TLR3-linked bicyclic peptide ligands

Abstract

The present invention relates to peptide ligands capable of binding to TLR3. In particular, the present invention discloses the peptide ligand described herein, and a bicyclic peptide ligand comprising a molecular scaffold, wherein three cysteine ​​residues of the peptide ligand form covalent bonds with the molecular scaffold to form two loop sequences. The present invention also includes pharmaceutical compositions, polymer-binding complexes and drug conjugates comprising the peptide ligand, and the use of the peptide ligand in the prevention, suppression or treatment of TLR3-mediated diseases or disorders, such as autoimmune diseases, inflammatory conditions and cancer.

Description

[Technical Field]

[0001] The present invention relates to peptide ligands capable of binding to TLR3. In particular, the present invention discloses the peptide ligand described herein, and a bicyclic peptide ligand comprising a molecular scaffold, wherein three reactive groups (e.g., cysteine ​​residues) of the peptide ligand form covalent bonds with the molecular scaffold to form two loop sequences. The present invention also includes pharmaceutical compositions, polymer-binding complexes and drug conjugates comprising the peptide ligand, and the use of the peptide ligand in the prevention, suppression or treatment of TLR3-mediated diseases or disorders, such as autoimmune diseases, inflammatory conditions and cancer. [Background technology]

[0002] Cyclic peptides can bind to protein targets with high affinity and target specificity, and are therefore an attractive molecular class for therapeutic drug development. In fact, several cyclic peptides have already been successfully used in clinical settings, such as the antimicrobial peptide vancomycin, the immunosuppressant cyclosporine, or the anticancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24). Good binding properties result from the relatively large interaction surface formed between the peptide and the target, as well as the reduced conformational flexibility of the cyclic structure. Typically, macrocyclic molecules bind to a surface of several hundred square angstroms, for example, the cyclic peptide CXCR4 antagonist CVX15 (400 Å). 2 (Wu et al. (2007), Science 330, 1066-71), a cyclic peptide having an Arg-Gly-Asp motif that binds to integrin αVb3 (355Å 2 )(Xiong et al. (2002), Science 296 (5565), 151-5), or the cyclic peptide inhibitor upain-1 (603Å) that binds to urokinase-type plasminogen activator. 2There is also Zhao et al. (2007), J Struct Biol 160 (1), 1-10).

[0003] Due to their cyclic configuration, macrocyclic peptide molecules are less flexible than linear peptides, resulting in less entropy loss during binding to the target and higher binding affinity. This reduced flexibility also leads to the fixation of target-specific conformations, increasing binding specificity compared to linear peptides. This effect is exemplified by the potent and selective inhibitory effect of matrix metalloproteinase 8 (MMP-8), which loses more selectivity than other MMPs when its ring is opened (Cherney et al. (1998), J Med Chem 41 (11), 1749-51). The favorable binding properties achieved by macrocyclization are even more pronounced in polycyclic peptides with two or more peptide rings, such as vancomycin, nisin, and actinomycin.

[0004] Various research teams have previously attached polypeptides containing cysteine ​​residues to synthetic molecular structures (Kemp and McNamara (1985), J. Org. Chem; Timmerman et al. (2005), ChemBioChem). Meloen and collaborators used tris(bromomethyl)benzene and related molecules for the rapid and quantitative cyclization of multiple peptide loops onto a synthetic scaffold for structural mimicry of protein surfaces (Timmerman et al. (2005), ChemBioChem). Methods for generating candidate drug compounds, wherein the compounds are produced by attaching cysteine-containing polypeptides to a molecular scaffold such as tris(bromomethyl)benzene, are disclosed in WO2004 / 077062 and WO2006 / 078161.

