[Nle]CQRDQLYGLC (SEQ ID NO: 100);

[2240] CTEL[HLeu]CQRDQLYGLC (SEQ ID NO: 101);

[2241] CTELMCQR[Gla]QLYGLC (SEQ ID NO: 102);

[2242] CTELMCQRDQL[3FTyr]GLC (SEQ ID NO: 103);

[2243] CTELMCQRDQL[2FTyr]GLC (SEQ ID NO: 104);

[2244] CANTVCAYWETRGLC (SEQ ID NO: 105);

[2245] CANTVCAY[5FTrp]ETRGLC (SEQ ID NO: 106);

[2246] CPLDLCEYWSVRGLC (SEQ ID NO: 107);

[2247] CPLDLCEYWSSRGLC (SEQ ID NO: 108);

[2248] C[HyP]LDLCEYWSSRGLC (SEQ ID NO: 109);

[2249] CP[tBuAla]DLCEYWSSRGLC (SEQ ID NO: 110);

[2250] CP[Cba]DLCEYWSSRGLC (SEQ ID NO: 111);

[2251] CPLD[AlloIle]CEYWSSRGLC (SEQ ID NO: 112);

[2252] CPLD[tBuAla]CEYWSSRGLC (SEQ ID NO: 113);

[2253] CPLD[Cba]CEYWSSRGLC (SEQ ID NO: 114);

[2254] CPLDVCEYWSSSRGLC (SEQ ID NO: 115);

[2255] CPLDLCE[4FPhe]WSSRGLC (SEQ ID NO: 116);

[2256] CPLDLCEY[2Nal]SSRGLC (SEQ ID NO: 117);

[2257] CPLDLCEY[1Nal]SSRGLC (SEQ ID NO: 118);

[2258] CPLDLCEY[5FTrp]SSRGLC (SEQ ID NO: 119);

[2259] CPLDLCEY[4MeoTrp]SSRGLC (SEQ ID NO: 120);

[2260] CPLDLCEY[Trp(S)]SSRGLC (SEQ ID NO: 121);

[2261] CPLDLCEYWSS[HArg]GLC (SEQ ID NO: 122);

[2262] CPLDLCEYWSS[Cit]GLC (SEQ ID NO: 123);

[2263] CPLDLCEYWSSR[dA]LC (SEQ ID NO: 124);

[2264] CPLDLCEYWSSRG[tBuAla]C (SEQ ID NO: 125);

[2265] CPLDLCEYWSSRG[Cba]C (SEQ ID NO: 126);

[2266] [dC][dP][dL][dD][dL][dC][dE][dY][dW][dS][dS][dR]G[dL][dC] (SEQ ID NO:127);

[2267] CP[Cba]DLCEY[5FTrp]SSRGLC (SEQ ID NO: 128);

[2268] CPLDLCEYW[K(PYA)]SRGLC (SEQ ID NO: 129, referred to herein as BCY21632 when complexed with a derivative of TATA having the following structure):

[2269]

[2270] in (Indicates the junction of three cysteine ​​residues);

[2271] CPLDLCEYW[K(PYA)]SRGL[Cysam] (SEQ ID NO: 130, referred to herein as BCY21637 when complexed with a derivative of TATA having the following structure:

[2272]

[2273] in (Indicates the junction of three cysteine ​​residues);

[2274] CPLDLCEY[5FTrp]ESRGLC (SEQ ID NO: 131);

[2275] CPNDLCEY[5FTrp]SSRGLC (SEQ ID NO: 132);

[2276] CPLDLCEY[5FTrp]SSR[dA]LC (SEQ ID NO: 133);

[2277] CPLDLCEY[5FTrp]SSR[dE]LC (SEQ ID NO: 134);

[2278] CPLD[tBuAla]CEY[5FTrp]SS[HArg][dA]LC (SEQ ID NO: 135);

[2279] CP[Cba]DLCEY[5FTrp]SS[HArg][dA]LC (SEQ ID NO: 136);

[2280] CPNDLCEYWSVRGLC (SEQ ID NO: 137);

[2281] CITLQCARDMLYGLC (SEQ ID NO: 138);

[2282] CSTLQCERDMLYGLC (SEQ ID NO: 139);

[2283] CISLACARDMLYGLC (SEQ ID NO: 140);

[2284] CSTLQCQRDMLYGLC (SEQ ID NO: 141);

[2285] CMYRACWVAEEWRPC (SEQ ID NO: 142);

[2286] CMYRACYYDHEWRPC (SEQ ID NO: 143);

[2287] CMYRACFYDDEWRPC (SEQ ID NO: 144);

[2288] CMYRACAYDDEWRPC (SEQ ID NO: 145);

[2289] CMYRACFADDEWRPC (SEQ ID NO: 146);

[2290] CMYRACFYADEWRPC (SEQ ID NO: 147);

[2291] CMYRACFYDAEWRPC (SEQ ID NO: 148);

[2292] C[Nle]YRACFYDDEWRPC (SEQ ID NO: 149);

[2293] C[Nva]YRACFYDEWRPC (SEQ ID NO: 150);

[2294] C[TfNle]YRACFYDDEWRPC (SEQ ID NO: 151);

[2295] C[CF3Nva]YRACFYDDEWRPC (SEQ ID NO: 152);

[2296] CM[26DiMeTyr]RACHYDEWRPC (SEQ ID NO: 153);

[2297] CMY[HArg]ACFYDDEWRPC (SEQ ID NO: 154);

[2298] CMY[Agb]ACFYDDEWRPC (SEQ ID NO: 155);

[2299] CMY[Cit]ACFYDDEWRPC (SEQ ID NO: 156);

[2300] CMYR[CF3Ala]CFYDDEWRPC (SEQ ID NO: 157);

[2301] CMYRAC[1Nal]YDEWRPC (SEQ ID NO: 158);

[2302] CMYRAC[2Nal]YDEWRPC (SEQ ID NO: 159);

[2303] CMYRAC[4MePhe]YDEWRPC (SEQ ID NO: 160);

[2304] CMYRAC[3MePhe]YDEWRPC (SEQ ID NO: 161);

[2305] CMYRAC[2MePhe]YDEWRPC (SEQ ID NO: 162);

[2306] CMYRAC[4FPhe]YDEWRPC (SEQ ID NO: 163);

[2307] CMYRAC[3FPhe]YDDEWRPC (SEQ ID NO: 164);

[2308] CMYRAC[2FPhe]YDDEWRPC (SEQ ID NO: 165);

[2309] CMYRACF[4FPhe]DDEWRPC (SEQ ID NO: 166);

[2310] CMYRACF[3tBuTyr]DDEWRPC (SEQ ID NO: 167);

[2311] CMYRACF[26DiMeTyr]DDEWRPC (SEQ ID NO: 168);

[2312] CMYRACF[3FTyr]DDEWRPC (SEQ ID NO: 169);

[2313] CMYRACF[2FTyr]DDEWRPC (SEQ ID NO: 170);

[2314] CMYRACF[DOPA]DDEWRPC (SEQ ID NO: 171);

[2315] CMYRACFYDDE[1Nal]RPC (SEQ ID NO: 172);

[2316] CMYRACFYDDE[2Nal]RPC (SEQ ID NO: 173);

[2317] CMYRACFYDDE[4FTrp]RPC (SEQ ID NO: 174);

[2318] CMYRACFYDDE[5FTrp]RPC (SEQ ID NO: 175);

[2319] CMYRACFYDDE[6FTrp]RPC (SEQ ID NO: 176);

[2320] CMYRACFYDDE[7FTrp]RPC (SEQ ID NO: 177);

[2321] CMYRACFYDDE[Trp(Me)]RPC (SEQ ID NO: 178);

[2322] CMYRACFYDDE[2MeTrp]RPC (SEQ ID NO: 179);

[2323] CMYRACFYDDE[5MeTrp]RPC (SEQ ID NO: 180);

[2324] CMYRACFYDDE[6MeTrp]RPC (SEQ ID NO: 181);

[2325] CMYRACFYDDE[7MeTrp]RPC (SEQ ID NO: 182);

[2326] CMYRACFYDDEW[HArg]PC (SEQ ID NO: 183);

[2327] CMYRACFYDDEW[Agb]PC (SEQ ID NO: 184);

[2328] CMYRACFYDDEW[Cit]PC (SEQ ID NO: 185);

[2329] CMYRACFYDDEWR[HyP]C (SEQ ID NO: 186);

[2330] CMYRACFYDDEWR[Aze]C (SEQ ID NO: 187);

[2331] CMYRACFYDDEWR[Pip]C (SEQ ID NO: 188);

[2332] CMYRACFYDDEWR[44DFP]C (SEQ ID NO: 189);

[2333] CMYRACFYDDEWR[4FlPro]C (SEQ ID NO: 190);

[2334] CMYRACFYDDEWR[trans-4FlPro]C (SEQ ID NO: 191);

[2335] C[CF3Nva]YRACFYDDE[1Nal]RPC (SEQ ID NO: 192);

[2336] C[CF3Nva]YRAC[4MePhe]YDDE[st1Nal]RPC (SEQ ID NO: 193);

[2337] CLYRACFYDDEWRPC (SEQ ID NO: 194);

[2338] CLYRAC[4MePhe]YDDE[1Nal]RPC (SEQ ID NO: 195); and

[2339] CHYRACFYDDEWRPC (SEQ ID NO: 196), for example:

[2340] The molecular scaffold is a derivative of TATA and has the following structure:

[2341]

[2342] in This represents the junction of three cysteine ​​residues, and X. 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2343] A-(SEQ ID NO: 65)-A (referred to as BCY15206 in this document);

[2344] A-(SEQ ID NO: 65)-A-[Sar6][KFl] (referred to as BCY15194 in this paper);

[2345] Ac-(SEQ ID NO: 66)-A-[K(PYA)] (referred to as BCY23135 in this paper);

[2346] Ac-(SEQ ID NO: 66)-[K(PYA)] (referred to as BCY23136 in this paper);

[2347] A-(SEQ ID NO: 66)-A-[K(PYA)] (referred to as BCY20791 in this document);

[2348] A-(SEQ ID NO: 67)-A (referred to as BCY15808 in this document);

[2349] A-(SEQ ID NO: 68)-A (referred to as BCY15810 in this document);

[2350] A-(SEQ ID NO: 69)-A (referred to as BCY16655 in this document);

[2351] A-(SEQ ID NO: 70)-A (referred to as BCY16656 in this document);

[2352] A-(SEQ ID NO: 71)-A (referred to as BCY16657 in this document);

[2353] A-(SEQ ID NO: 72)-A (referred to as BCY16658 in this document);

[2354] A-(SEQ ID NO: 73)-A (referred to as BCY16659 in this article);

[2355] A-(SEQ ID NO: 74)-A (referred to as BCY16660 in this document);

[2356] A-(SEQ ID NO: 75)-A (referred to as BCY16661 in this document);

[2357] A-(SEQ ID NO: 76)-A (referred to as BCY15207 in this document);

[2358] A-(SEQ ID NO: 76)-A-[Sar6]-[KFl] (referred to as BCY15195 in this paper);

[2359] A-(SEQ ID NO: 76)-A-[K(PYA)] (referred to as BCY15750 in this document);

[2360] A-(SEQ ID NO: 77)-A (referred to as BCY15811 in this document);

[2361] A-(SEQ ID NO: 78)-A (referred to as BCY15812 in this document);

[2362] A-(SEQ ID NO: 79)-A (referred to as BCY15813 in this article);

[2363] A-(SEQ ID NO: 80)-A (referred to as BCY15814 in this document);

[2364] A-(SEQ ID NO: 80)-A-[Sar6]-[KFl] (referred to as BCY15801 in this paper);

[2365] Ac-(SEQ ID NO: 80) (referred to as BCY17031 in this article);

[2366] A-(SEQ ID NO: 80)-A-[Sar6]-[K(Ac)] (referred to as BCY19384 in this paper);

[2367] A-(SEQ ID NO: 80)-AGAAAE (referred to as BCY19582 in this article);

[2368] A-(SEQ ID NO: 81)-A (referred to as BCY17032 in this document);

[2369] A-(SEQ ID NO: 82)-A (referred to as BCY17033 in this document);

[2370] A-(SEQ ID NO: 83)-A (referred to as BCY17035 in this document);

[2371] A-(SEQ ID NO: 84)-A (referred to as BCY17038 in this document);

[2372] A-(SEQ ID NO: 85)-A (referred to as BCY17040 in this document);

[2373] A-(SEQ ID NO: 86)-A (referred to as BCY17041 in this document);

[2374] A-(SEQ ID NO: 87)-A (referred to as BCY17042 in this document);

[2375] A-(SEQ ID NO: 88)-A (referred to as BCY17043 in this document);

[2376] Ac-(SEQ ID NO: 89) (referred to as BCY19197 in this article);

[2377] A-(SEQ ID NO: 90)-A (referred to as BCY16662 in this document);

[2378] A-(SEQ ID NO: 91)-A (referred to as BCY16663 in this document);

[2379] A-(SEQ ID NO: 91)-A-[Sar6]-[KFl] (referred to as BCY16639 in this paper);

[2380] A-(SEQ ID NO: 92)-A (referred to as BCY16664 in this article);

[2381] A-(SEQ ID NO: 93)-A (referred to as BCY16665 in this document);

[2382] A-(SEQ ID NO: 94)-A (referred to as BCY16666 in this document);

[2383] A-(SEQ ID NO: 95)-A (referred to as BCY16667 in this article);

[2384] A-(SEQ ID NO: 95)-A-[Sar6]-[KFl] (referred to as BCY16643 in this paper);

[2385] A-(SEQ ID NO: 95)-A-[K(PYA)] (referred to as BCY17238 in this document);

[2386] Ac-(SEQ ID NO: 95) (referred to as BCY19193 in this article);

[2387] A-(SEQ ID NO: 96)-A (referred to as BCY19192 in this article);

[2388] Ac-(SEQ ID NO: 96) (referred to as BCY19196 in this article);

[2389] Ac-(SEQ ID NO: 97) (referred to as BCY19194 in this article);

[2390] Ac-(SEQ ID NO: 98) (referred to as BCY19195 in this article);

[2391] Ac-(SEQ ID NO: 99) (referred to as BCY19198 in this article);

[2392] Ac-(SEQ ID NO: 100) (referred to as BCY19199 in this article);

[2393] Ac-(SEQ ID NO: 101) (referred to as BCY19200 in this article);

[2394] Ac-(SEQ ID NO: 102) (referred to as BCY19203 in this article);

[2395] Ac-(SEQ ID NO: 103) (referred to as BCY19205 in this article);

[2396] Ac-(SEQ ID NO: 104) (referred to as BCY19206 in this article);

[2397] A-(SEQ ID NO: 105)-A (referred to as BCY15208 in this document);

[2398] A-(SEQ ID NO: 105)-A-[K(PYA)] (referred to as BCY15751 in this document);

[2399] A-(SEQ ID NO: 106)-A-[K(PYA)] (referred to as BCY21608 in this document);

[2400] A-(SEQ ID NO: 107)-A (referred to as BCY15209 in this document);

[2401] A-(SEQ ID NO: 107)-A-[Sar6]-[KFl] (referred to as BCY15197 in this paper);

[2402] A-(SEQ ID NO: 108)-A (referred to as BCY15727 in this document);

[2403] A-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY17452 in this document);

[2404] Ac-(SEQ ID NO: 108)-[K(PYA)] (referred to as BCY19157 in this paper);

[2405] Ac-A-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY19158 in this document);

[2406] A-(SEQ ID NO: 108)-A-[Sar6]-[(K(Ac)] (referred to as BCY19385 in this paper);

[2407] A-(SEQ ID NO: 108)-AGAAAE (referred to as BCY19580 in this article);

[2408] A-(SEQ ID NO: 108)-KMTHE (referred to as BCY21192 in this article);

[2409] A-(SEQ ID NO: 108)-NDSLN (referred to as BCY21193 in this document);

[2410] A-(SEQ ID NO: 108)-SVNAN (referred to as BCY21194 in this paper);

[2411] A-(SEQ ID NO: 108)-QGHTPL (referred to as BCY21195 in this paper);

[2412] A-(SEQ ID NO: 108)-EMEHSN (referred to as BCY21196 in this document);

[2413] MRQ-(SEQ ID NO: 108)-ETP (referred to as BCY21197 in this document);

[2414] EHM-(SEQ ID NO: 108)-TQS (referred to as BCY21198 in this article);

[2415] EPKRQ-(SEQ ID NO: 108)-A (referred to as BCY21199 in this document);

[2416] ANYAN-(SEQ ID NO: 108)-A (referred to as BCY21200 in this document);

[2417] DSFHQ-(SEQ ID NO: 108)-A (referred to as BCY21201 in this document);

[2418] MRQ-(SEQ ID NO: 108)-ETP-[K(PYA)] (referred to as BCY21993 in this document);

[2419] EPKRQ-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY21994 in this paper);

[2420] Ac-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY23137 in this article);

[2421] Ac-(SEQ ID NO: 108)-E-[K(PYA)] (referred to as BCY23174 in this paper);

[2422] A-(SEQ ID NO: 108)-E-[K(PYA)] (referred to as BCY23179 in this document);

[2423] A-(SEQ ID NO: 109)-A-[K(PYA)] (referred to as BCY19159 in this document);