[0005] Combinatorial approaches based on phage display have been developed for generating and screening large libraries of bicyclic peptides against a target of interest (Heinis et al. (2009), Nat Chem Biol 5 (7), 502-7 and WO2009 / 098450). Briefly, a combinatorial library of linear peptides comprising three cysteine residues and two regions of six random amino acids (Cys-(Xaa)6-Cys-(Xaa)6-Cys) is displayed on phage and cyclized by covalently bonding cysteine side chains to a small molecule scaffold. Summary of the Invention

[0006] According to a first aspect of the present invention, there is provided a peptide ligand, which is: 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 -X40 -YACLDC(sequence number 5); 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 (Sequence ID 6) Selected from, in the formula, X1 represents D, N, P, Y, 26 DiMeTyr, 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; X15 This 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 This represents C or dC; X 21 dE represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe, or dE; X 22 dY 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 28This represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro; X 29 This represents C, dC, or Cysam; X 30 represents P, Cis-HyP, HyP, or Pip; X 31 represents E, Q, or R; X 32 This represents P, Aze, Cis-HyP, or HyP; X 33 This represents F, Y, 2FTyr, 2Nal, 3FTyr, 4FPhe, or 4tBuPhe; X 34 represents N, S, or Dap; X 35 represents T or Dap; X 36 This 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 This 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 45represents A, H, M, Q, S, V, Y, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, or HSer; 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 X 54 represents C, dC, or Cysam, Provided is a peptide ligand or a modified derivative thereof and / or a pharmaceutically acceptable salt thereof, comprising a polypeptide having the amino acid sequence.

[0007] A further aspect of the present invention provides a bicyclic peptide ligand or a pharmaceutically acceptable salt thereof that can bind to TLR3, wherein the bicyclic peptide ligand comprises a peptide ligand (e.g., the peptide ligand described herein) comprising a polypeptide having three reactive groups, and the polypeptide is bound to a molecular scaffold.

[0008] A further aspect of the present invention provides a pharmaceutical composition comprising a peptide ligand or bicyclic peptide ligand described herein in combination with one or more pharmaceutically acceptable additives.

[0009] A further aspect of the present invention provides a polymer-binding complex comprising at least two bicyclic peptide ligands described herein, wherein the peptide ligands may be the same or different.

[0010] A further aspect of the present invention provides a drug conjugate comprising a peptide ligand, a bicyclic peptide ligand, or a polymer-binding complex described herein, conjugated to one or more effectors and / or functional groups.

[0011] A further aspect of the present invention provides peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymer-bound complexes, or drug conjugates described herein for use in preventing, suppressing, or treating TLR3-mediated diseases or disorders. [Brief explanation of the drawing]

[0012] [Figure 1] Images of monocyte-derived macrophages after incubation with selected bicyclic peptides of the present invention. [Modes for carrying out the invention]

[0013] [Definition] Unless otherwise defined herein, all terms used herein have the same meaning as those to those skilled in the art. Those skilled in the art should refer, in particular, 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 terms in the art.

[0014] In this disclosure, the term “amino acid” is used in its broadest sense and means including organic compounds containing amine (NH2) and carboxyl (COOH) functional groups, along with side chains specific to each amino acid (e.g., R group). In some embodiments, amino acids refer to naturally occurring Lα-amino acids or residues. One- and three-letter abbreviations commonly used 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, 2d ed., pp. 71-92, Worth Publishers, New York). The general term “amino acid” further includes D-amino acids, retro-inversoamino acids, and chemically modified amino acids such as amino acid analogs, naturally occurring amino acids not typically incorporated into proteins such as norleucine, and chemically synthesized compounds having properties known in the art to be characteristic of amino acids, such as β-amino acids. For example, analogs or mimetic forms of phenylalanine or proline, which restrict the conformation of peptide compounds as naturally occurring Phe or Pro, are included within the definition of an amino acid. Such analogs and mimetic forms are referred to herein as “functional equivalents” of their respective amino acids. Other examples of amino acids are listed in Roberts and Vellaccio, The Peptides: Analysis, Synthesis, Biology, Gross and Meiehofer, eds., Vol. 5 p. 341, Academic Press, Inc., NY 1983 (these are included herein by attribution). The chemical properties of 20 major amino acids are shown in Table A below. [Table 1]

[0015] The terms “polypeptide” and “peptide” / “peptide ligand” are used interchangeably herein and refer to polymers of amino acid residues as well as their variants and synthetic analogs. Thus, these terms apply to amino acid polymers, where one or more amino acid residues are synthetic or naturally occurring amino acids, such as chemical analogs of the corresponding naturally occurring amino acids, as well as naturally occurring amino acid polymers. Polypeptides may also undergo maturation or post-translational modification processes, including but not limited to glycosylation, proteolytic cleavage, lipidation, signal peptide cleavage, propeptide cleavage, and phosphorylation.