[2424] A-(SEQ ID NO: 110)-A-[K(PYA)] (referred to as BCY19161 in this document);

[2425] A-(SEQ ID NO: 111)-A-[K(PYA)] (referred to as BCY19162 in this paper);

[2426] A-(SEQ ID NO: 112)-A-[K(PYA)] (referred to as BCY19163 in this document);

[2427] A-(SEQ ID NO: 113)-A-[K(PYA)] (referred to as BCY19164 in this paper);

[2428] A-(SEQ ID NO: 114)-A-[K(PYA)] (referred to as BCY19165 in this document);

[2429] A-(SEQ ID NO: 115)-A-[K(PYA)] (referred to as BCY19166 in this document);

[2430] A-(SEQ ID NO: 116)-A-[K(PYA)] (referred to as BCY19167 in this document);

[2431] A-(SEQ ID NO: 117)-A (referred to as BCY19170 in this document);

[2432] A-(SEQ ID NO: 117)-A-[K(PYA)] (referred to as BCY19284 in this document);

[2433] Ac-(SEQ ID NO: 117)-[K(PYA)] (referred to as BCY19995 in this paper);

[2434] A-(SEQ ID NO: 118)-A-[K(PYA)] (referred to as BCY19171 in this document);

[2435] A-(SEQ ID NO: 119)-A-[K(PYA)] (referred to as BCY19177 in this document);

[2436] MRQ-(SEQ ID NO: 119)-ETP-[K(PYA)] (referred to as BCY21995 in this document);

[2437] EPKRQ-(SEQ ID NO: 119)-A-[K(PYA)] (referred to as BCY21996 in this document);

[2438] MRQ-(SEQ ID NO: 119)-ETP (referred to as BCY21997 in this document);

[2439] EPKRQ-(SEQ ID NO: 119)-A (referred to as BCY21998 in this document);

[2440] Ac-(SEQ ID NO: 119)-[K(PYA)] (referred to as BCY22499 in this paper);

[2441] A-(SEQ ID NO: 120)-A-[K(PYA)] (referred to as BCY19179 in this document);

[2442] A-(SEQ ID NO: 121)-A-[K(PYA)] (referred to as BCY19181 in this document);

[2443] A-(SEQ ID NO: 122)-A-[K(PYA)] (referred to as BCY19184 in this document);

[2444] A-(SEQ ID NO: 123)-A-[K(PYA)] (referred to as BCY19185 in this document);

[2445] A-(SEQ ID NO: 124)-A-[K(PYA)] (referred to as BCY19187 in this document);

[2446] A-(SEQ ID NO: 125)-A-[K(PYA)] (referred to as BCY19188 in this document);

[2447] A-(SEQ ID NO: 126)-A-[K(PYA)] (referred to as BCY19189 in this document);

[2448] [dA]-(SEQ ID NO: 127)-[dA]-[K(PYA)] (referred to as BCY20840 in this document);

[2449] A-(SEQ ID NO: 128)-A-[K(PYA)] (referred to as BCY21040 in this document);

[2450] A-(SEQ ID NO: 129)-A (referred to as BCY21631 in this document);

[2451] A-(SEQ ID NO: 129) (referred to as BCY21633 in this article);

[2452] Ac-(SEQ ID NO: 129) (referred to as BCY21634 in this article);

[2453] A-(SEQ ID NO: 130) (referred to as BCY21635 in this document);

[2454] Ac-(SEQ ID NO: 130) (referred to as BCY21636 in this article);

[2455] Ac-(SEQ ID NO: 131)-[K(PYA)] (referred to as BCY23702 in this paper);

[2456] Ac-(SEQ ID NO: 132)-[K(PYA)] (referred to as BCY23703 in this paper);

[2457] Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl] (referred to herein as BCY25601);

[2458] Ac-(SEQ ID NO: 133)-[K(PYA)] (referred to as BCY23704 in this paper);

[2459] Ac-(SEQ ID NO: 134)-[K(PYA)] (referred to as BCY23705 in this paper);

[2460] Ac-(SEQ ID NO: 135)-[K(PYA)] (referred to as BCY23706 in this paper);

[2461] Ac-(SEQ ID NO: 136)-[K(PYA)] (referred to as BCY23707 in this paper);

[2462] Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl] (referred to herein as BCY25602);

[2463] A-(SEQ ID NO: 137)-A (referred to as BCY15729 in this article);

[2464] A-(SEQ ID NO: 138)-A (referred to as BCY15210 in this document);

[2465] A-(SEQ ID NO: 138)-A-[Sar6]-[KFl] (referred to as BCY15198 in this paper);

[2466] A-(SEQ ID NO: 138)-A-[K(PYA)] (referred to as BCY15752 in this document);

[2467] A-(SEQ ID NO: 139)-A (referred to as BCY15731 in this article);

[2468] A-(SEQ ID NO: 139)-A-[Sar6]-[KFl] (referred to as BCY15730 in this article);

[2469] A-(SEQ ID NO: 140)-A (referred to as BCY15733 in this article);

[2470] A-(SEQ ID NO: 141)-A (referred to herein as BCY15735); and

[2471] A-(SEQ ID NO: 141)-A-[Sar6]-[KFl] (referred to as BCY15734 in this paper);

[2472] or its modified derivatives and / or pharmaceutically acceptable salts, or

[2473] The molecular scaffold is a derivative of TATB and has the following structure:

[2474]

[2475] in This represents the junction of three cysteine ​​residues, and X. 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2476] A-(SEQ ID NO: 142)-A (referred to as BCY17001 in this document);

[2477] A-(SEQ ID NO: 143)-A (referred to as BCY18128 in this document);

[2478] A-(SEQ ID NO: 143)-A-[K(PYA)] (referred to as BCY19743 in this document);

[2479] A-(SEQ ID NO: 144)-A (referred to as BCY18129 in this article);

[2480] A-(SEQ ID NO: 144)-A-[K(PYA)] (referred to as BCY19744 in this document);

[2481] Ac-A-(SEQ ID NO: 144)-A (referred to as BCY24131 in this article);

[2482] Ac-(SEQ ID NO: 144) (referred to as BCY24135 in this article);

[2483] A-(SEQ ID NO: 144) (referred to as BCY24450 in this document);

[2484] Ac-A-(SEQ ID NO: 144) (referred to as BCY24451 in this article);

[2485] (SEQ ID NO: 144)-A (referred to as BCY24452 in this document);

[2486] Ac-(SEQ ID NO: 144)-A (referred to as BCY24453 in this article);

[2487] AHGG-(SEQ ID NO: 144)-EVHA (referred to as BCY25863 in this article);

[2488] AIKP-(SEQ ID NO: 144)-QHEA (referred to as BCY25864 in this article);

[2489] ADST-(SEQ ID NO: 144)-QHPA (referred to as BCY25865 in this document);

[2490] ALNG-(SEQ ID NO: 144)-PLSA (referred to as BCY25866 in this document);

[2491] ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)] (referred to as BCY28840 in this document);

[2492] A-(SEQ ID NO: 145)-A (referred to as BCY24442 in this document);

[2493] A-(SEQ ID NO: 146)-A (referred to as BCY24443 in this article);

[2494] A-(SEQ ID NO: 147)-A (referred to as BCY24444 in this article);

[2495] A-(SEQ ID NO: 148)-A (referred to as BCY24445 in this document);

[2496] A-(SEQ ID NO: 149)-A (referred to as BCY24456 in this document);

[2497] A-(SEQ ID NO: 150)-A (referred to as BCY24457 in this document);

[2498] A-(SEQ ID NO: 151)-A (referred to as BCY24458 in this document);

[2499] A-(SEQ ID NO: 152)-A (referred to as BCY24459 in this article);

[2500] A-(SEQ ID NO: 153)-A (referred to as BCY24462 in this document);

[2501] A-(SEQ ID NO: 154)-A (referred to as BCY24466 in this document);

[2502] A-(SEQ ID NO: 155)-A (referred to as BCY24467 in this document);

[2503] A-(SEQ ID NO: 156)-A (referred to as BCY24468 in this document);

[2504] A-(SEQ ID NO: 157)-A (referred to as BCY24469 in this article);

[2505] A-(SEQ ID NO: 158)-A (referred to as BCY24471 in this document);

[2506] A-(SEQ ID NO: 159)-A (referred to as BCY24472 in this article);

[2507] A-(SEQ ID NO: 160)-A (referred to as BCY24473 in this document);

[2508] A-(SEQ ID NO: 161)-A (referred to as BCY24474 in this document);

[2509] A-(SEQ ID NO: 162)-A (referred to as BCY24475 in this document);

[2510] A-(SEQ ID NO: 163)-A (referred to as BCY24477 in this article);

[2511] A-(SEQ ID NO: 164)-A (referred to as BCY24478 in this document);

[2512] A-(SEQ ID NO: 165)-A (referred to as BCY24479 in this article);

[2513] A-(SEQ ID NO: 166)-A (referred to as BCY24480 in this document);

[2514] A-(SEQ ID NO: 167)-A (referred to as BCY24481 in this document);

[2515] A-(SEQ ID NO: 168)-A (referred to as BCY24482 in this document);

[2516] A-(SEQ ID NO: 169)-A (referred to as BCY24483 in this article);

[2517] A-(SEQ ID NO: 170)-A (referred to as BCY24484 in this document);

[2518] A-(SEQ ID NO: 171)-A (referred to as BCY24485 in this document);

[2519] A-(SEQ ID NO: 172)-A (referred to as BCY24486 in this document);

[2520] A-(SEQ ID NO: 173)-A (referred to as BCY24487 in this article);

[2521] A-(SEQ ID NO: 174)-A (referred to as BCY24488 in this document);

[2522] A-(SEQ ID NO: 175)-A (referred to as BCY24489 in this document);

[2523] A-(SEQ ID NO: 176)-A (referred to as BCY24490 in this document);

[2524] A-(SEQ ID NO: 177)-A (referred to as BCY24491 in this document);

[2525] A-(SEQ ID NO: 178)-A (referred to as BCY24492 in this article);

[2526] A-(SEQ ID NO: 179)-A (referred to as BCY24493 in this article);

[2527] A-(SEQ ID NO: 180)-A (referred to as BCY24495 in this document);

[2528] A-(SEQ ID NO: 181)-A (referred to as BCY24496 in this document);

[2529] A-(SEQ ID NO: 182)-A (referred to as BCY24497 in this document);

[2530] A-(SEQ ID NO: 183)-A (referred to as BCY24498 in this document);

[2531] A-(SEQ ID NO: 184)-A (referred to as BCY24499 in this article);

[2532] A-(SEQ ID NO: 185)-A (referred to as BCY24500 in this document);

[2533] A-(SEQ ID NO: 186)-A (referred to as BCY24501 in this document);

[2534] A-(SEQ ID NO: 187)-A (referred to as BCY24503 in this document);

[2535] A-(SEQ ID NO: 188)-A (referred to as BCY24504 in this document);

[2536] A-(SEQ ID NO: 189)-A (referred to as BCY24505 in this document);

[2537] A-(SEQ ID NO: 190)-A (referred to as BCY24506 in this document);

[2538] A-(SEQ ID NO: 191)-A (referred to as BCY24509 in this document);

[2539] ALNG-(SEQ ID NO: 192)-PLSA (referred to herein as BCY28838);

[2540] ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)] (referred to as BCY28841 in this document);

[2541] ALNG-(SEQ ID NO: 193)-PLSA (referred to as BCY28839 in this article);

[2542] ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)] (referred to as BCY28842 in this document);

[2543] ALEQN-(SEQ ID NO: 194)-A (referred to as BCY25861 in this document);

[2544] ALEQN-(SEQ ID NO: 194)-A-[K(PYA)] (referred to as BCY28843 in this document);

[2545] ALEQN-(SEQ ID NO: 195)-A (referred to as BCY28844 in this document);

[2546] ALEQN-(SEQ ID NO: 195)-A-[K(PYA)] (referred to herein as BCY28845); and

[2547] AHAGT-(SEQ ID NO: 196)-A (referred to as BCY25859 in this document);

[2548] Or its modified derivatives and / or pharmaceutically acceptable salts.

[2549] 6. The bicyclic peptide ligand according to aspect 2, wherein CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 The peptide ligand of -C (SEQ ID NO: 4) contains an amino acid sequence selected from the following:

[2550] CQPTPRCPFSTWPC (referred to in this document as SEQ ID NO: 197);

[2551] CQPTPQCPYSTWPC (referred to herein as SEQ ID NO: 198, and as BCY20723 when complexed with a derivative of TATB having the following structure):

[2552]

[2553] in (Indicates the junction of three cysteine ​​residues);

[2554] CQPT[HyP]QCPYSTWPC (referred to in this paper as SEQ ID NO: 199);

[2555] CQPT[cis-HyP]QCPYSTWPC (referred to herein as SEQ ID NO: 200);

[2556] CQPT[Pip]QCPYSTWPC (referred to in this document as SEQ ID NO: 201);

[2557] CQPTPECPYSTWPC (referred to in this document as SEQ ID NO: 202);

[2558] CQPTPQC[HyP]YSTWPC (referred to in this paper as SEQ ID NO: 203);

[2559] CQPTPQC[cis-HyP]YSTWPC (referred to herein as SEQ ID NO: 204);

[2560] CQPTPQC[Aze]YSTWPC (referred to in this paper as SEQ ID NO: 205);

[2561] CQPTPQCP[2Nal]STWPC (referred to herein as SEQ ID NO: 206);

[2562] CQPTPQCP[4tBuPhe]STWPC (referred to herein as SEQ ID NO: 207);

[2563] CQPTPQCP[4FPhe]STWPC (referred to herein as SEQ ID NO: 208);

[2564] CQPTPQCP[3FTyr]STWPC (referred to herein as SEQ ID NO: 209);

[2565] CQPTPQCP[2FTyr]STWPC (referred to herein as SEQ ID NO: 210);

[2566] CQPTPQCPY[Dap]TWPC (referred to herein as SEQ ID NO: 211);

[2567] CQPTPQCPYS[Dap]WPC (referred to herein as SEQ ID NO: 212);

[2568] CQPTPQCPYST[2Nal]PC (referred to herein as SEQ ID NO: 213);

[2569] CQPTPQCPYST[1Nal]PC (referred to herein as SEQ ID NO: 214);

[2570] CQPTPQCPYST[6FTrp]PC (referred to herein as SEQ ID NO: 215);

[2571] CQPTPQCPYST[5FTrp]PC (referred to herein as SEQ ID NO: 216);

[2572] CQPTPQCPYST[6ClTrp]PC (referred to herein as SEQ ID NO: 217);

[2573] CQPTPQCPYST[4MeoTrp]PC (referred to herein as SEQ ID NO: 218);

[2574] CQPTPQCPYST[5MeoTrp]PC (referred to herein as SEQ ID NO: 219);

[2575] CQPTPQCPYST[Trp(S)]PC (referred to herein as SEQ ID NO: 220);

[2576] CQPTPQCPYST[AzaTrp]PC (referred to in this paper as SEQ ID NO: 221);

[2577] CQPTPQCPYSTW[HyP]C (referred to in this paper as SEQ ID NO: 222);

[2578] CQPTPQCPYSTW[cis-HyP]C (referred to herein as SEQ ID NO: 223);

[2579] CQPTPQCPYSTW[Aze]C (referred to in this paper as SEQ ID NO: 224);

[2580] CQPTPQCPYSTW[Pip]C (referred to herein as SEQ ID NO: 225); and

[2581] CQPTPECPYNTWPC (referred to herein as SEQ ID NO: 226), for example

[2582] The molecular scaffold is a derivative of TATB and has the following structure:

[2583]

[2584] in This indicates the junction of three cysteine ​​residues, and CQPTX. 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 The peptide ligand of -C (SEQ ID NO: 4) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2585] A-(SEQ ID NO: 197)-A (referred to as BCY16999 in this document);

[2586] A-(SEQ ID NO: 197)-A-[K(PYA)] (referred to as BCY17693 in this paper);

[2587] A-(SEQ ID NO: 197)-A-[Sar6]-[K(Ac)] (referred to as BCY19387 in this paper);

[2588] A-(SEQ ID NO: 198)-A (referred to as BCY18126 in this document);

[2589] Ac-A-(SEQ ID NO: 198)-A (referred to as BCY20725 in this document);

[2590] A-(SEQ ID NO: 198)-NLNLK (referred to as BCY21770 in this article);

[2591] VNENI-(SEQ ID NO: 198)-A (referred to as BCY21771 in this article);

[2592] A-(SEQ ID NO: 198)-RNPHD (referred to as BCY21772 in this paper);

[2593] A-(SEQ ID NO: 198)-IHNNG (referred to as BCY21774 in this paper);

[2594] TNEGI-(SEQ ID NO: 198)-A (referred to as BCY21778 in this article);

[2595] VNENI-(SEQ ID NO: 198)-A-[K(PYA)] (referred to as BCY23767 in this document);

[2596] A-(SEQ ID NO: 199)-A (referred to as BCY20731 in this document);

[2597] A-(SEQ ID NO: 200)-A (referred to as BCY20732 in this document);

[2598] A-(SEQ ID NO: 201)-A (referred to as BCY20734 in this document);

[2599] A-(SEQ ID NO: 202)-A (referred to herein as BCY20735);

[2600] A-(SEQ ID NO: 203)-A (referred to as BCY20736 in this document);

[2601] A-(SEQ ID NO: 204)-A (referred to as BCY20737 in this document);

[2602] A-(SEQ ID NO: 205)-A (referred to as BCY20738 in this document);

[2603] A-(SEQ ID NO: 206)-A (referred to as BCY20741 in this document);

[2604] A-(SEQ ID NO: 207)-A (referred to as BCY20742 in this document);

[2605] A-(SEQ ID NO: 208)-A (referred to as BCY20743 in this document);

[2606] A-(SEQ ID NO: 209)-A (referred to as BCY20746 in this document);

[2607] A-(SEQ ID NO: 210)-A (referred to as BCY20747 in this document);

[2608] A-(SEQ ID NO: 211)-A (referred to as BCY20748 in this document);

[2609] A-(SEQ ID NO: 212)-A (referred to as BCY20749 in this document);

[2610] A-(SEQ ID NO: 213)-A (referred to as BCY20751 in this document);

[2611] A-(SEQ ID NO: 214)-A (referred to as BCY20752 in this document);

[2612] A-(SEQ ID NO: 215)-A (referred to as BCY20756 in this document);

[2613] A-(SEQ ID NO: 216)-A (referred to as BCY20757 in this document);

[2614] A-(SEQ ID NO: 217)-A (referred to as BCY20758 in this document);

[2615] A-(SEQ ID NO: 218)-A (referred to as BCY20759 in this document);

[2616] A-(SEQ ID NO: 219)-A (referred to as BCY20760 in this document);

[2617] A-(SEQ ID NO: 220)-A (referred to as BCY20761 in this document);

[2618] A-(SEQ ID NO: 221)-A (referred to as BCY20762 in this document);

[2619] A-(SEQ ID NO: 222)-A (referred to as BCY20763 in this document);

[2620] A-(SEQ ID NO: 223)-A (referred to as BCY20764 in this document);

[2621] A-(SEQ ID NO: 224)-A (referred to as BCY20765 in this document);

[2622] A-(SEQ ID NO: 225)-A (referred to as BCY20766 in this document);

[2623] A-(SEQ ID NO: 226)-A (referred to herein as BCY18127); and

[2624] A-(SEQ ID NO: 226)-A-[K(PYA)] (referred to as BCY19742 in this paper);

[2625] Or its modified derivatives and / or pharmaceutically acceptable salts.

[2626] 7. The bicyclic peptide ligand according to aspect 2, wherein CYYX 38 -X 39 -X 40 The peptide ligand of -YACLDC (SEQ ID NO: 5) comprises an amino acid sequence selected from the following:

[2627] CYYPDYYACLDC (referred to as SEQ ID NO: 227 in this document);

[2628] CYYENYYACLDC (referred to herein as SEQ ID NO: 228); and

[2629] CYYPDWYACLDC (referred to herein as SEQ ID NO: 229), for example

[2630] The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-S-triazine derivative of TBMT, which has the following structure:

[2631]

[2632] in This indicates the junction of three cysteine ​​residues, and CYYX. 38 -X 39 -X 40 The peptide ligand of -YACLDC (SEQ ID NO: 5) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2633] A-(SEQ ID NO: 227)-A (referred to as BCY17007 in this document);

[2634] A-(SEQ ID NO: 228)-A (referred to as BCY18135 in this document);

[2635] A-(SEQ ID NO: 229)-A (referred to herein as BCY18136); and

[2636] A-(SEQ ID NO: 229)-A-[K(PYA)] (referred to as BCY19747 in this document);

[2637] Or its modified derivatives and / or pharmaceutically acceptable salts.

[2638] 8. The bicyclic peptide ligand according to aspect 2, wherein X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) comprises an amino acid sequence selected from the following:

[2639] CNNPVMTYWCTKGIC (referred to in this article as SEQ ID NO: 230);

[2640] CNNPVMTYWCEKGIC (referred to in this article as SEQ ID NO: 231);

[2641] CDNEVITYWCTKGIC (referred to as SEQ ID NO: 232 in this article);

[2642] CDNEV[tBuAla]TYWCTKGIC (referred to in this paper as SEQ ID NO: 233);

[2643] CDNEVFTYWCTKGIC (referred to in this article as SEQ ID NO: 234);

[2644] CDNEV[Cba]TYWCTKGIC (referred to in this article as SEQ ID NO: 235);

[2645] CDNEVITY[2Nal]CTKGIC (referred to as SEQ ID NO: 236 in this paper);

[2646] CDNEVITY[1Nal]CTKGIC (referred to as SEQ ID NO: 237 in this paper);

[2647] CDNEVITYWCT[Orn]GIC (referred to as SEQ ID NO: 238 in this article);

[2648] CDNEVITYWCT[HArg]GIC (referred to as SEQ ID NO: 239 in this paper);

[2649] CDNEVITYWCTK[dA]IC (referred to herein as SEQ ID NO: 240);

[2650] CDNEVITYWCTKG[tBuGly]C (referred to as SEQ ID NO: 241 in this paper);

[2651] CDNEVIT[DOPA]WCTKGIC (referred to in this paper as SEQ ID NO: 242);

[2652] CDNPVFTYWCTKGIC (referred to in this article as SEQ ID NO: 243);

[2653] CNNPVMAYWCTKGIC (referred to in this article as SEQ ID NO: 244);

[2654] CPNPVITYWCTKGIC (referred to in this article as SEQ ID NO: 245);

[2655] CDNEVITYWCQMGVC (referred to in this document as SEQ ID NO: 246);

[2656] CDNEVITYWCQRGVC (referred to as SEQ ID NO: 247 in this document);

[2657] CDNEVITYWCMRGIC (referred to in this article as SEQ ID NO: 248);

[2658] CDNEVITYWCQRGIC (referred to in this article as SEQ ID NO: 249);

[2659] CDNEVITY[6FTrp]CQRGIC (referred to in this paper as SEQ ID NO: 250);

[2660] CDNEVITY[5FTrp]CQRGIC (referred to in this paper as SEQ ID NO: 251);

[2661] CDNEVITY[5MeoTrp]CQRGIC (referred to as SEQ ID NO: 252 in this document);

[2662] CDNEVITY[Trp(S)]CQRGIC (referred to as SEQ ID NO: 253 in this paper);

[2663] CDNEVITY[AzaTrp]CQRGIC (referred to as SEQ ID NO: 254 in this document);

[2664] CDNEVITYWCQ[HArg]GIC (referred to as SEQ ID NO: 255 in this paper);

[2665] CDNEVITYWCQ[Cit]GIC (referred to as SEQ ID NO: 256 in this document);

[2666] CDNEVFEYWCTKGIC (referred to in this article as SEQ ID NO: 257);

[2667] CDNEVITYWCERGIC (referred to in this article as SEQ ID NO: 258);

[2668] CDNEVITYWCEMGIC (referred to in this article as SEQ ID NO: 259);

[2669] CSNPVFAYWCSRQMC (referred to in this document as SEQ ID NO: 260);

[2670] CSNPVFAYWCERGIC (referred to herein as SEQ ID NO: 261, and, when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure, referred to herein as BCY21615):

[2671]

[2672] in (Indicates the junction of three cysteine ​​residues);

[2673] CSNPVFAYWCER[K(PYA)]IC (referred to herein as SEQ ID NO: 262);

[2674] CSNPVFAYWCER[dK(PYA)]IC (referred to herein as SEQ ID NO: 263);

[2675] CSNPVFAYWCER[S-aMeLys(PYA)]IC (referred to herein as SEQ ID NO: 264);

[2676] CSNPVFAYWCER[R-aMeLys(PYA)]IC (referred to herein as SEQ ID NO: 265);

[2677] C[K(PYA)]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 266);

[2678] CSNPVFAY[5FTrp]CERGIC (referred to in this paper as SEQ ID NO: 267);

[2679] CSNPVFAYWCERGI[Cysam] (referred to herein as SEQ ID NO: 268, and referred herein as BCY21623 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure):

[2680]

[2681] in (Indicates the junction of three cysteine ​​residues);

[2682] C[K(PYA)]NPVFAYWCERGI[Cysam] (referred to as SEQ ID NO: 269 in this paper);

[2683] CSNPVFAYWC[Dap]RGIC (referred to herein as SEQ ID NO: 270);

[2684] CKNPVFAYWC[PG]RGIC (referred to in this paper as SEQ ID NO: 271);

[2685] CENPVFAYWCERGIC (referred to in this article as SEQ ID NO: 272);

[2686] C[dA]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 273);

[2687] CGNPVFAYWCERGIC (referred to in this article as SEQ ID NO: 274);

[2688] C[Aib]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 275);

[2689] CSN[trans-4FlPro]VFAYWCERGIC (referred to herein as SEQ ID NO: 276);

[2690] CSN[4FlPro]VFAYWCERGIC (referred to herein as SEQ ID NO: 277);

[2691] CSN[HyP]VFAYWCERGIC (referred to in this paper as SEQ ID NO: 278);

[2692] CSN[cis-HyP]VFAYWCERGIC (referred to herein as SEQ ID NO: 279);

[2693] CSNP[HSer]FAYWCERGIC (referred to in this article as SEQ ID NO: 280);

[2694] CSNPV[2FPhe]AYWCERGIC (referred to in this paper as SEQ ID NO: 281);

[2695] CSNPV[4CF3Phe]AYWCERGIC (referred to in this paper as SEQ ID NO: 282);

[2696] CSNPVFSYWCERGIC (referred to in this article as SEQ ID NO: 283);

[2697] CSNPVF[Dap]YWCERGIC (referred to in this paper as SEQ ID NO: 284);

[2698] CSNPVF[CF3Ala]YWCERGIC (referred to in this paper as SEQ ID NO: 285);

[2699] CSNPVFA[2FTyr]WCERGIC (referred to herein as SEQ ID NO: 286);

[2700] CSNPVFA[3FTyr]WCERGIC (referred to in this paper as SEQ ID NO: 287);

[2701] CSNPVFAY[4FTrp]CERGIC (referred to in this paper as SEQ ID NO: 288);

[2702] CSNPVFAYWCE[Cit]GIC (referred to in this paper as SEQ ID NO: 289);

[2703] CSNPVFAYWCER[dA]IC (referred to herein as SEQ ID NO: 290);

[2704] CSNPVFAYWCERG[Nva]C (referred to in this paper as SEQ ID NO: 291);

[2705] CSNPVFAYWCERG[Nle]C (referred to in this paper as SEQ ID NO: 292);

[2706] CSNPVFAYWCERG[EPA]C (referred to in this document as SEQ ID NO: 293);

[2707] CSNPVFAYWCERG[tBuGly]C (referred to in this paper as SEQ ID NO: 294);

[2708] CSN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 295 in this document);

[2709] C[Aib]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 296 in this document);

[2710] C[dS]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 297 in this paper);

[2711] C[K(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 298 in this document);

[2712] C[dK(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 299 in this paper);

[2713] [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 300 in this document);

[2714] CSN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to as SEQ ID NO: 301 in this document);

[2715] [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to as SEQ ID NO: 302 in this document);

[2716] CSNPVFAYWCSRNLC (referred to in this paper as SEQ ID NO: 303);

[2717] CSNPVFAYWCSRGLC (referred to in this document as SEQ ID NO: 304);

[2718] CTTDMMWKVCRTLDC (referred to as SEQ ID NO: 305 in this document);

[2719] CATDHMWKVCRTLDC (referred to as SEQ ID NO: 306 in this document);

[2720] CKTDAMWKVCRTLDC (referred to as SEQ ID NO: 307 in this article);

[2721] CSTDQMWKVCRTLDC (referred to as SEQ ID NO: 308 in this document);

[2722] CSTDYMWKVCRTLDC (referred to herein as SEQ ID NO: 309, and referred herein as BCY23141 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure):

[2723]

[2724] in (Indicates the junction of three cysteine ​​residues);

[2725] CSTDY[Nle]WKVCRTLDC (referred to as SEQ ID NO: 310 in this document);

[2726] CATDYMWKVCRTLDC (referred to as SEQ ID NO: 311 in this document);

[2727] CSTDAMWKVCRTLDC (referred to as SEQ ID NO: 312 in this document);

[2728] CSTDYAWKVCRTLDC (referred to as SEQ ID NO: 313 in this document);

[2729] CSTDYMWKACRTLDC (referred to in this document as SEQ ID NO: 314);

[2730] CSTDYMWKVCRALDC (referred to in this document as SEQ ID NO: 315);

[2731] CSTDYMWKVCRTADC (referred to in this paper as SEQ ID NO: 316);

[2732] C[CF3Ala]TDYMWKVCRTLDC (referred to as SEQ ID NO: 317 in this document);

[2733] C[HSer]TDYMWKVCRTLDC (referred to as SEQ ID NO: 318 in this document);

[2734] CTTDYMWKVCRTLDC (referred to as SEQ ID NO: 319 in this document);

[2735] C[3HyV]TDYMWKVCRTLDC (referred to as SEQ ID NO: 320 in this document);

[2736] CS[3HyV]DYMWKVCRTLDC (referred to as SEQ ID NO: 321 in this document);

[2737] C[Dap]TDYMWKVCRTLDC (referred to in this document as SEQ ID NO: 322);

[2738] CSTD[4FPhe]MWKVCRTLDC (referred to as SEQ ID NO: 323 in this document);

[2739] CSTD[1Nal]MWKVCRTLDC (referred to as SEQ ID NO: 324 in this paper);

[2740] CSTD[2Nal]MWKVCRTLDC (referred to as SEQ ID NO: 325 in this document);

[2741] CSTD[26DiMeTyr]MWKVCRTLDC (referred to herein as SEQ ID NO: 326);

[2742] CSTD[3FTyr]MWKVCRTLDC (referred to in this paper as SEQ ID NO: 327);

[2743] CSTD[2FTyr]MWKVCRTLDC (referred to in this paper as SEQ ID NO: 328);

[2744] CSTD[DOPA]MWKVCRTLDC (referred to in this document as SEQ ID NO: 329);

[2745] CSTDY[Nva]WKVCRTLDC (referred to as SEQ ID NO: 330 in this document);

[2746] CSTDY[TfNle]WKVCRTLDC (referred to as SEQ ID NO: 331 in this document);

[2747] CSTDYEWKVCRTLDC (referred to as SEQ ID NO: 332 in this document);

[2748] CSTDY[CF3Nva]WKVCRTLDC (referred to as SEQ ID NO: 333 in this document);

[2749] CSTDYM[1Nal]KVCRTLDC (referred to as SEQ ID NO: 334 in this paper);

[2750] CSTDYM[4FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 335);

[2751] CSTDYM[5FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 336);

[2752] CSTDYM[6FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 337);

[2753] CSTDYM[7FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 338);

[2754] CSTDYM[2MeTrp]KVCRTLDC (referred to as SEQ ID NO: 339 in this paper);

[2755] CSTDYM[4MeTrp]KVCRTLDC (referred to as SEQ ID NO: 340 in this paper);

[2756] CSTDYM[5MeTrp]KVCRTLDC (referred to as SEQ ID NO: 341 in this paper);

[2757] CSTDYM[6MeTrp]KVCRTLDC (referred to as SEQ ID NO: 342 in this paper);

[2758] CSTDYM[7MeTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 343);

[2759] CSTDYM[AzaTrp]KVCRTLDC (referred to as SEQ ID NO: 344 in this paper);

[2760] CSTDYMW[HArg]VCRTLDC (referred to in this paper as SEQ ID NO: 345);

[2761] CSTDYMW[Orn]VCRTLDC (referred to in this document as SEQ ID NO: 346);

[2762] CSTDYMW[Agb]VCRTLDC (referred to in this document as SEQ ID NO: 347);

[2763] CSTDYMWK[tBuGly]CRTLDC (referred to in this paper as SEQ ID NO: 348);

[2764] CSTDYMWK[Cbg]CRTLDC (referred to in this document as SEQ ID NO: 349);

[2765] CSTDYMWK[C5g]CRTLDC (referred to herein as SEQ ID NO: 350);

[2766] CSTDYMWK[3HyV]CRTLDC (referred to herein as SEQ ID NO: 351);

[2767] CSTDYMWKVC[HArg]TLDC (referred to in this paper as SEQ ID NO: 352);

[2768] CSTDYMWKVC[Arg(Me)]TLDC (referred to in this paper as SEQ ID NO: 353);

[2769] CSTDYMWKVCR[3HyV]LDC (referred to in this paper as SEQ ID NO: 354);

[2770] CSTDYMWKVCRT[tBuAla]DC (referred to herein as SEQ ID NO: 355);

[2771] CSTDYMWKVCRT[Cba]DC (referred to herein as SEQ ID NO: 356);

[2772] CSTDYMWKVCRT[Nva]DC (referred to herein as SEQ ID NO: 357);

[2773] CSTDYMWKVCRT[Nle]DC (referred to herein as SEQ ID NO: 358);

[2774] CTTDMAWRDCRTLDC (referred to in this document as SEQ ID NO: 359);

[2775] CTTDMAWRLCRTLDC (referred to in this article as SEQ ID NO: 360);

[2776] CTTDMVWKVCRTLDC (referred to as SEQ ID NO: 361 in this document);

[2777] CVTDYMWKVCRTLDC (referred to as SEQ ID NO: 362 in this document);