[0016] [Peptides and peptide ligands] The present invention provides peptides that can bind to TLR3. The TLR3-binding peptides described herein may include, for example, peptide ligands comprising the peptide ligand covalently bound to a molecular scaffold (e.g., a molecular scaffold as described in more detail herein) such that two or more peptide loops are formed on the molecular scaffold. A peptide ligand may be directly or indirectly bound to another peptide ligand (e.g., via a linker, spacer, or hinge portion) (i.e., two or more peptide ligands, which may be identical or different, may be bound together) to form a complex as described in more detail herein. A peptide, a peptide ligand, or a complex comprising multiple peptide ligands may be directly or indirectly bound (e.g., via a linker) to one or more effector groups and / or functional groups, such as one or more cytotoxic agents, radiochelators, or chromophores.

[0017] Accordingly, one embodiment provides a peptide ligand comprising a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1 to 366 described herein, or a modified derivative thereof, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the peptide can bind to TLR3. In some embodiments, the peptide is specific to TLR3.

[0019] (TLR3-binding peptide) Toll-like receptors (TLRs) are a family of transmembrane proteins that play important roles 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, or cluster of differentiation 283), which is known for its ability to detect double-stranded RNA (dsRNA), a common viral pathogen-associated molecular pattern.

[0020] TLR3 was first discovered in the late 1990s as a pattern recognition receptor involved in the recognition of viral infection. It is expressed in various immune cells including dendritic cells, macrophages and natural killer cells, as well as in non-immune cells such as epithelial cells.

[0021] The structure of TLR3 consists of an extracellular domain containing leucine-rich repeats (LRRs) 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 depend on the adaptor molecule MyD88 for signal transduction, but instead utilizes TIR domain-containing adaptor inducing interferon-β (TRIF), which is also known as TICAM-1.

[0022] Upon binding to dsRNA, TLR3 undergoes dimerization (Leonard et al (2008) PNAS 105(1), 258-263), resulting in the recruitment of TRIF to the TIR domain. This triggers a signaling cascade that ultimately activates transcription factors, such as interferon regulators (IRFs) and nuclear factor kappa B (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 interferons (IFNs), pro-inflammatory cytokines, and other molecules involved in antiviral defense.

[0023] TLR3 activation and subsequent production of type I interferons and pro-inflammatory cytokines contribute to the antiviral immune response. Type I interferons are important for establishing antiviral status in adjacent cells, inhibiting viral replication, and activating immune cells. Furthermore, TLR3 activation can enhance the antigen-presenting ability of dendritic cells and promote the initiation of adaptive immune responses.

[0024] TLR3s are involved in immune responses to various viral infections, including RNA viruses such as influenza, picornaviruses, and coronaviruses. Their role in antiviral defense makes TLR3s an attractive target for the development of antiviral therapies and vaccine adjuvants. Furthermore, dysregulation of TLR3 signaling is associated with autoimmune diseases and chronic inflammatory conditions.

[0025] In summary, Toll-like receptor 3 (TLR3) is an essential component of the innate immune system, recognizing viral double-stranded RNA and initiating an immune response. Its activation triggers the production of type I interferons and pro-inflammatory cytokines, promoting antiviral defense and shaping an adaptive immune response. Studying TLR3 provides valuable insights into host-viral interactions and has potential implications for developing therapeutic interventions against viral infections.

[0026] The therapeutic effect of drugs that bind to TLR3 is understood to depend on whether the binding exerts an agonist or antagonist effect. Over the past few years, numerous studies have demonstrated the efficacy of TLR3 agonists in enhancing tumor-specific immune responses in mice and patients, particularly in combination with other therapeutic approaches (Le Naour et al (2020) Oncoimmunology 9(1), 1771143). A detailed review of the association between TLRs and oncology can be found in Naour and Kroemer (2023) Oncoimmunology 12(1), 2180237.

[0027] In one embodiment, the peptide ligand is specific to TLR3 (i.e., it binds to it). The peptide ligand may be specific to a particular epitope of TLR3, for example, the soluble ectodomain of human TLR3 (i.e., it binds to it). In some embodiments, the peptide ligand is specific to the membrane-proximal C-terminus of TLR3 (i.e., it binds to it). In some embodiments, the peptide ligand is specific to the inside of the horseshoe of TLR3, in contact with one-third of the β-chains (residues 18-26) of the 27 β-chains of the LRR motif (i.e., it binds to it).

[0028] In some embodiments, the peptide ligand has the amino acid sequence: C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (Sequence number 1) The formula comprises a polypeptide 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 a modified derivative thereof and / or a pharmaceutically acceptable salt thereof. In some embodiments, each of X1 to X3 is 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 embodiments, each of X4 to X9 is 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.

[0029] In some embodiments, 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; and / or X9 represents D, F, L, 1Nal, 2Nal, 4tBuPhe, Cba, or tBuAla. In some embodiments, X1-X2-X3 is P-P-G. In some embodiments, X5 is P, and / or X6 is R. In some embodiments, X4-X5-X6-X7-X8-X9 is S-P-R-F / Y-H-L.

[0030] In some embodiments, the peptide ligand has the amino acid sequence: C-X 10 -X 11 -Y-Y-C-X 12 -Q-T-X 13 -X 14 -F-C (SEQ ID NO: 2) , wherein each of X 10 ~X 14 is independently a polypeptide selected from S, T, K, E, Q, R, V and H; or a modified derivative thereof and / or a pharmaceutically acceptable salt thereof. In some embodiments, X 10 and X 11 are each independently selected from S, T and K. In some embodiments, X 12 ~X 14 are each independently selected from E, Q, R, V and H.

[0031] In some embodiments, 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 This represents H or R.

[0032] In some embodiments, the peptide ligand has the amino acid sequence: 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 (Sequence ID 3); It has, in the formula X 16 ~X 19 and X 21 ~X 28 Each of is independently 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, Cb a, dL, tBuAla, Agb, Cit, dD, HArg, AlloIle, CF3Ala, HLeu, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, Selected from 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 is C or dC; X 20 is C or dC; and X 29This comprises a polypeptide which is C, dC, or Cystam; or a modified derivative thereof and / or a pharmaceutically acceptable salt thereof. In some embodiments, X 16 ~X 19 Each of these 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 ~X 28 Each of these 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.

[0033] In some embodiments, X 16 is a letter that 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 21dE represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe, or dE; X 22 dY represents A, R, V, Y, 26DiMeTyr, 2FTyr, 3FTyr, 3tBuTyr, 4FPhe, DOPA, or dY; X 23 is represented by 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 This 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 This represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro; X 15 This represents C or dC; X 20 represents C or dC; and X 29 represents C, dC, or Cysam. In some embodiments, X 16 -X 17 -X 18 -X 19 is a PLDL. In some embodiments, X 16 -X 17 -X 18 -X 19 This is M / CF3Nva-YRA. In some embodiments, X 22 is Y, and / or X 23 is W or 5FTrp. In some embodiments, X 21 -X 22 -X 23 -X 24 -X 25 -X26 -X 27 -X 28 This is EYW / 5FTrp-SS / VRGL. In some embodiments, X 26 is W or 1 Nal, and / or X 27 is R, and / or X 28 In some embodiments, 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.

[0034] In some embodiments, the peptide ligand has the amino acid sequence: CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C(sequence number 4) It has, in the formula X 30 ~X 37 Each of these independently comprises a polypeptide 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 a modified derivative thereof and / or a pharmaceutically acceptable salt. In some embodiments, X 30 and X 31 Each is independently selected from P, E, Q, R, Cis-HyP, HyP, and Pip. In some embodiments, X 32 ~X 37Each of these 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.

[0035] In some embodiments, 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 is represented by 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 embodiments, X 30 In some embodiments, X 30 -X 31 is PR / Q. In some embodiments, X 36 In some embodiments, X 32 -X 33 -X 34 -X 35 -X 36 -X 37 This is PF / YSTWP.

[0036] In some embodiments, the peptide ligand has the amino acid sequence: CYYX 38 -X 39 -X 40 -YACLDC(Sequence ID 5) It has, in the formula X 38 ~X 40Each of these comprises a polypeptide independently selected from E, P, D, N, W, and Y, or a modified derivative thereof and / or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, X 38 represents E or P; X 39 represents D or N; and / or X 40 This represents W or Y.