[2778] CYTDSMWKVCRTLDC (referred to as SEQ ID NO: 363 in this document);

[2779] CTTDMMWKVCREPDC (referred to in this document as SEQ ID NO: 364);

[2780] CTTDMMWKVCRSMDC (referred to herein as SEQ ID NO: 365); and

[2781] CTTDMMWKVCRTLDC (referred to in this document as SEQ ID NO: 366), for example

[2782] The molecular scaffold is a derivative of TATA and has the following structure:

[2783]

[2784] in This represents the junction of three cysteine ​​residues, and X. 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following:

[2785] A-(SEQ ID NO: 230)-A (referred to as BCY15211 in this document);

[2786] A-(SEQ ID NO: 230)-A-[Sar6]-[KFl] (referred to as BCY15199 in this paper);

[2787] A-(SEQ ID NO: 231)-A (referred to as BCY15737 in this document);

[2788] A-(SEQ ID NO: 232)-A (referred to as BCY15739 in this article);

[2789] A-(SEQ ID NO: 232)-A-[Sar6]-[KFl] (referred to as BCY15738 in this paper);

[2790] A-(SEQ ID NO: 232)-A-[Sar6]-[K(Ac)] (referred to as BCY19386 in this paper);

[2791] A-(SEQ ID NO: 232)-AGAAAE (referred to as BCY19581 in this article);

[2792] A-(SEQ ID NO: 233)-A (referred to as BCY17047 in this document);

[2793] A-(SEQ ID NO: 234)-A (referred to as BCY17049 in this article);

[2794] A-(SEQ ID NO: 235)-A (referred to as BCY17051 in this document);

[2795] A-(SEQ ID NO: 236)-A (referred to as BCY17055 in this document);

[2796] A-(SEQ ID NO: 237)-A (referred to as BCY17056 in this document);

[2797] A-(SEQ ID NO: 238)-A (referred to as BCY17057 in this document);

[2798] A-(SEQ ID NO: 239)-A (referred to as BCY17058 in this document);

[2799] A-(SEQ ID NO: 240)-A (referred to as BCY17059 in this document);

[2800] A-(SEQ ID NO: 241)-A (referred to as BCY17061 in this document);

[2801] A-(SEQ ID NO: 242)-A (referred to as BCY17656 in this document);

[2802] A-(SEQ ID NO: 243)-A (referred to as BCY15741 in this article);

[2803] A-(SEQ ID NO: 244)-A (referred to as BCY15743 in this article);

[2804] A-(SEQ ID NO: 245)-A (referred to as BCY15745 in this document);

[2805] A-(SEQ ID NO: 246)-A (referred to as BCY16668 in this document);

[2806] A-(SEQ ID NO: 247)-A (referred to as BCY16669 in this document);

[2807] A-(SEQ ID NO: 248)-A (referred to as BCY16670 in this document);

[2808] A-(SEQ ID NO: 249)-A (referred to as BCY16671 in this article);

[2809] A-(SEQ ID NO: 249)-A-[Sar6]-[KFl] (referred to as BCY16647 in this paper);

[2810] Ac-A-(SEQ ID NO: 249)-A (referred to as BCY19586 in this article);

[2811] A-(SEQ ID NO: 250)-A (referred to as BCY18510 in this document);

[2812] A-(SEQ ID NO: 251)-A (referred to as BCY18511 in this document);

[2813] A-(SEQ ID NO: 251)-A-[K(PYA)] (referred to as BCY25826 in this document);

[2814] A-(SEQ ID NO: 252)-A (referred to as BCY18514 in this document);

[2815] A-(SEQ ID NO: 253)-A (referred to as BCY18515 in this document);

[2816] A-(SEQ ID NO: 254)-A (referred to as BCY18518 in this document);

[2817] A-(SEQ ID NO: 255)-A (referred to as BCY18519 in this document);

[2818] A-(SEQ ID NO: 256)-A (referred to as BCY18520 in this document);

[2819] A-(SEQ ID NO: 257)-A (referred to as BCY16672 in this document);

[2820] A-(SEQ ID NO: 258)-A (referred to as BCY16673 in this article);

[2821] A-(SEQ ID NO: 258)-A-[Sar6]-[KFl] (referred to as BCY16649 in this paper);

[2822] A-(SEQ ID NO: 258)-A-[K(PYA)] (referred to as BCY17237 in this document);

[2823] Ac-A-(SEQ ID NO: 258)-A (referred to herein as BCY19585); and

[2824] A-(SEQ ID NO: 259)-A (referred to as BCY16674 in this article);

[2825] or its modified derivatives and / or pharmaceutically acceptable salts, or

[2826] The molecular scaffold ...

Claims

1. A peptide ligand comprising a polypeptide having an amino acid sequence selected from: C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1); C-X 10 -X 11 -Y-Y-C-X 12 -Q-T-X 13 -X 14 -F-C (SEQ ID NO: 2); X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 (SEQ ID NO: 3); C-Q-P-T-X 30 -X 31 -C-X 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4); C-Y-Y-X 38 -X 39 -X 40 -Y-A-C-L-D-C (SEQ ID NO: 5); and X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -C-X 50 -X 51 -X 52 -X 53 -X 54 (SEQ ID NO: 6); in: X1 represents D, N, P, Y, 26DiMeTyr, 2FTyr, 3FTyr, or 4FPhe; X2 represents A, I, N, P, S, T, Aze, Cba, cis-HyP, tBuAla, or tBuGly; X3 represents A, G, N, P, Q, R, Aib, Aze, cis-HyP, dA, HyP, or Pip; X4 represents L, S, or Cba; X5 represents K, P, R, W, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me) or Trp(S); X6 represents M, R, or HArg; X7 represents A, F, Q, Y, 2FTyr, 3FTyr, 3tBuTyr, or 4FPhe; X8 represents H, I, N, V, Cbg, His1Me, His3Me, or tBuGly; X9 represents D, F, L, 1Nal, 2Nal, 4tBuPhe, Cba, or tBuAla; X 10 Represents S or T; X 11 Represents K or S; X 12 Represents E or Q; X 13 Represents R or V; X 14 Represents H or R; X 15 Represents C or dC; X 16 Represents A, D, H, I, L, M, N, P, S, T, W, CF3Nva, dP, HyP, Nle, Nva, or TfNle; X 17 Represents E, L, N, P, Q, S, T, Y, 26DiMeTyr, Cba, dL, or tBuAla; X 18 Represents D, E, L, P, R, T, Agb, Cba, Cit, dD, HArg, or tBuAla; X 19 Represents A, E, I, L, M, Q, V, AlloIle, Cba, CF3Ala, dL, HLeu, Nle or tBuAla; X 20 Represents C or dC; X 21 Represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe or dE; X 22 Represents A, R, V, Y, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, DOPA, or dY; X 23 Represents A, D, W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, dW, Gla, or Trp(S); X 24 Represents A, D, E, H, M, Q, S, Y, dS, K (PYA) or Nle; X 25 Represents E, F, L, N, S, T, V, Cba, or dS; X 26 represents R, W, Y, 1Nal, 2FTyr, 2MeTrp, 2Nal, 3FTyr, 4FTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, Cit, dR, HArg or Trp(Me); X 27 Represents G, R, S, Agb, Cit, dA, dE, or HArg; X 28 Represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro; X 29 Represents C, dC, or Cysam; X 30 Represents P, cis-HyP, HyP, or Pip; X 31 Represents E, Q, or R; X 32 Represents P, Aze, cis-HyP, or HyP; X 33 Represents F, Y, 2FTyr, 2Nal, 3FTyr, 4FPhe, or 4tBuPhe; X 34 Represents N, S, or Dap; X 35 Represents T or Dap; X 36 Represents W, 1Nal, 2Nal, 4MeoTrp, 5FTrp, 5MeoTrp, 6ClTrp, 6FTrp, AzaTrp, or Trp(S); X 37 Represents P, Aze, cis-HyP, HyP, or Pip; X 38 Represents E or P; X 39 Represents D or N; X 40 Represents W or Y; X 41 Represents C or dC; X 42 Represents A, D, E, G, K, N, P, S, T, V, Y, 3HyV, Aib, CF3Ala, dA, Dap, dK(PYA), dS, HSe or K(PYA); X 43 Represents N, T, or 3HyV; X 44 Represents D, E, P, 4FlPro, cis-HyP, HyP, or trans-4FlPro; X 45 Represents A, H, M, Q, S, V, Y, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, or HSe; X 46 Represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, or TfNle; X 47 represents A, E, S, T, W, 1Nal, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, AzaTrp, CF3Ala or Dap; X 48 Represents K, R, Y, 2FTyr, 3FTyr, Agb, DOPA, HArg, or Orn; X 49 Represents A, D, L, V, W, 1Nal, 2Nal, 3HyV, 4FTrp, 5FTrp, 5MeoTrp, 6FTrp, AzaTrp, C5g, Cbg, tBuGly, or Trp(S); X 50 Represents E, M, Q, R, S, T, Arg(Me), Dap, HArg, or PG; X 51 Represents A, E, K, M, R, S, T, 3HyV, Cit, HArg, or Orn; X 52 Represents A, G, L, M, N, P, Q, Cba, dA, dK(PYA), K(PYA), Nle, Nva, R-aMeLys(PYA), S-aMeLys(PYA) or tBuAla; X 53 Represents D, I, L, M, V, EPA, Nle, Nva, or tBuGly; and / or X 54 Represents C, dC, or Cysam; Or its modified derivatives and / or pharmaceutically acceptable salts.

2. A bicyclic peptide ligand or a pharmaceutically acceptable salt thereof capable of binding TLR3, comprising a peptide ligand containing a polypeptide having three reactive groups, wherein the polypeptide is linked to a molecular scaffold.

3. The bicyclic peptide ligand or a pharmaceutically acceptable salt thereof according to claim 2, wherein the peptide ligand is as defined in claim 1, and wherein three cysteine ​​or Cysam residues of the peptide ligand are covalently bonded to the molecular scaffold to form two cyclic sequences.

4. The bicyclic peptide ligand according to claim 3, wherein the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) comprises a polypeptide having an amino acid sequence selected from: CDIACLKMYNFC (SEQ ID NO: 7); CDIGCLRMYNFC (SEQ ID NO: 8); CD[tBuAla]GCLRMYNFC (SEQ ID NO: 9); CD[tBuGly]GCLRMYNFC (SEQ ID NO: 10); CD[Cba]GCLRMYNFC (SEQ ID NO: 11); CDI[dA]CLRMYNFC (SEQ ID NO: 12); CDI[Aib]CLRMYNFC (SEQ ID NO: 13); CDIGC[Cba]RMYNFC (SEQ ID NO: 14); CDIGCL[HArg]MYNFC (SEQ ID NO: 15); CDIGCL[Agb]MYNFC (SEQ ID NO: 16); CDIGCLRMYN[1Nal]C (SEQ ID NO: 17); CDIGCLRMYN[2Nal]C (SEQ ID NO: 18); CDIGCLRMYN[4tBuPhe]C (SEQ ID NO: 19); CDIQCLRMYNFC (SEQ ID NO: 20); CNIQCLRMYNFC (SEQ ID NO: 21); CDIRCLRMYNFC (SEQ ID NO: 22); CDINCLRMYNFC (SEQ ID NO: 23); CPPGCSPRFHLC (SEQ ID NO: 24); CPPGCSPRYHLC (SEQ ID NO: 25; when complexed with a derivative of TATB having the following structure, it is referred to herein as BCY21542: in (Indicates the junction of three cysteine ​​residues); CP[cis-HyP]GCSPRYHLC (SEQ ID NO: 26); CP[Aze]GCSPRYHLC (SEQ ID NO: 27); CPPGCSP[HArg]YHLC (SEQ ID NO: 28); CPPGCSPR[4FPhe]HLC (SEQ ID NO: 29); CPPGCSPR[3tBuTyr]HLC (SEQ ID NO: 30); CPPGCSPR[3FTyr]HLC (SEQ ID NO: 31); CPPGCSPR[2FTyr]HLC (SEQ ID NO: 32); CPPGCSPRY[His1Me]LC (SEQ ID NO: 33); CPPGCSPRY[His3Me]LC (SEQ ID NO: 34); CPPGCSPRYH[tBuAla]C (SEQ ID NO: 35); CPPGCSPRYH[Cba]C (SEQ ID NO: 36); CPPGCSPRYNLC (SEQ ID NO: 37); CYNPCLWRQVDC (SEQ ID NO: 38; referred to herein as BCY21497 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure): in (Indicates the junction of three cysteine ​​residues); CYAPCLWRQVDC (SEQ ID NO: 39); CYNPCLWRAVDC (SEQ ID NO: 40); C[4FPhe]NPCLWRQVDC (SEQ ID NO: 41); C[26DiMeTyr]NPCLWRQVDC (SEQ ID NO: 42); C[3FTyr]NPCLWRQVDC (SEQ ID NO: 43); C[2FTyr]NPCLWRQVDC (SEQ ID NO: 44); CYN[HyP]CLWRQVDC (SEQ ID NO: 45); CYN[cis-HyP]CLWRQVDC (SEQ ID NO: 46); CYN[Aze]CLWRQVDC (SEQ ID NO: 47); CYN[Pip]CLWRQVDC (SEQ ID NO: 48); CYNPC[Cba]WRQVDC (SEQ ID NO: 49); CYNPCL[6MeTrp]RQVDC (SEQ ID NO: 50); CYNPCL[6FTrp]RQVDC (SEQ ID NO: 51); CYNPCL[5FTrp]RQVDC (SEQ ID NO: 52); CYNPCL[6ClTrp]RQVDC (SEQ ID NO: 53); CYNPCL[5MeoTrp]RQVDC (SEQ ID NO: 54); CYNPCL[Trp(S)]RQVDC (SEQ ID NO: 55); CYNPCL[Trp(Me)]RQVDC (SEQ ID NO: 56); CYNPCLWRQ[tBuGly]DC (SEQ ID NO: 57); CYNPCLWRQ[Cbg]DC (SEQ ID NO: 58); CYNPCLWRQIDC (SEQ ID NO: 59); CYSPCLWRQVDC (SEQ ID NO: 60); and CYTPCLWRQVDC (SEQ ID NO: 61), for example: The molecular scaffold is a derivative of TATA and has the following structure: in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 7)-A-[Sar6]-[KFl] (referred to as BCY15200 in this paper); A-(SEQ ID NO: 7)-A (referred to as BCY15212 in this document); A-(SEQ ID NO: 8)-A (referred to as BCY15747 in this document); A-(SEQ ID NO: 8)-A-[K(PYA)] (referred to as BCY19281 in this document); A-(SEQ ID NO: 9)-A (referred to as BCY17064 in this document); A-(SEQ ID NO: 10)-A (referred to as BCY17065 in this document); A-(SEQ ID NO: 11)-A (referred to as BCY17066 in this document); A-(SEQ ID NO: 12)-A (referred to as BCY17067 in this document); A-(SEQ ID NO: 13)-A (referred to as BCY17068 in this document); A-(SEQ ID NO: 14)-A (referred to as BCY17070 in this document); A-(SEQ ID NO: 15)-A (referred to as BCY17071 in this document); A-(SEQ ID NO: 16)-A (referred to as BCY17072 in this document); A-(SEQ ID NO: 17)-A (referred to as BCY17079 in this document); A-(SEQ ID NO: 18)-A (referred to as BCY17080 in this document); A-(SEQ ID NO: 19)-A (referred to as BCY17081 in this document); A-(SEQ ID NO: 20)-A (referred to as BCY16675 in this document); A-(SEQ ID NO: 21)-A (referred to as BCY16676 in this document); A-(SEQ ID NO: 22)-A (referred to herein as BCY16677); and A-(SEQ ID NO: 23)-A (referred to as BCY16678 in this document); or its modified derivatives and / or pharmaceutically acceptable salts, or The molecular scaffold is a derivative of TATB and has the following structure: in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 24)-A (referred to as BCY16997 in this document); A-(SEQ ID NO: 25)-A (referred to as BCY18125 in this document); A-(SEQ ID NO: 25)-A-[K(PYA)] (referred to as BCY19741 in this document); A-(SEQ ID NO: 25) (referred to as BCY21538 in this document); Ac-A-(SEQ ID NO: 25) (referred to as BCY21539 in this document); (SEQ ID NO: 25)-A (referred to herein as BCY21540); Ac-(SEQ ID NO: 25)-A (referred to as BCY21541 in this article); Ac-(SEQ ID NO: 25) (referred to as BCY21543 in this article); Ac-A-(SEQ ID NO: 25)-A (referred to as BCY21544 in this article); A-(SEQ ID NO: 25)-DKTTV (referred to as BCY21769 in this document); TVKTP-(SEQ ID NO: 25)-A (referred to as BCY21775 in this document); A-(SEQ ID NO: 25)-DIHNN (referred to as BCY21777 in this paper); A-(SEQ ID NO: 26)-A (referred to as BCY21550 in this document); A-(SEQ ID NO: 27)-A (referred to as BCY21551 in this document); A-(SEQ ID NO: 28)-A (referred to as BCY21558 in this document); A-(SEQ ID NO: 29)-A (referred to as BCY21561 in this document); A-(SEQ ID NO: 30)-A (referred to as BCY21562 in this document); A-(SEQ ID NO: 31)-A (referred to as BCY21564 in this article); A-(SEQ ID NO: 32)-A (referred to as BCY21565 in this document); A-(SEQ ID NO: 33)-A (referred to as BCY21566 in this article); A-(SEQ ID NO: 34)-A (referred to as BCY21567 in this article); A-(SEQ ID NO: 35)-A (referred to as BCY21568 in this document); A-(SEQ ID NO: 36)-A (referred to herein as BCY21569); and A-(SEQ ID NO: 37)-A (referred to as BCY16998 in this document); or its modified derivatives and / or pharmaceutically acceptable salts, or The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, which has the following structure: in The linker site representing three cysteine ​​residues, and the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1), further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 38)-A (referred to as BCY18251 in this document); A-(SEQ ID NO: 38)-A-[K(PYA)] (referred to as BCY19587 in this document); A-(SEQ ID NO: 38) (referred to as BCY21493 in this article); (SEQ ID NO: 38)-A (referred to as BCY21495 in this document); Ac-(SEQ ID NO: 38) (referred to as BCY21498 in this article); YYYEW-(SEQ ID NO: 38)-A (referred to as BCY21773 in this document); A-(SEQ ID NO: 39)-A (referred to as BCY21485 in this document); A-(SEQ ID NO: 40)-A (referred to as BCY21490 in this document); A-(SEQ ID NO: 41)-A (referred to as BCY21500 in this document); A-(SEQ ID NO: 42)-A (referred to as BCY21502 in this document); A-(SEQ ID NO: 43)-A (referred to as BCY21503 in this document); A-(SEQ ID NO: 44)-A (referred to as BCY21504 in this document); A-(SEQ ID NO: 45)-A (referred to as BCY21505 in this document); A-(SEQ ID NO: 46)-A (referred to as BCY21506 in this document); A-(SEQ ID NO: 47)-A (referred to as BCY21507 in this document); A-(SEQ ID NO: 48)-A (referred to as BCY21508 in this document); A-(SEQ ID NO: 49)-A (referred to as BCY21510 in this document); A-(SEQ ID NO: 50)-A (referred to as BCY21515 in this document); A-(SEQ ID NO: 51)-A (referred to as BCY21517 in this document); A-(SEQ ID NO: 52)-A (referred to as BCY21518 in this document); A-(SEQ ID NO: 53)-A (referred to as BCY21519 in this article); A-(SEQ ID NO: 54)-A (referred to as BCY21521 in this document); A-(SEQ ID NO: 55)-A (referred to as BCY21522 in this document); A-(SEQ ID NO: 56)-A (referred to as BCY21523 in this document); A-(SEQ ID NO: 57)-A (referred to as BCY21527 in this document); A-(SEQ ID NO: 58)-A (referred to as BCY21528 in this document); A-(SEQ ID NO: 59)-A (referred to as BCY19930 in this document); A-(SEQ ID NO: 59)-VYNVN (referred to as BCY21776 in this paper); A-(SEQ ID NO: 60)-A (referred to herein as BCY19931); and A-(SEQ ID NO: 61)-A (referred to as BCY19932 in this document); Or its modified derivatives and / or pharmaceutically acceptable salts.