[0038] In some embodiments, the peptide ligand has the amino acid sequence: 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 (Sequence ID 6) It has, in the formula X 42 ~X 53 Each of is independently 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), 4F lPro, Cis-Hyp, HyP, trans-4FlPro, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, 2FPhe, 4CF3Phe, Cba, CF3Nv Selected from a, 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 is C or dC; X 54is a polypeptide which is C, dC or Cystam; or a modified derivative thereof and / or a pharmaceutically acceptable salt thereof. In some embodiments, X 42 ~X 49 are each 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 embodiments, X 50 ~X 53 are each 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.

[0039] In some embodiments, 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 HSer; X 46represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, or TfNle; X 47 X represents A, E, S, T, W, 1Nal, 2MeTrp, 4FTrp, 4MeTrp, 5FTrp, 5MeTrp, 6FTrp, 6MeTrp, 7FTrp, 7MeTrp, AzaTrp, CF3Ala, or Dap; X 48 is represented by K, R, Y, 2FTyr, 3FTyr, Agb, DOPA, HARg, or Orn; X 49 This 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 This 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; X 41 represents C or dC; and X 54 represents C, dC, or Cysam. In some embodiments, X 48 is Y, and / or X 49 is W and / or 5FTrp. In some embodiments, X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 This is N / DNP / EVM / ITYW / 5FTrp. In some embodiments, X 47 is W, and / or X 48 is K and / or X 49In some embodiments, X 42 -X 43 -X 44 -X 45 -X 46 -X 47 -X 48 -X 49 is T / STDM / YM / Nle-WKV. In some embodiments, X 50 -X 51 -X 52 -X 53 In some embodiments, X 50 In some embodiments, X 50 -X 51 -X 52 -X 53 It is an RTLD.

[0040] In one embodiment, the peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) is as follows: CDIACLKMYNFC(Sequence ID 7); CDIGCLRMYNFC(Sequence ID 8); CD[tBuAla]GCLRMYNFC(Sequence ID 9); CD[tBuGly]GCLRMYNFC(Sequence ID 10); CD[Cba]GCLRMYNFC(Sequence ID 11); CDI[dA]CLRMYNFC(Sequence ID 12); CDI[Aib]CLRMYNFC(Sequence ID 13); CDIGC[Cba]RMYNFC (Sequence ID 14): CDIGCL[HArg]MYNFC (Sequence ID 15): CDIGCL[Agb]MYNFC(Sequence ID 16); CDIGCLRMYN[1Nal]C(sequence ID 17); CDIGCLRMYN[2Nal]C(Sequence ID 18); CDIGCLRMYN[4tBuPhe]C(Sequence ID 19); CDIQCLRMYNFC(Sequence ID 20); CNIQCLRMYNFC(Sequence ID 21); CDIRCLRMYNFC(Sequence ID 22); CDINCLRMYNFC(Sequence ID 23); CPPGCSPRFHLC(Sequence ID 24); CPPGCSPRYHLC(Sequence ID 25; structure below: [ka] When complexed with a derivative of TATB, which has the formula where * indicates a binding site of three cysteine ​​residues, it is called BCY21542); CP[Cis-HyP]GCSPRYHLC(Sequence ID 26); CP[Aze]GCSPRYHLC(sequence number 27); CPPGCSP[HArg]YHLC(Sequence ID 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(Sequence ID 33); CPPGCSPRY[His3Me]LC(SEQ ID NO: 34); CPPGCSPRYH[tBuAla]C(sequence code 35); CPPGCSPRYH[Cba]C(Sequence ID 36); CPPGCSPRYNLC(Sequence ID 37); CYNPCLWRQVDC(SEQ ID NO: 38; structure below: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21497); CYAPCLWRQVDC(Sequence ID 39); CYNPCLWRAVDC(SEQ ID NO: 40); C[4FPhe]NPCLWRQVDC(Sequence ID 41); C[26DiMeTyr]NPCLWRQVDC(Sequence ID 42); C[3FTyr]NPCLWRQVDC(Sequence ID 43); C[2FTyr]NPCLWRQVDC(Sequence ID 44); CYN[HyP]CLWRQVDC(Sequence ID 45); CYN[Cis-HyP]CLWRQVDC(Sequence ID 46); CYN[Aze]CLWRQVDC(Sequence ID 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(Sequence ID 55); CYNPCL[Trp(Me)]RQVDC(Sequence ID 56); CYNPCLWRQ[tBuGly]DC(SEQ ID NO: 57); CYNPCLWRQ[Cbg]DC(SEQ ID NO: 58); CYNPCLWRQIDC(Sequence ID 59); CYSPCLWRQVDC(SEQ ID NO: 60); and CYTPCLWRQVDC (Sequence ID 61) Contains more selected amino acid sequences.