5. The bicyclic peptide ligand according to claim 3, wherein CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 The peptide ligand of -FC (SEQ ID NO: 2) contains an amino acid sequence selected from the following: CTSYYCEQTRHFC (SEQ ID NO: 62); CTKYYCEQTRHFC (SEQ ID NO: 63); and CSKYYCQQTVRFC (SEQ ID NO: 64), for example: The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, which has the following structure: in This indicates the junction of three cysteine ​​residues, and CX. 10 -X 11 -YYCX 12 -QTX 13 -X 14 The peptide ligand of -FC (SEQ ID NO: 2) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 62)-A (referred to as BCY17006 in this document); A-(SEQ ID NO: 63)-A (referred to as BCY18134 in this article); A-(SEQ ID NO: 63)-A-[K(PYA] (referred to herein as BCY19746); and A-(SEQ ID NO: 64)-A (referred to as BCY17012 in this document); Or its modified derivatives and / or pharmaceutically acceptable salts.

6. The bicyclic peptide ligand according to claim 3, wherein X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) comprises an amino acid sequence selected from the following: CTNEVCTYWYNRGLC (SEQ ID NO: 65); CANEVCEYWYNRGLC (SEQ ID NO: 66); CPLDLCEYWSFRGLC (SEQ ID NO: 67); CTNEVCRYWYNRGLC (SEQ ID NO: 68); CDSPVCEYWSFRGLC (SEQ ID NO: 69); CHNEVCEYWSFRGLC (SEQ ID NO: 70); CSNEVCEYWSFRGLC (SEQ ID NO: 71); CSNPVCEYWSFRGLC (SEQ ID NO: 72); CNNPVCEYWSFRGLC (SEQ ID NO: 73); CDNEVCEYWSFRGLC (SEQ ID NO: 74); CTSEVCEYWSFRGLC (SEQ ID NO: 75); CSTLVCQRDQLYSLC (SEQ ID NO: 76); CHNEVCLYWYNRGLC (SEQ ID NO: 77); CWNPVCEYWYNRGLC (SEQ ID NO: 78); CATLQCQRDMLYGLC (SEQ ID NO: 79); CSTLVCQRDQLYGLC (SEQ ID NO: 80); CST[tBuAla]VCQRDQLYGLC (SEQ ID NO: 81); CST[Cba]VCQRDQLYGLC (SEQ ID NO: 82); CSTL[tBuAla]CQRDQLYGLC (SEQ ID NO: 83); CSTLVCQRD[Nle]LYGLC (SEQ ID NO: 84); CSTLVCQRDQ[Cba]YGLC (SEQ ID NO: 85); CSTLVCQRDQLY[dA]LC (SEQ ID NO: 86); CSTLVCQRDQLYG[tBuAla]C (SEQ ID NO: 87); CSTLVCQRDQLYG[Cba]C (SEQ ID NO: 88); CST[tBuAla]VCQRDQLY[dA]LC (SEQ ID NO: 89); CNPLICQRDQLYGLC (SEQ ID NO: 90); CISLACQRDQLYGLC (SEQ ID NO: 91); CSTLECQRDQLYGLC (SEQ ID NO: 92); CNTLVCQRDQLYGLC (SEQ ID NO: 93); CTQLMCQRDQLYGLC (SEQ ID NO: 94); CTELMCQRDQLYGLC (SEQ ID NO: 95); CTE[tBuAla]MCQRDQLY[dA]LC (SEQ ID NO: 96); CTELMCQRDQLY[dA]LC (SEQ ID NO: 97); CTE[tBuAla]MCQRDQLYGLC (SEQ ID NO: 98); CTELACQRDQLYGLC (SEQ ID NO: 99); CTEL[Nle]CQRDQLYGLC (SEQ ID NO: 100); CTEL[HLeu]CQRDQLYGLC (SEQ ID NO: 101); CTELMCQR[Gla]QLYGLC (SEQ ID NO: 102); CTELMCQRDQL[3FTyr]GLC (SEQ ID NO: 103); CTELMCQRDQL[2FTyr]GLC (SEQ ID NO: 104); CANTVCAYWETRGLC (SEQ ID NO: 105); CANTVCAY[5FTrp]ETRGLC (SEQ ID NO: 106); CPLDLCEYWSVRGLC (SEQ ID NO: 107); CPLDLCEYWSSRGLC (SEQ ID NO: 108); C[HyP]LDLCEYWSSRGLC (SEQ ID NO: 109); CP[tBuAla]DLCEYWSSRGLC (SEQ ID NO: 110); CP[Cba]DLCEYWSSRGLC (SEQ ID NO: 111); CPLD[AlloIle]CEYWSSRGLC (SEQ ID NO: 112); CPLD[tBuAla]CEYWSSRGLC (SEQ ID NO: 113); CPLD[Cba]CEYWSSRGLC (SEQ ID NO: 114); CPLDVCEYWSSSRGLC (SEQ ID NO: 115); CPLDLCE[4FPhe]WSSRGLC (SEQ ID NO: 116); CPLDLCEY[2Nal]SSRGLC (SEQ ID NO: 117); CPLDLCEY[1Nal]SSRGLC (SEQ ID NO: 118); CPLDLCEY[5FTrp]SSRGLC (SEQ ID NO: 119); CPLDLCEY[4MeoTrp]SSRGLC (SEQ ID NO: 120); CPLDLCEY[Trp(S)]SSRGLC (SEQ ID NO: 121); CPLDLCEYWSS[HArg]GLC (SEQ ID NO: 122); CPLDLCEYWSS[Cit]GLC (SEQ ID NO: 123); CPLDLCEYWSSR[dA]LC (SEQ ID NO: 124); CPLDLCEYWSSRG[tBuAla]C (SEQ ID NO: 125); CPLDLCEYWSSRG[Cba]C (SEQ ID NO: 126); [dC][dP][dL][dD][dL][dC][dE][dY][dW][dS][dS][dR]G[dL][dC] (SEQ ID NO:127); CP[Cba]DLCEY[5FTrp]SSRGLC (SEQ ID NO: 128); CPLDLCEYW[K(PYA)]SRGLC (SEQ ID NO: 129, referred to herein as BCY21632 when complexed with a derivative of TATA having the following structure): in (Indicates the junction of three cysteine ​​residues); CPLDLCEYW[K(PYA)]SRGL[Cysam] (SEQ ID NO: 130, referred to herein as BCY21637 when complexed with a derivative of TATA having the following structure: in (Indicates the junction of three cysteine ​​residues); CPLDLCEY[5FTrp]ESRGLC (SEQ ID NO: 131); CPNDLCEY[5FTrp]SSRGLC (SEQ ID NO: 132); CPLDLCEY[5FTrp]SSR[dA]LC (SEQ ID NO: 133); CPLDLCEY[5FTrp]SSR[dE]LC (SEQ ID NO: 134); CPLD[tBuAla]CEY[5FTrp]SS[HArg][dA]LC (SEQ ID NO: 135); CP[Cba]DLCEY[5FTrp]SS[HArg][dA]LC (SEQ ID NO: 136); CPNDLCEYWSVRGLC (SEQ ID NO: 137); CITLQCARDMLYGLC (SEQ ID NO: 138); CSTLQCERDMLYGLC (SEQ ID NO: 139); CISLACARDMLYGLC (SEQ ID NO: 140); CSTLQCQRDMLYGLC (SEQ ID NO: 141); CMYRACWVAEEWRPC (SEQ ID NO: 142); CMYRACYYDHEWRPC (SEQ ID NO: 143); CMYRACFYDDEWRPC (SEQ ID NO: 144); CMYRACAYDDEWRPC (SEQ ID NO: 145); CMYRACFADDEWRPC (SEQ ID NO: 146); CMYRACFYADEWRPC (SEQ ID NO: 147); CMYRACFYDAEWRPC (SEQ ID NO: 148); C[Nle]YRACFYDDEWRPC (SEQ ID NO: 149); C[Nva]YRACFYDEWRPC (SEQ ID NO: 150); C[TfNle]YRACFYDDEWRPC (SEQ ID NO: 151); C[CF3Nva]YRACFYDDEWRPC (SEQ ID NO: 152); CM[26DiMeTyr]RACHYDEWRPC (SEQ ID NO: 153); CMY[HArg]ACFYDDEWRPC (SEQ ID NO: 154); CMY[Agb]ACFYDDEWRPC (SEQ ID NO: 155); CMY[Cit]ACFYDDEWRPC (SEQ ID NO: 156); CMYR[CF3Ala]CFYDDEWRPC (SEQ ID NO: 157); CMYRAC[1Nal]YDEWRPC (SEQ ID NO: 158); CMYRAC[2Nal]YDEWRPC (SEQ ID NO: 159); CMYRAC[4MePhe]YDEWRPC (SEQ ID NO: 160); CMYRAC[3MePhe]YDEWRPC (SEQ ID NO: 161); CMYRAC[2MePhe]YDEWRPC (SEQ ID NO: 162); CMYRAC[4FPhe]YDEWRPC (SEQ ID NO: 163); CMYRAC[3FPhe]YDEWRPC (SEQ ID NO: 164); CMYRAC[2FPhe]YDEWRPC (SEQ ID NO: 165); CMYRACF[4FPhe]DWRPC (SEQ ID NO: 166); CMYRACF[3tBuTyr]DWRPC (SEQ ID NO: 167); CMYRACF[26DiMeTyr]DWRPC (SEQ ID NO: 168); CMYRACF[3FTyr]DWRPC (SEQ ID NO: 169); CMYRACF[2FTyr]DWRPC (SEQ ID NO: 170); CMYRACF[DOPA]DWRPC (SEQ ID NO: 171); CMYRACFYDDE[1Nal]RPC (SEQ ID NO: 172); CMYRACFYDDE[2Nal]RPC (SEQ ID NO: 173); CMYRACFYDDE[4FTrp]RPC (SEQ ID NO: 174); CMYRACFYDDE[5FTrp]RPC (SEQ ID NO: 175); CMYRACFYDDE[6FTrp]RPC (SEQ ID NO: 176); CMYRACFYDDE[7FTrp]RPC (SEQ ID NO: 177); CMYRACFYDDE[Trp(Me)]RPC (SEQ ID NO: 178); CMYRACFYDDE[2MeTrp]RPC (SEQ ID NO: 179); CMYRACFYDDE[5MeTrp]RPC (SEQ ID NO: 180); CMYRACFYDDE[6MeTrp]RPC (SEQ ID NO: 181); CMYRACFYDDE[7MeTrp]RPC (SEQ ID NO: 182); CMYRACFYDDEW[HArg]PC (SEQ ID NO: 183); CMYRACFYDDEW[Agb]PC (SEQ ID NO: 184); CMYRACFYDDEW[Cit]PC (SEQ ID NO: 185); CMYRACFYDDEWR[HyP]C (SEQ ID NO: 186); CMYRACFYDDEWR[Aze]C (SEQ ID NO: 187); CMYRACFYDDEWR[Pip]C (SEQ ID NO: 188); CMYRACFYDDEWR[44DFP]C (SEQ ID NO: 189); CMYRACFYDDEWR[4FlPro]C (SEQ ID NO: 190); CMYRACFYDDEWR[trans-4FlPro]C (SEQ ID NO: 191); C[CF3Nva]YRACFYDDE[1Nal]RPC (SEQ ID NO: 192); C[CF3Nva]YRAC[4MePhe]YDDE[1Nal]RPC (SEQ ID NO: 193); CLYRACFYDDEWRPC (SEQ ID NO: 194); CLYRAC[4MePhe]YDDE[1Nal]RPC (SEQ ID NO: 195); and CHYRACFYDDEWRPC (SEQ ID NO: 196), for example: The molecular scaffold is a derivative of TATA and has the following structure: in This represents the junction of three cysteine ​​residues, and X. 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 65)-A (referred to as BCY15206 in this document); A-(SEQ ID NO: 65)-A-[Sar6][KFl] (referred to as BCY15194 in this paper); Ac-(SEQ ID NO: 66)-A-[K(PYA)] (referred to as BCY23135 in this paper); Ac-(SEQ ID NO: 66)-[K(PYA)] (referred to as BCY23136 in this paper); A-(SEQ ID NO: 66)-A-[K(PYA)] (referred to as BCY20791 in this document); A-(SEQ ID NO: 67)-A (referred to as BCY15808 in this document); A-(SEQ ID NO: 68)-A (referred to as BCY15810 in this document); A-(SEQ ID NO: 69)-A (referred to as BCY16655 in this document); A-(SEQ ID NO: 70)-A (referred to as BCY16656 in this document); A-(SEQ ID NO: 71)-A (referred to as BCY16657 in this document); A-(SEQ ID NO: 72)-A (referred to as BCY16658 in this document); A-(SEQ ID NO: 73)-A (referred to as BCY16659 in this article); A-(SEQ ID NO: 74)-A (referred to as BCY16660 in this document); A-(SEQ ID NO: 75)-A (referred to as BCY16661 in this document); A-(SEQ ID NO: 76)-A (referred to as BCY15207 in this document); A-(SEQ ID NO: 76)-A-[Sar6]-[KFl] (referred to as BCY15195 in this paper); A-(SEQ ID NO: 76)-A-[K(PYA)] (referred to as BCY15750 in this document); A-(SEQ ID NO: 77)-A (referred to as BCY15811 in this document); A-(SEQ ID NO: 78)-A (referred to as BCY15812 in this document); A-(SEQ ID NO: 79)-A (referred to as BCY15813 in this article); A-(SEQ ID NO: 80)-A (referred to as BCY15814 in this document); A-(SEQ ID NO: 80)-A-[Sar6]-[KFl] (referred to as BCY15801 in this paper); Ac-(SEQ ID NO: 80) (referred to as BCY17031 in this article); A-(SEQ ID NO: 80)-A-[Sar6]-[K(Ac)] (referred to as BCY19384 in this paper); A-(SEQ ID NO: 80)-AGAAAE (referred to as BCY19582 in this article); A-(SEQ ID NO: 81)-A (referred to as BCY17032 in this document); A-(SEQ ID NO: 82)-A (referred to as BCY17033 in this document); A-(SEQ ID NO: 83)-A (referred to as BCY17035 in this document); A-(SEQ ID NO: 84)-A (referred to as BCY17038 in this document); A-(SEQ ID NO: 85)-A (referred to as BCY17040 in this document); A-(SEQ ID NO: 86)-A (referred to as BCY17041 in this document); A-(SEQ ID NO: 87)-A (referred to as BCY17042 in this document); A-(SEQ ID NO: 88)-A (referred to as BCY17043 in this document); Ac-(SEQ ID NO: 89) (referred to as BCY19197 in this article); A-(SEQ ID NO: 90)-A (referred to as BCY16662 in this document); A-(SEQ ID NO: 91)-A (referred to as BCY16663 in this document); A-(SEQ ID NO: 91)-A-[Sar6]-[KFl] (referred to as BCY16639 in this paper); A-(SEQ ID NO: 92)-A (referred to as BCY16664 in this article); A-(SEQ ID NO: 93)-A (referred to as BCY16665 in this document); A-(SEQ ID NO: 94)-A (referred to as BCY16666 in this document); A-(SEQ ID NO: 95)-A (referred to as BCY16667 in this article); A-(SEQ ID NO: 95)-A-[Sar6]-[KFl] (referred to as BCY16643 in this paper); A-(SEQ ID NO: 95)-A-[K(PYA)] (referred to as BCY17238 in this document); Ac-(SEQ ID NO: 95) (referred to as BCY19193 in this article); A-(SEQ ID NO: 96)-A (referred to as BCY19192 in this article); Ac-(SEQ ID NO: 96) (referred to as BCY19196 in this article); Ac-(SEQ ID NO: 97) (referred to as BCY19194 in this article); Ac-(SEQ ID NO: 98) (referred to as BCY19195 in this article); Ac-(SEQ ID NO: 99) (referred to as BCY19198 in this article); Ac-(SEQ ID NO: 100) (referred to as BCY19199 in this article); Ac-(SEQ ID NO: 101) (referred to as BCY19200 in this article); Ac-(SEQ ID NO: 102) (referred to as BCY19203 in this article); Ac-(SEQ ID NO: 103) (referred to as BCY19205 in this article); Ac-(SEQ ID NO: 104) (referred to as BCY19206 in this article); A-(SEQ ID NO: 105)-A (referred to as BCY15208 in this document); A-(SEQ ID NO: 105)-A-[K(PYA)] (referred to as BCY15751 in this document); A-(SEQ ID NO: 106)-A-[K(PYA)] (referred to as BCY21608 in this document); A-(SEQ ID NO: 107)-A (referred to as BCY15209 in this document); A-(SEQ ID NO: 107)-A-[Sar6]-[KFl] (referred to as BCY15197 in this paper); A-(SEQ ID NO: 108)-A (referred to as BCY15727 in this document); A-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY17452 in this document); Ac-(SEQ ID NO: 108)-[K(PYA)] (referred to as BCY19157 in this paper); Ac-A-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY19158 in this document); A-(SEQ ID NO: 108)-A-[Sar6]-[(K(Ac)] (referred to as BCY19385 in this paper); A-(SEQ ID NO: 108)-AGAAAE (referred to as BCY19580 in this article); A-(SEQ ID NO: 108)-KMTHE (referred to as BCY21192 in this article); A-(SEQ ID NO: 108)-NDSLN (referred to as BCY21193 in this document); A-(SEQ ID NO: 108)-SVNAN (referred to as BCY21194 in this paper); A-(SEQ ID NO: 108)-QGHTPL (referred to as BCY21195 in this document); A-(SEQ ID NO: 108)-EMEHSN (referred to as BCY21196 in this document); MRQ-(SEQ ID NO: 108)-ETP (referred to as BCY21197 in this article); EHM-(SEQ ID NO: 108)-TQS (referred to as BCY21198 in this article); EPKRQ-(SEQ ID NO: 108)-A (referred to as BCY21199 in this article); ANYAN-(SEQ ID NO: 108)-A (referred to as BCY21200 in this document); DSFHQ-(SEQ ID NO: 108)-A (referred to as BCY21201 in this document); MRQ-(SEQ ID NO: 108)-ETP-[K(PYA)] (referred to as BCY21993 in this document); EPKRQ-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY21994 in this document); Ac-(SEQ ID NO: 108)-A-[K(PYA)] (referred to as BCY23137 in this article); Ac-(SEQ ID NO: 108)-E-[K(PYA)] (referred to as BCY23174 in this paper); A-(SEQ ID NO: 108)-E-[K(PYA)] (referred to as BCY23179 in this document); A-(SEQ ID NO: 109)-A-[K(PYA)] (referred to as BCY19159 in this document); A-(SEQ ID NO: 110)-A-[K(PYA)] (referred to as BCY19161 in this document); A-(SEQ ID NO: 111)-A-[K(PYA)] (referred to as BCY19162 in this paper); A-(SEQ ID NO: 112)-A-[K(PYA)] (referred to as BCY19163 in this document); A-(SEQ ID NO: 113)-A-[K(PYA)] (referred to as BCY19164 in this paper); A-(SEQ ID NO: 114)-A-[K(PYA)] (referred to as BCY19165 in this document); A-(SEQ ID NO: 115)-A-[K(PYA)] (referred to as BCY19166 in this document); A-(SEQ ID NO: 116)-A-[K(PYA)] (referred to as BCY19167 in this document); A-(SEQ ID NO: 117)-A (referred to as BCY19170 in this document); A-(SEQ ID NO: 117)-A-[K(PYA)] (referred to as BCY19284 in this document); Ac-(SEQ ID NO: 117)-[K(PYA)] (referred to as BCY19995 in this paper); A-(SEQ ID NO: 118)-A-[K(PYA)] (referred to as BCY19171 in this document); A-(SEQ ID NO: 119)-A-[K(PYA)] (referred to as BCY19177 in this document); MRQ-(SEQ ID NO: 119)-ETP-[K(PYA)] (referred to as BCY21995 in this document); EPKRQ-(SEQ ID NO: 119)-A-[K(PYA)] (referred to as BCY21996 in this document); MRQ-(SEQ ID NO: 119)-ETP (referred to as BCY21997 in this document); EPKRQ-(SEQ ID NO: 119)-A (referred to as BCY21998 in this document); Ac-(SEQ ID NO: 119)-[K(PYA)] (referred to as BCY22499 in this paper); A-(SEQ ID NO: 120)-A-[K(PYA)] (referred to as BCY19179 in this document); A-(SEQ ID NO: 121)-A-[K(PYA)] (referred to as BCY19181 in this document); A-(SEQ ID NO: 122)-A-[K(PYA)] (referred to as BCY19184 in this document); A-(SEQ ID NO: 123)-A-[K(PYA)] (referred to as BCY19185 in this document); A-(SEQ ID NO: 124)-A-[K(PYA)] (referred to as BCY19187 in this document); A-(SEQ ID NO: 125)-A-[K(PYA)] (referred to as BCY19188 in this document); A-(SEQ ID NO: 126)-A-[K(PYA)] (referred to as BCY19189 in this document); [dA]-(SEQ ID NO: 127)-[dA]-[K(PYA)] (referred to as BCY20840 in this document); A-(SEQ ID NO: 128)-A-[K(PYA)] (referred to as BCY21040 in this document); A-(SEQ ID NO: 129)-A (referred to as BCY21631 in this document); A-(SEQ ID NO: 129) (referred to as BCY21633 in this article); Ac-(SEQ ID NO: 129) (referred to as BCY21634 in this article); A-(SEQ ID NO: 130) (referred to as BCY21635 in this document); Ac-(SEQ ID NO: 130) (referred to as BCY21636 in this article); Ac-(SEQ ID NO: 131)-[K(PYA)] (referred to as BCY23702 in this paper); Ac-(SEQ ID NO: 132)-[K(PYA)] (referred to as BCY23703 in this paper); Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl] (referred to herein as BCY25601); Ac-(SEQ ID NO: 133)-[K(PYA)] (referred to as BCY23704 in this paper); Ac-(SEQ ID NO: 134)-[K(PYA)] (referred to as BCY23705 in this paper); Ac-(SEQ ID NO: 135)-[K(PYA)] (referred to as BCY23706 in this paper); Ac-(SEQ ID NO: 136)-[K(PYA)] (referred to as BCY23707 in this paper); Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl] (referred to herein as BCY25602); A-(SEQ ID NO: 137)-A (referred to as BCY15729 in this article); A-(SEQ ID NO: 138)-A (referred to as BCY15210 in this document); A-(SEQ ID NO: 138)-A-[Sar6]-[KFl] (referred to as BCY15198 in this paper); A-(SEQ ID NO: 138)-A-[K(PYA)] (referred to as BCY15752 in this document); A-(SEQ ID NO: 139)-A (referred to as BCY15731 in this article); A-(SEQ ID NO: 139)-A-[Sar6]-[KFl] (referred to as BCY15730 in this article); A-(SEQ ID NO: 140)-A (referred to as BCY15733 in this article); A-(SEQ ID NO: 141)-A (referred to herein as BCY15735); and A-(SEQ ID NO: 141)-A-[Sar6]-[KFl] (referred to as BCY15734 in this paper); or its modified derivatives and / or pharmaceutically acceptable salts, or The molecular scaffold is a derivative of TATB and has the following structure: in This represents the junction of three cysteine ​​residues, and X. 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 142)-A (referred to as BCY17001 in this document); A-(SEQ ID NO: 143)-A (referred to as BCY18128 in this document); A-(SEQ ID NO: 143)-A-[K(PYA)] (referred to as BCY19743 in this document); A-(SEQ ID NO: 144)-A (referred to as BCY18129 in this article); A-(SEQ ID NO: 144)-A-[K(PYA)] (referred to as BCY19744 in this document); Ac-A-(SEQ ID NO: 144)-A (referred to as BCY24131 in this article); Ac-(SEQ ID NO: 144) (referred to as BCY24135 in this article); A-(SEQ ID NO: 144) (referred to as BCY24450 in this document); Ac-A-(SEQ ID NO: 144) (referred to as BCY24451 in this article); (SEQ ID NO: 144)-A (referred to as BCY24452 in this document); Ac-(SEQ ID NO: 144)-A (referred to as BCY24453 in this article); AHGG-(SEQ ID NO: 144)-EVHA (referred to as BCY25863 in this article); AIKP-(SEQ ID NO: 144)-QHEA (referred to as BCY25864 in this article); ADST-(SEQ ID NO: 144)-QHPA (referred to as BCY25865 in this document); ALNG-(SEQ ID NO: 144)-PLSA (referred to as BCY25866 in this document); ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)] (referred to as BCY28840 in this document); A-(SEQ ID NO: 145)-A (referred to as BCY24442 in this document); A-(SEQ ID NO: 146)-A (referred to as BCY24443 in this article); A-(SEQ ID NO: 147)-A (referred to as BCY24444 in this article); A-(SEQ ID NO: 148)-A (referred to as BCY24445 in this document); A-(SEQ ID NO: 149)-A (referred to as BCY24456 in this document); A-(SEQ ID NO: 150)-A (referred to as BCY24457 in this document); A-(SEQ ID NO: 151)-A (referred to as BCY24458 in this document); A-(SEQ ID NO: 152)-A (referred to as BCY24459 in this article); A-(SEQ ID NO: 153)-A (referred to as BCY24462 in this document); A-(SEQ ID NO: 154)-A (referred to as BCY24466 in this document); A-(SEQ ID NO: 155)-A (referred to as BCY24467 in this document); A-(SEQ ID NO: 156)-A (referred to as BCY24468 in this document); A-(SEQ ID NO: 157)-A (referred to as BCY24469 in this article); A-(SEQ ID NO: 158)-A (referred to as BCY24471 in this document); A-(SEQ ID NO: 159)-A (referred to as BCY24472 in this article); A-(SEQ ID NO: 160)-A (referred to as BCY24473 in this document); A-(SEQ ID NO: 161)-A (referred to as BCY24474 in this document); A-(SEQ ID NO: 162)-A (referred to as BCY24475 in this document); A-(SEQ ID NO: 163)-A (referred to as BCY24477 in this article); A-(SEQ ID NO: 164)-A (referred to as BCY24478 in this document); A-(SEQ ID NO: 165)-A (referred to as BCY24479 in this article); A-(SEQ ID NO: 166)-A (referred to as BCY24480 in this document); A-(SEQ ID NO: 167)-A (referred to as BCY24481 in this document); A-(SEQ ID NO: 168)-A (referred to as BCY24482 in this document); A-(SEQ ID NO: 169)-A (referred to as BCY24483 in this article); A-(SEQ ID NO: 170)-A (referred to as BCY24484 in this document); A-(SEQ ID NO: 171)-A (referred to as BCY24485 in this document); A-(SEQ ID NO: 172)-A (referred to as BCY24486 in this document); A-(SEQ ID NO: 173)-A (referred to as BCY24487 in this article); A-(SEQ ID NO: 174)-A (referred to as BCY24488 in this document); A-(SEQ ID NO: 175)-A (referred to as BCY24489 in this document); A-(SEQ ID NO: 176)-A (referred to as BCY24490 in this document); A-(SEQ ID NO: 177)-A (referred to as BCY24491 in this document); A-(SEQ ID NO: 178)-A (referred to as BCY24492 in this article); A-(SEQ ID NO: 179)-A (referred to as BCY24493 in this article); A-(SEQ ID NO: 180)-A (referred to as BCY24495 in this document); A-(SEQ ID NO: 181)-A (referred to as BCY24496 in this document); A-(SEQ ID NO: 182)-A (referred to as BCY24497 in this document); A-(SEQ ID NO: 183)-A (referred to as BCY24498 in this document); A-(SEQ ID NO: 184)-A (referred to as BCY24499 in this article); A-(SEQ ID NO: 185)-A (referred to as BCY24500 in this document); A-(SEQ ID NO: 186)-A (referred to as BCY24501 in this document); A-(SEQ ID NO: 187)-A (referred to as BCY24503 in this document); A-(SEQ ID NO: 188)-A (referred to as BCY24504 in this document); A-(SEQ ID NO: 189)-A (referred to as BCY24505 in this document); A-(SEQ ID NO: 190)-A (referred to as BCY24506 in this document); A-(SEQ ID NO: 191)-A (referred to as BCY24509 in this document); ALNG-(SEQ ID NO: 192)-PLSA (referred to herein as BCY28838); ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)] (referred to as BCY28841 in this document); ALNG-(SEQ ID NO: 193)-PLSA (referred to as BCY28839 in this article); ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)] (referred to as BCY28842 in this document); ALEQN-(SEQ ID NO: 194)-A (referred to as BCY25861 in this document); ALEQN-(SEQ ID NO: 194)-A-[K(PYA)] (referred to as BCY28843 in this document); ALEQN-(SEQ ID NO: 195)-A (referred to as BCY28844 in this document); ALEQN-(SEQ ID NO: 195)-A-[K(PYA)] (referred to herein as BCY28845); and AHAGT-(SEQ ID NO: 196)-A (referred to as BCY25859 in this document); Or its modified derivatives and / or pharmaceutically acceptable salts.

7. The bicyclic peptide ligand according to claim 3, wherein CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 The peptide ligand of -C (SEQ ID NO: 4) contains an amino acid sequence selected from the following: CQPTPRCPFSTWPC (referred to in this document as SEQ ID NO: 197); CQPTPQCPYSTWPC (referred to herein as SEQ ID NO: 198, and referred to herein as BCY20723 when complexed with a derivative of TATB having the following structure): in (Indicates the junction of three cysteine ​​residues); CQPT[HyP]QCPYSTWPC (referred to in this paper as SEQ ID NO: 199); CQPT[cis-HyP]QCPYSTWPC (referred to herein as SEQ ID NO: 200); CQPT[Pip]QCPYSTWPC (referred to in this document as SEQ ID NO: 201); CQPTPECPYSTWPC (referred to in this document as SEQ ID NO: 202); CQPTPQC[HyP]YSTWPC (referred to in this paper as SEQ ID NO: 203); CQPTPQC[cis-HyP]YSTWPC (referred to herein as SEQ ID NO: 204); CQPTPQC[Aze]YSTWPC (referred to herein as SEQ ID NO: 205); CQPTPQCP[2Nal]STWPC (referred to herein as SEQ ID NO: 206); CQPTPQCP[4tBuPhe]STWPC (referred to herein as SEQ ID NO: 207); CQPTPQCP[4FPhe]STWPC (referred to herein as SEQ ID NO: 208); CQPTPQCP[3FTyr]STWPC (referred to herein as SEQ ID NO: 209); CQPTPQCP[2FTyr]STWPC (referred to herein as SEQ ID NO: 210); CQPTPQCPY[Dap]TWPC (referred to herein as SEQ ID NO: 211); CQPTPQCPYS[Dap]WPC (referred to herein as SEQ ID NO: 212); CQPTPQCPYST[2Nal]PC (referred to in this paper as SEQ ID NO: 213); CQPTPQCPYST[1Nal]PC (referred to herein as SEQ ID NO: 214); CQPTPQCPYST[6FTrp]PC (referred to herein as SEQ ID NO: 215); CQPTPQCPYST[5FTrp]PC (referred to herein as SEQ ID NO: 216); CQPTPQCPYST[6ClTrp]PC (referred to herein as SEQ ID NO: 217); CQPTPQCPYST[4MeoTrp]PC (referred to herein as SEQ ID NO: 218); CQPTPQCPYST[5MeoTrp]PC (referred to herein as SEQ ID NO: 219); CQPTPQCPYST[Trp(S)]PC (referred to herein as SEQ ID NO: 220); CQPTPQCPYST[AzaTrp]PC (referred to in this paper as SEQ ID NO: 221); CQPTPQCPYSTW[HyP]C (referred to in this paper as SEQ ID NO: 222); CQPTPQCPYSTW[cis-HyP]C (referred to herein as SEQ ID NO: 223); CQPTPQCPYSTW[Aze]C (referred to in this paper as SEQ ID NO: 224); CQPTPQCPYSTW[Pip]C (referred to herein as SEQ ID NO: 225); and CQPTPECPYNTWPC (referred to herein as SEQ ID NO: 226), for example The molecular scaffold is a derivative of TATB and has the following structure: in This indicates the junction of three cysteine ​​residues, and CQPTX. 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 The peptide ligand of -C (SEQ ID NO: 4) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 197)-A (referred to as BCY16999 in this document); A-(SEQ ID NO: 197)-A-[K(PYA)] (referred to as BCY17693 in this paper); A-(SEQ ID NO: 197)-A-[Sar6]-[K(Ac)] (referred to as BCY19387 in this paper); A-(SEQ ID NO: 198)-A (referred to as BCY18126 in this document); Ac-A-(SEQ ID NO: 198)-A (referred to as BCY20725 in this document); A-(SEQ ID NO: 198)-NLNLK (referred to as BCY21770 in this article); VNENI-(SEQ ID NO: 198)-A (referred to as BCY21771 in this article); A-(SEQ ID NO: 198)-RNPHD (referred to as BCY21772 in this paper); A-(SEQ ID NO: 198)-IHNNG (referred to as BCY21774 in this paper); TNEGI-(SEQ ID NO: 198)-A (referred to as BCY21778 in this article); VNENI-(SEQ ID NO: 198)-A-[K(PYA)] (referred to as BCY23767 in this document); A-(SEQ ID NO: 199)-A (referred to as BCY20731 in this document); A-(SEQ ID NO: 200)-A (referred to as BCY20732 in this document); A-(SEQ ID NO: 201)-A (referred to as BCY20734 in this document); A-(SEQ ID NO: 202)-A (referred to herein as BCY20735); A-(SEQ ID NO: 203)-A (referred to as BCY20736 in this document); A-(SEQ ID NO: 204)-A (referred to as BCY20737 in this document); A-(SEQ ID NO: 205)-A (referred to as BCY20738 in this document); A-(SEQ ID NO: 206)-A (referred to as BCY20741 in this document); A-(SEQ ID NO: 207)-A (referred to as BCY20742 in this document); A-(SEQ ID NO: 208)-A (referred to as BCY20743 in this document); A-(SEQ ID NO: 209)-A (referred to as BCY20746 in this document); A-(SEQ ID NO: 210)-A (referred to as BCY20747 in this document); A-(SEQ ID NO: 211)-A (referred to as BCY20748 in this document); A-(SEQ ID NO: 212)-A (referred to as BCY20749 in this document); A-(SEQ ID NO: 213)-A (referred to as BCY20751 in this document); A-(SEQ ID NO: 214)-A (referred to as BCY20752 in this document); A-(SEQ ID NO: 215)-A (referred to as BCY20756 in this document); A-(SEQ ID NO: 216)-A (referred to as BCY20757 in this document); A-(SEQ ID NO: 217)-A (referred to as BCY20758 in this document); A-(SEQ ID NO: 218)-A (referred to as BCY20759 in this document); A-(SEQ ID NO: 219)-A (referred to as BCY20760 in this document); A-(SEQ ID NO: 220)-A (referred to as BCY20761 in this document); A-(SEQ ID NO: 221)-A (referred to as BCY20762 in this document); A-(SEQ ID NO: 222)-A (referred to as BCY20763 in this document); A-(SEQ ID NO: 223)-A (referred to as BCY20764 in this document); A-(SEQ ID NO: 224)-A (referred to as BCY20765 in this document); A-(SEQ ID NO: 225)-A (referred to as BCY20766 in this document); A-(SEQ ID NO: 226)-A (referred to herein as BCY18127); and A-(SEQ ID NO: 226)-A-[K(PYA)] (referred to as BCY19742 in this paper); Or its modified derivatives and / or pharmaceutically acceptable salts.

8. The bicyclic peptide ligand according to claim 3, wherein CYYX 38 -X 39 -X 40 The peptide ligand of -YACLDC (SEQ ID NO: 5) comprises an amino acid sequence selected from the following: CYYPDYYACLDC (referred to as SEQ ID NO: 227 in this document); CYYENYYACLDC (referred to herein as SEQ ID NO: 228); and CYYPDWYACLDC (referred to herein as SEQ ID NO: 229), for example The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, which has the following structure: in This indicates the junction of three cysteine ​​residues, and CYYX. 38 -X 39 -X 40 The peptide ligand of -YACLDC (SEQ ID NO: 5) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 227)-A (referred to as BCY17007 in this document); A-(SEQ ID NO: 228)-A (referred to as BCY18135 in this document); A-(SEQ ID NO: 229)-A (referred to herein as BCY18136); and A-(SEQ ID NO: 229)-A-[K(PYA)] (referred to as BCY19747 in this document); Or its modified derivatives and / or pharmaceutically acceptable salts.