[0041] In one embodiment, CX 10 -X11 -YYCX 12 -QTX 13 -X 14 -The peptide ligand for FC (SEQ ID NO: 2) is as follows: CTSYYCEQTRHFC(Sequence ID 62); CTKYYCEQTRHFC(SEQ ID NO: 63); and CSKYYCQQTVRFC(Sequence ID 64) Contains more selected amino acid sequences.

[0042] One embodiment, 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 for (SEQ ID NO: 3) is as follows: CTNEVCTYWYNRGLC(Sequence ID 65); CANEVCEYWYNRGLC(Sequence ID 66); CPLDLCEYWSFRGLC(Sequence ID 67); CTNEVCRYWYNRGLC(Sequence ID 68); CDSPVCEYWSFRGLC(Sequence ID 69); CHNEVCEYWSFRGLC(Sequence ID 70); CSNEVCEYWSFRGLC(Sequence ID 71); CSNPVCEYWSFRGLC(Sequence ID 72); CNNPVCEYWSFRGLC(Sequence ID 73); CDNEVCEYWSFRGLC(Sequence ID 74); CTSEVCEYWSFRGLC(Sequence ID 75); CSTLVCQRDQLYSLC(Sequence ID 76); CHNEVCLYWYNRGLC(Sequence ID 77); CWNPVCEYWYNRGLC(Sequence ID 78); CATLQCQRDMLYGLC(Sequence ID 79); CSTLVCQRDQLYGLC(Sequence ID 80); CST[tBuAla]VCQRDQLYGLC(Sequence ID 81); CST[Cba]VCQRDQLYGLC(Sequence ID 82); CSTL[tBuAla]CQRDQLYGLC(Sequence ID 83); CSTLVCQRD[Nle]LYGLC(SEQ ID NO: 84); CSTLVCQRDQ[Cba]YGLC(SEQ ID NO: 85); CSTLVCQRDQLY[dA]LC(Sequence ID 86); CSTLVCQRDQLYG[tBuAla]C(Sequence ID 87); CSTLVCQRDQLYG[Cba]C(Sequence ID 88); CST[tBuAla]VCQRDQLY[dA]LC(Sequence ID 89); CNPLICQRDQLYGLC(Sequence ID 90); CISLACQRDQLYGLC(Sequence ID 91); CSTLECQRDQLYGLC(Sequence ID 92); CNTLVCQRDQLYGLC(Sequence ID 93); CTQLMCQRDQLYGLC(Sequence ID 94); CTELMCQRDQLYGLC(Sequence ID 95); CTE[tBuAla]MCQRDQLY[dA]LC(Sequence ID 96); CTELMCQRDQLY[dA]LC(Sequence ID 97); CTE[tBuAla]MCQRDQLYGLC(Sequence ID 98); CTELACQRDQLYGLC(Sequence ID 99); CTEL[Nle]CQRDQLYGLC(Sequence ID 100); CTEL[HLeu]CQRDQLYGLC(Sequence ID 101); CTELMCQR[Gla]QLYGLC(Sequence ID 102); CTELMCQRDQL[3FTyr]GLC(Sequence ID 103); CTELMCQRDQL[2FTyr]GLC(Sequence ID 104); CANTVCAYWETRGLC(Sequence ID 105); CANTVCAY[5FTrp]ETRGLC(sequence number 106); CPLDLCEYWSVRGLC(Sequence ID 107); CPLDLCEYWSSRGLC(Sequence ID 108); C[HyP]LDLCEYWSSRGLC(sequence number 109); CP[tBuAla]DLCEYWSSRGLC(Sequence ID 110); CP[Cba]DLCEYWSSRGLC(Sequence ID 111); CPLD[AlloIle]CEYWSSRGLC(Sequence ID 112); CPLD[tBuAla]CEYWSSRGLC(Sequence ID 113); CPLD[Cba]CEYWSSRGLC(SEQ ID NO: 114); CPLDVCEYWSSRGLC(Sequence ID 115); CPLDLCE[4FPhe]WSSRGLC(Sequence ID 116); CPLDLCEY[2Nal]SSRGLC(Sequence ID 117); CPLDLCEY[1Nal]SSRGLC(Sequence ID 118); CPLDLCEY[5FTrp]SSRGLC(Sequence