9. The bicyclic peptide ligand according to claim 3, wherein X 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) comprises an amino acid sequence selected from the following: CNNPVMTYWCTKGIC (referred to in this article as SEQ ID NO: 230); CNNPVMTYWCEKGIC (referred to in this article as SEQ ID NO: 231); CDNEVITYWCTKGIC (referred to as SEQ ID NO: 232 in this article); CDNEV[tBuAla]TYWCTKGIC (referred to in this paper as SEQ ID NO: 233); CDNEVFTYWCTKGIC (referred to in this article as SEQ ID NO: 234); CDNEV[Cba]TYWCTKGIC (referred to in this article as SEQ ID NO: 235); CDNEVITY[2Nal]CTKGIC (referred to as SEQ ID NO: 236 in this paper); CDNEVITY[1Nal]CTKGIC (referred to as SEQ ID NO: 237 in this paper); CDNEVITYWCT[Orn]GIC (referred to as SEQ ID NO: 238 in this article); CDNEVITYWCT[HArg]GIC (referred to as SEQ ID NO: 239 in this paper); CDNEVITYWCTK[dA]IC (referred to herein as SEQ ID NO: 240); CDNEVITYWCTKG[tBuGly]C (referred to as SEQ ID NO: 241 in this paper); CDNEVIT[DOPA]WCTKGIC (referred to in this paper as SEQ ID NO: 242); CDNPVFTYWCTKGIC (referred to in this article as SEQ ID NO: 243); CNNPVMAYWCTKGIC (referred to in this article as SEQ ID NO: 244); CPNPVITYWCTKGIC (referred to in this article as SEQ ID NO: 245); CDNEVITYWCQMGVC (referred to in this document as SEQ ID NO: 246); CDNEVITYWCQRGVC (referred to as SEQ ID NO: 247 in this document); CDNEVITYWCMRGIC (referred to in this article as SEQ ID NO: 248); CDNEVITYWCQRGIC (referred to in this article as SEQ ID NO: 249); CDNEVITY[6FTrp]CQRGIC (referred to in this paper as SEQ ID NO: 250); CDNEVITY[5FTrp]CQRGIC (referred to in this paper as SEQ ID NO: 251); CDNEVITY[5MeoTrp]CQRGIC (referred to as SEQ ID NO: 252 in this document); CDNEVITY[Trp(S)]CQRGIC (referred to as SEQ ID NO: 253 in this paper); CDNEVITY[AzaTrp]CQRGIC (referred to as SEQ ID NO: 254 in this document); CDNEVITYWCQ[HArg]GIC (referred to as SEQ ID NO: 255 in this paper); CDNEVITYWCQ[Cit]GIC (referred to as SEQ ID NO: 256 in this document); CDNEVFEYWCTKGIC (referred to in this article as SEQ ID NO: 257); CDNEVITYWCERGIC (referred to in this article as SEQ ID NO: 258); CDNEVITYWCEMGIC (referred to in this article as SEQ ID NO: 259); CSNPVFAYWCSRQMC (referred to in this document as SEQ ID NO: 260); CSNPVFAYWCERGIC (referred to herein as SEQ ID NO: 261, and referred herein as BCY21615 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure): in (Indicates the junction of three cysteine ​​residues); CSNPVFAYWCER[K(PYA)]IC (referred to herein as SEQ ID NO: 262); CSNPVFAYWCER[dK(PYA)]IC (referred to herein as SEQ ID NO: 263); CSNPVFAYWCER[S-aMeLys(PYA)]IC (referred to herein as SEQ ID NO: 264); CSNPVFAYWCER[R-aMeLys(PYA)]IC (referred to herein as SEQ ID NO: 265); C[K(PYA)]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 266); CSNPVFAY[5FTrp]CERGIC (referred to in this paper as SEQ ID NO: 267); CSNPVFAYWCERGI[Cysam] (referred to herein as SEQ ID NO: 268, and referred herein as BCY21623 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure): in (Indicates the junction of three cysteine ​​residues); C[K(PYA)]NPVFAYWCERGI[Cysam] (referred to as SEQ ID NO: 269 in this paper); CSNPVFAYWC[Dap]RGIC (referred to herein as SEQ ID NO: 270); CKNPVFAYWC[PG]RGIC (referred to in this paper as SEQ ID NO: 271); CENPVFAYWCERGIC (referred to in this article as SEQ ID NO: 272); C[dA]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 273); CGNPVFAYWCERGIC (referred to in this article as SEQ ID NO: 274); C[Aib]NPVFAYWCERGIC (referred to in this paper as SEQ ID NO: 275); CSN[trans-4FlPro]VFAYWCERGIC (referred to herein as SEQ ID NO: 276); CSN[4FlPro]VFAYWCERGIC (referred to herein as SEQ ID NO: 277); CSN[HyP]VFAYWCERGIC (referred to in this paper as SEQ ID NO: 278); CSN[cis-HyP]VFAYWCERGIC (referred to herein as SEQ ID NO: 279); CSNP[HSer]FAYWCERGIC (referred to in this article as SEQ ID NO: 280); CSNPV[2FPhe]AYWCERGIC (referred to in this paper as SEQ ID NO: 281); CSNPV[4CF3Phe]AYWCERGIC (referred to in this paper as SEQ ID NO: 282); CSNPVFSYWCERGIC (referred to in this article as SEQ ID NO: 283); CSNPVF[Dap]YWCERGIC (referred to in this paper as SEQ ID NO: 284); CSNPVF[CF3Ala]YWCERGIC (referred to in this paper as SEQ ID NO: 285); CSNPVFA[2FTyr]WCERGIC (referred to herein as SEQ ID NO: 286); CSNPVFA[3FTyr]WCERGIC (referred to in this paper as SEQ ID NO: 287); CSNPVFAY[4FTrp]CERGIC (referred to in this paper as SEQ ID NO: 288); CSNPVFAYWCE[Cit]GIC (referred to in this paper as SEQ ID NO: 289); CSNPVFAYWCER[dA]IC (referred to herein as SEQ ID NO: 290); CSNPVFAYWCERG[Nva]C (referred to in this paper as SEQ ID NO: 291); CSNPVFAYWCERG[Nle]C (referred to in this paper as SEQ ID NO: 292); CSNPVFAYWCERG[EPA]C (referred to in this document as SEQ ID NO: 293); CSNPVFAYWCERG[tBuGly]C (referred to in this paper as SEQ ID NO: 294); CSN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 295 in this document); C[Aib]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 296 in this document); C[dS]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 297 in this paper); C[K(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 298 in this document); C[dK(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 299 in this paper); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to as SEQ ID NO: 300 in this document); CSN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to as SEQ ID NO: 301 in this document); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to as SEQ ID NO: 302 in this document); CSNPVFAYWCSRNLC (referred to in this document as SEQ ID NO: 303); CSNPVFAYWCSRGLC (referred to in this document as SEQ ID NO: 304); CTTDMMWKVCRTLDC (referred to as SEQ ID NO: 305 in this document); CATDHMWKVCRTLDC (referred to as SEQ ID NO: 306 in this document); CKTDAMWKVCRTLDC (referred to as SEQ ID NO: 307 in this article); CSTDQMWKVCRTLDC (referred to as SEQ ID NO: 308 in this document); CSTDYMWKVCRTLDC (referred to herein as SEQ ID NO: 309, and referred herein as BCY23141 when complexed with a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT having the following structure): in (Indicates the junction of three cysteine ​​residues); CSTDY[Nle]WKVCRTLDC (referred to as SEQ ID NO: 310 in this document); CATDYMWKVCRTLDC (referred to as SEQ ID NO: 311 in this document); CSTDAMWKVCRTLDC (referred to as SEQ ID NO: 312 in this document); CSTDYAWKVCRTLDC (referred to as SEQ ID NO: 313 in this document); CSTDYMWKACRTLDC (referred to in this document as SEQ ID NO: 314); CSTDYMWKVCRALDC (referred to in this document as SEQ ID NO: 315); CSTDYMWKVCRTADC (referred to in this paper as SEQ ID NO: 316); C[CF3Ala]TDYMWKVCRTLDC (referred to as SEQ ID NO: 317 in this document); C[HSer]TDYMWKVCRTLDC (referred to as SEQ ID NO: 318 in this document); CTTDYMWKVCRTLDC (referred to as SEQ ID NO: 319 in this document); C[3HyV]TDYMWKVCRTLDC (referred to as SEQ ID NO: 320 in this document); CS[3HyV]DYMWKVCRTLDC (referred to as SEQ ID NO: 321 in this document); C[Dap]TDYMWKVCRTLDC (referred to in this document as SEQ ID NO: 322); CSTD[4FPhe]MWKVCRTLDC (referred to as SEQ ID NO: 323 in this document); CSTD[1Nal]MWKVCRTLDC (referred to as SEQ ID NO: 324 in this paper); CSTD[2Nal]MWKVCRTLDC (referred to as SEQ ID NO: 325 in this document); CSTD[26DiMeTyr]MWKVCRTLDC (referred to herein as SEQ ID NO: 326); CSTD[3FTyr]MWKVCRTLDC (referred to in this paper as SEQ ID NO: 327); CSTD[2FTyr]MWKVCRTLDC (referred to in this paper as SEQ ID NO: 328); CSTD[DOPA]MWKVCRTLDC (referred to in this document as SEQ ID NO: 329); CSTDY[Nva]WKVCRTLDC (referred to as SEQ ID NO: 330 in this document); CSTDY[TfNle]WKVCRTLDC (referred to as SEQ ID NO: 331 in this document); CSTDYEWKVCRTLDC (referred to as SEQ ID NO: 332 in this document); CSTDY[CF3Nva]WKVCRTLDC (referred to as SEQ ID NO: 333 in this document); CSTDYM[1Nal]KVCRTLDC (referred to as SEQ ID NO: 334 in this paper); CSTDYM[4FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 335); CSTDYM[5FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 336); CSTDYM[6FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 337); CSTDYM[7FTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 338); CSTDYM[2MeTrp]KVCRTLDC (referred to as SEQ ID NO: 339 in this paper); CSTDYM[4MeTrp]KVCRTLDC (referred to as SEQ ID NO: 340 in this paper); CSTDYM[5MeTrp]KVCRTLDC (referred to as SEQ ID NO: 341 in this paper); CSTDYM[6MeTrp]KVCRTLDC (referred to as SEQ ID NO: 342 in this paper); CSTDYM[7MeTrp]KVCRTLDC (referred to in this paper as SEQ ID NO: 343); CSTDYM[AzaTrp]KVCRTLDC (referred to as SEQ ID NO: 344 in this paper); CSTDYMW[HArg]VCRTLDC (referred to in this paper as SEQ ID NO: 345); CSTDYMW[Orn]VCRTLDC (referred to in this document as SEQ ID NO: 346); CSTDYMW[Agb]VCRTLDC (referred to in this document as SEQ ID NO: 347); CSTDYMWK[tBuGly]CRTLDC (referred to in this paper as SEQ ID NO: 348); CSTDYMWK[Cbg]CRTLDC (referred to in this document as SEQ ID NO: 349); CSTDYMWK[C5g]CRTLDC (referred to herein as SEQ ID NO: 350); CSTDYMWK[3HyV]CRTLDC (referred to herein as SEQ ID NO: 351); CSTDYMWKVC[HArg]TLDC (referred to in this paper as SEQ ID NO: 352); CSTDYMWKVC[Arg(Me)]TLDC (referred to in this paper as SEQ ID NO: 353); CSTDYMWKVCR[3HyV]LDC (referred to in this paper as SEQ ID NO: 354); CSTDYMWKVCRT[tBuAla]DC (referred to herein as SEQ ID NO: 355); CSTDYMWKVCRT[Cba]DC (referred to herein as SEQ ID NO: 356); CSTDYMWKVCRT[Nva]DC (referred to herein as SEQ ID NO: 357); CSTDYMWKVCRT[Nle]DC (referred to herein as SEQ ID NO: 358); CTTDMAWRDCRTLDC (referred to in this document as SEQ ID NO: 359); CTTDMAWRLCRTLDC (referred to in this article as SEQ ID NO: 360); CTTDMVWKVCRTLDC (referred to as SEQ ID NO: 361 in this document); CVTDYMWKVCRTLDC (referred to as SEQ ID NO: 362 in this document); CYTDSMWKVCRTLDC (referred to as SEQ ID NO: 363 in this document); CTTDMMWKVCREPDC (referred to in this document as SEQ ID NO: 364); CTTDMMWKVCRSMDC (referred to herein as SEQ ID NO: 365); and CTTDMMWKVCRTLDC (referred to in this document as SEQ ID NO: 366), for example The molecular scaffold is a derivative of TATA and has the following structure: in This represents the junction of three cysteine ​​residues, and X. 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 230)-A (referred to as BCY15211 in this document); A-(SEQ ID NO: 230)-A-[Sar6]-[KFl] (referred to as BCY15199 in this paper); A-(SEQ ID NO: 231)-A (referred to as BCY15737 in this document); A-(SEQ ID NO: 232)-A (referred to as BCY15739 in this article); A-(SEQ ID NO: 232)-A-[Sar6]-[KFl] (referred to as BCY15738 in this paper); A-(SEQ ID NO: 232)-A-[Sar6]-[K(Ac)] (referred to as BCY19386 in this paper); A-(SEQ ID NO: 232)-AGAAAE (referred to as BCY19581 in this article); A-(SEQ ID NO: 233)-A (referred to as BCY17047 in this document); A-(SEQ ID NO: 234)-A (referred to as BCY17049 in this article); A-(SEQ ID NO: 235)-A (referred to as BCY17051 in this document); A-(SEQ ID NO: 236)-A (referred to as BCY17055 in this document); A-(SEQ ID NO: 237)-A (referred to as BCY17056 in this document); A-(SEQ ID NO: 238)-A (referred to as BCY17057 in this document); A-(SEQ ID NO: 239)-A (referred to as BCY17058 in this document); A-(SEQ ID NO: 240)-A (referred to as BCY17059 in this document); A-(SEQ ID NO: 241)-A (referred to as BCY17061 in this document); A-(SEQ ID NO: 242)-A (referred to as BCY17656 in this document); A-(SEQ ID NO: 243)-A (referred to as BCY15741 in this article); A-(SEQ ID NO: 244)-A (referred to as BCY15743 in this article); A-(SEQ ID NO: 245)-A (referred to as BCY15745 in this document); A-(SEQ ID NO: 246)-A (referred to as BCY16668 in this document); A-(SEQ ID NO: 247)-A (referred to as BCY16669 in this document); A-(SEQ ID NO: 248)-A (referred to as BCY16670 in this document); A-(SEQ ID NO: 249)-A (referred to as BCY16671 in this article); A-(SEQ ID NO: 249)-A-[Sar6]-[KFl] (referred to as BCY16647 in this paper); Ac-A-(SEQ ID NO: 249)-A (referred to as BCY19586 in this article); A-(SEQ ID NO: 250)-A (referred to as BCY18510 in this document); A-(SEQ ID NO: 251)-A (referred to as BCY18511 in this document); A-(SEQ ID NO: 251)-A-[K(PYA)] (referred to as BCY25826 in this document); A-(SEQ ID NO: 252)-A (referred to as BCY18514 in this document); A-(SEQ ID NO: 253)-A (referred to as BCY18515 in this document); A-(SEQ ID NO: 254)-A (referred to as BCY18518 in this document); A-(SEQ ID NO: 255)-A (referred to as BCY18519 in this document); A-(SEQ ID NO: 256)-A (referred to as BCY18520 in this document); A-(SEQ ID NO: 257)-A (referred to as BCY16672 in this document); A-(SEQ ID NO: 258)-A (referred to as BCY16673 in this article); A-(SEQ ID NO: 258)-A-[Sar6]-[KFl] (referred to as BCY16649 in this paper); A-(SEQ ID NO: 258)-A-[K(PYA)] (referred to as BCY17237 in this document); Ac-A-(SEQ ID NO: 258)-A (referred to herein as BCY19585); and A-(SEQ ID NO: 259)-A (referred to as BCY16674 in this article); or its modified derivatives and / or pharmaceutically acceptable salts, or The molecular scaffold is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, which has the following structure: in This represents the junction of three cysteine ​​residues, and X. 41 -X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 -CX 50 -X 51 -X 52 -X 53 -X 54 The peptide ligand of (SEQ ID NO: 6) further comprises an N-terminal and / or C-terminal addition and contains an amino acid sequence selected from the following: A-(SEQ ID NO: 260)-A (referred to as BCY17002 in this document); A-(SEQ ID NO: 260)-A-[K(PYA)] (referred to as BCY19745 in this document); A-(SEQ ID NO: 261)-A (referred to as BCY18130 in this document); A-(SEQ ID NO: 261)-A-[K(PYA)] (referred to as BCY20847 in this document); [PYA]-A-(SEQ ID NO: 261)-A (referred to herein as BCY20852); Ac-(SEQ ID NO: 261) (referred to as BCY21616 in this article); A-(SEQ ID NO: 261) (referred to as BCY21617 in this document); Ac-A-(SEQ ID NO: 261) (referred to as BCY21618 in this document); [PYA]-(SEQ ID NO: 261) (referred to herein as BCY21619); [GuanAc]-(SEQ ID NO: 261)-A (referred to as BCY23043 in this document); A-(SEQ ID NO: 261)-[CF3Ala] (referred to as BCY23080 in this article); A-(SEQ ID NO: 261)-S (referred to as BCY23081 in this document); A-(SEQ ID NO: 262)-A (referred to as BCY20848 in this document); A-(SEQ ID NO: 263)-A (referred to as BCY20849 in this document); A-(SEQ ID NO: 264)-A (referred to as BCY20850 in this document); A-(SEQ ID NO: 265)-A (referred to as BCY20851 in this document); A-(SEQ ID NO: 266)-A (referred to as BCY20853 in this document); A-(SEQ ID NO: 266) (referred to as BCY21620 in this document); A-(SEQ ID NO: 267)-A (referred to as BCY21622 in this document); A-(SEQ ID NO: 267)-A-[K(PYA)] (referred to as BCY21607 in this document); Ac-(SEQ ID NO: 268) (referred to as BCY21624 in this article); A-(SEQ ID NO: 268) (referred to as BCY21625 in this document); [PYA]-(SEQ ID NO: 268) (referred to herein as BCY21626); A-(SEQ ID NO: 269) (referred to as BCY21627 in this document); Ac-(SEQ ID NO: 270) (referred to as BCY22879 in this article); Ac-(SEQ ID NO: 271) (referred to as BCY22880 in this article); A-(SEQ ID NO: 272)-A (referred to as BCY23044 in this document); A-(SEQ ID NO: 273)-A (referred to as BCY23045 in this document); A-(SEQ ID NO: 274)-A (referred to as BCY23046 in this document); A-(SEQ ID NO: 275)-A (referred to as BCY23047 in this document); A-(SEQ ID NO: 276)-A (referred to as BCY23050 in this document); A-(SEQ ID NO: 277)-A (referred to as BCY23051 in this document); A-(SEQ ID NO: 278)-A (referred to as BCY23052 in this document); A-(SEQ ID NO: 279)-A (referred to as BCY23053 in this document); A-(SEQ ID NO: 280)-A (referred to as BCY23054 in this document); A-(SEQ ID NO: 281)-A (referred to as BCY23058 in this document); A-(SEQ ID NO: 282)-A (referred to as BCY23059 in this document); A-(SEQ ID NO: 283)-A (referred to as BCY23062 in this document); A-(SEQ ID NO: 284)-A (referred to as BCY23063 in this document); A-(SEQ ID NO: 285)-A (referred to as BCY23064 in this document); A-(SEQ ID NO: 286)-A (referred to as BCY23066 in this document); A-(SEQ ID NO: 287)-A (referred to as BCY23067 in this document); A-(SEQ ID NO: 288)-A (referred to as BCY23068 in this document); A-(SEQ ID NO: 289)-A (referred to as BCY23071 in this document); A-(SEQ ID NO: 290)-A (referred to as BCY23072 in this document); A-(SEQ ID NO: 291)-A (referred to as BCY23073 in this document); A-(SEQ ID NO: 292)-A (referred to as BCY23074 in this document); A-(SEQ ID NO: 293)-A (referred to as BCY23075 in this document); A-(SEQ ID NO: 294)-A (referred to as BCY23079 in this document); [GuanAc]-(SEQ ID NO: 295)-COOH (referred to as BCY27058 in this paper); [GuanAc]-(SEQ ID NO: 295) (referred to as BCY27059 in this document); [CIA]-[K(PYA)]-(SEQ ID NO: 295)-A (referred to as BCY27064 in this article); [CIA]-[dK(PYA)]-(SEQ ID NO: 295)-A (referred to as BCY27065 in this document); [GuanAc]-(SEQ ID NO: 296) (referred to as BCY27060 in this document); [GuanAc]-(SEQ ID NO: 297) (referred to as BCY27061 in this document); [GuanAc]-(SEQ ID NO: 298) (referred to as BCY27062 in this document); [GuanAc]-(SEQ ID NO: 299) (referred to as BCY27063 in this document); [GuanAc]-(SEQ ID NO: 300) (referred to as BCY27066 in this document); [GuanAc]-(SEQ ID NO: 301) (referred to as BCY27067 in this document); [GuanAc]-(SEQ ID NO: 302) (referred to as BCY27068 in this document); A-(SEQ ID NO: 303)-A (referred to as BCY18131 in this document); A-(SEQ ID NO: 304)-A (referred to as BCY18132 in this article); A-(SEQ ID NO: 305)-A-[K(PYA)] (referred to as BCY19588 in this document); A-(SEQ ID NO: 306)-A (referred to as BCY19933 in this document); A-(SEQ ID NO: 307)-A (referred to as BCY19934 in this article); A-(SEQ ID NO: 308)-A (referred to as BCY19935 in this document); A-(SEQ ID NO: 309)-A (referred to as BCY19936 in this document); A-(SEQ ID NO: 309)-A-[K(PYA)] (referred to as BCY21606 in this document); Ac-(SEQ ID NO: 309) (referred to as BCY23139 in this article); Ac-A-(SEQ ID NO: 309)-A (referred to as BCY23140 in this article); [dA]-(SEQ ID NO: 309)-A (referred to herein as BCY32061); A-(SEQ ID NO: 309) (referred to as BCY32074 in this document); Ac-A-(SEQ ID NO: 309) (referred to as BCY32075 in this article); (SEQ ID NO: 309)-A (referred to as BCY32076 in this document); Ac-(SEQ ID NO: 309)-A (referred to as BCY32077 in this article); A-(SEQ ID NO: 309)-A-[dK(PYA)] (referred to as BCY32126 in this paper); A-(SEQ ID NO: 309)-[K(PYA)] (referred to as BCY32127 in this document); A-(SEQ ID NO: 309)-[dK(PYA)] (referred to as BCY32128 in this paper); A-(SEQ ID NO: 310)-A (referred to as BCY23138 in this document); A-(SEQ ID NO: 310)-A-[K(PYA)] (referred to as BCY24613 in this document); A-(SEQ ID NO: 311)-A (referred to as BCY32062 in this document); A-(SEQ ID NO: 312)-A (referred to as BCY32065 in this document); A-(SEQ ID NO: 313)-A (referred to as BCY32066 in this document); A-(SEQ ID NO: 314)-A (referred to as BCY32069 in this document); A-(SEQ ID NO: 315)-A (referred to as BCY32071 in this document); A-(SEQ ID NO: 316)-A (referred to as BCY32072 in this document); A-(SEQ ID NO: 317)-A (referred to as BCY32078 in this document); A-(SEQ ID NO: 318)-A (referred to as BCY32079 in this document); A-(SEQ ID NO: 319)-A (referred to as BCY32080 in this document); A-(SEQ ID NO: 320)-A (referred to as BCY32081 in this document); A-(SEQ ID NO: 321)-A (referred to as BCY32082 in this document); A-(SEQ ID NO: 322)-A (referred to as BCY32083 in this document); A-(SEQ ID NO: 323)-A (referred to as BCY32084 in this document); A-(SEQ ID NO: 324)-A (referred to as BCY32085 in this document); A-(SEQ ID NO: 325)-A (referred to as BCY32086 in this document); A-(SEQ ID NO: 326)-A (referred to as BCY32087 in this document); A-(SEQ ID NO: 327)-A (referred to as BCY32088 in this document); A-(SEQ ID NO: 328)-A (referred to as BCY32089 in this document); A-(SEQ ID NO: 329)-A (referred to as BCY32090 in this document); A-(SEQ ID NO: 330)-A (referred to as BCY32091 in this document); A-(SEQ ID NO: 331)-A (referred to as BCY32092 in this document); A-(SEQ ID NO: 332)-A (referred to as BCY32093 in this document); A-(SEQ ID NO: 333)-A (referred to as BCY32095 in this article); A-(SEQ ID NO: 334)-A (referred to as BCY32096 in this document); A-(SEQ ID NO: 335)-A (referred to as BCY32098 in this document); A-(SEQ ID NO: 336)-A (referred to as BCY32099 in this document); A-(SEQ ID NO: 337)-A (referred to as BCY32100 in this document); A-(SEQ ID NO: 338)-A (referred to as BCY32101 in this document); A-(SEQ ID NO: 339)-A (referred to as BCY32103 in this article); A-(SEQ ID NO: 340)-A (referred to as BCY32104 in this document); A-(SEQ ID NO: 341)-A (referred to as BCY32105 in this document); A-(SEQ ID NO: 342)-A (referred to as BCY32106 in this document); A-(SEQ ID NO: 343)-A (referred to as BCY32107 in this document); A-(SEQ ID NO: 344)-A (referred to as BCY32108 in this document); A-(SEQ ID NO: 345)-A (referred to as BCY32109 in this document); A-(SEQ ID NO: 346)-A (referred to as BCY32110 in this document); A-(SEQ ID NO: 347)-A (referred to as BCY32112 in this article); A-(SEQ ID NO: 348)-A (referred to as BCY32113 in this document); A-(SEQ ID NO: 349)-A (referred to as BCY32114 in this document); A-(SEQ ID NO: 350)-A (referred to as BCY32115 in this document); A-(SEQ ID NO: 351)-A (referred to as BCY32116 in this document); A-(SEQ ID NO: 352)-A (referred to as BCY32117 in this document); A-(SEQ ID NO: 353)-A (referred to as BCY32120 in this document); A-(SEQ ID NO: 354)-A (referred to as BCY32121 in this document); A-(SEQ ID NO: 355)-A (referred to as BCY32122 in this document); A-(SEQ ID NO: 356)-A (referred to as BCY32123 in this document); A-(SEQ ID NO: 357)-A (referred to as BCY32124 in this article); A-(SEQ ID NO: 358)-A (referred to as BCY32125 in this document); A-(SEQ ID NO: 359)-A (referred to as BCY19937 in this article); A-(SEQ ID NO: 360)-A (referred to as BCY19938 in this document); A-(SEQ ID NO: 361)-A (referred to as BCY19939 in this article); A-(SEQ ID NO: 362)-A (referred to as BCY19940 in this document); A-(SEQ ID NO: 363)-A (referred to as BCY19941 in this article); A-(SEQ ID NO: 364)-A (referred to as BCY19942 in this article); A-(SEQ ID NO: 365)-A (referred to herein as BCY19943); and A-(SEQ ID NO: 366)-A (referred to as BCY18253 in this article); Or its modified derivatives and / or pharmaceutically acceptable salts.

10. A polymeric binding complex or a pharmaceutically acceptable salt thereof, comprising at least two bicyclic peptide ligands according to any one of claims 3 to 9, wherein the peptide ligands may be the same or different.

11. The polymeric complex of claim 10 or a pharmaceutically acceptable salt thereof, comprising more than one identical bicyclic peptide (i.e., homopolymer).

12. The polymeric complex of claim 10 or a pharmaceutically acceptable salt thereof, comprising different bicyclic peptides (i.e., heteropolymers).

13. The polymeric conjugate complex of claim 10 or a pharmaceutically acceptable salt thereof, comprising two bicyclic peptides, said bicyclic peptides being identical (i.e., homodimers) or different (i.e., heterodimers), for example:

14. The polymeric conjugated complex of claim 10 or a pharmaceutically acceptable salt thereof, comprising three bicyclic peptides, said bicyclic peptides being identical (i.e., homotrimers) or different (i.e., heterotrimers), for example wherein the heterotrimer comprises one bicyclic peptide of a first sequence and two bicyclic peptides of a second sequence, particularly:

15. The polymeric conjugated complex of claim 10 or a pharmaceutically acceptable salt thereof, comprising four bicyclic peptides, said bicyclic peptides being identical (i.e., homotetramers) or different (i.e., heterotetramers), for example, said heterotetramer comprising one bicyclic peptide of a first sequence and three bicyclic peptides of a second sequence, or said heterotetramer comprising two bicyclic peptides of the first sequence and two bicyclic peptides of the second sequence, particularly:

16. A pharmaceutical composition comprising a peptide ligand according to claim 1, or a bicyclic peptide ligand according to any one of claims 2 to 9, or a polymeric conjugate according to any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

17. The peptide ligand of claim 1, or the bicyclic peptide ligand of any one of claims 2 to 9, or the polymeric binding complex of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16, for the prevention, inhibition or treatment of diseases or conditions mediated by TLR3.

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