ID 119); CPLDLCEY[4MeoTrp]SSRGLC(SEQ ID NO: 120); CPLDLCEY[Trp(S)]SSRGLC(Sequence ID 121); CPLDLCEYWSS[HArg]GLC(Sequence ID 122); CPLDLCEYWSS[Cit]GLC(Sequence ID 123); CPLDLCEYWSSR[dA]LC(Sequence ID 124); CPLDLCEYWSSRG[tBuAla]C(Sequence ID 125); CPLDLCEYWSSRG[Cba]C(Sequence ID 126); [dC][dP][dL][dD][dL][dC][dE][dY][dW][dS][dS][dR]G[dL][dC](Sequence ID 127); CP[Cba]DLCEY[5FTrp]SSRGLC(Sequence ID 128); CPLDLCEYW[K(PYA)]SRGLC(SEQ ID NO: 129, structure below: [ka] It has the following properties, where * indicates a binding site between three cysteine ​​residues; when complexed with a derivative of TATA, it is called BCY21632); CPLDLCEYW[K(PYA)]SRGL[Cysam](SEQ ID NO: 130, structure below: [ka] It has the following characteristics, where * indicates a binding site of three cysteine ​​residues; when complexed with a derivative of TATA, it is called BCY21637); CPLDLCEY[5FTrp]ESRGLC(Sequence ID 131); CPNDLCEY[5FTrp]SSRGLC(Sequence ID 132); CPLDLCEY[5FTrp]SSR[dA]LC(Sequence ID 133); CPLDLCEY[5FTrp]SSR[dE]LC(Sequence ID 134); CPLD[tBuAla]CEY[5FTrp]SS[HArg][dA]LC(Sequence ID 135); CP[Cba]DLCEY[5FTrp]SS[HArg][dA]LC(Sequence ID 136); CPNDLCEYWSVRGLC(Sequence ID 137); CITLQCARDMLYGLC(SEQ ID NO: 138); CSTLQCERDMLYGLC(Sequence ID 139); CISLACARDMLYGLC(SEQ ID NO: 140); CSTLQCQRDMLYGLC(Sequence ID 141); CMYRACWVAEEWRPC(sequence number 142); CMYRACYYDHEWRPC(sequence number 143); CMYRACFYDDEWRPC(sequence number 144); CMYRACAYDDEWRPC(sequence number 145); CMYRACFADDEWRPC(sequence number 146); CMYRACFYADEWRPC(sequence code 147); CMYRACFYDAEWRPC(sequence number 148); C[Nle]YRACFYDDEWRPC(sequence code 149); C[Nva]YRACFYDDEWRPC(sequence ID 150); C[TfNle]YRACFYDDEWRPC(sequence code 151); C[CF3Nva]YRACFYDDEWRPC(sequence number 152); CM[26DiMeTyr]RACFYDDEWRPC(Sequence ID 153); CMY[HArg]ACFYDDEWRPC(sequence number 154); CMY[Agb]ACFYDDEWRPC(sequence number 155); CMY[Cit]ACFYDDEWRPC(sequence number 156); CMYR[CF3Ala]CFYDDEWRPC(sequence number 157); CMYRAC[1Nal]YDDEWRPC(sequence ID 158); CMYRAC[2Nal]YDDEWRPC(sequence number 159); CMYRAC[4MePhe]YDDEWRPC(sequence ID 160); CMYRAC[3MePhe]YDDEWRPC(sequence number 161); CMYRAC[2MePhe]YDDEWRPC(sequence number 162); CMYRAC[4FPhe]YDDEWRPC(sequence number 163); CMYRAC[3FPhe]YDDEWRPC(sequence number 164); CMYRAC[2FPhe]YDDEWRPC(sequence number 165); CMYRACF[4FPhe]DDEWRPC(sequence number 166); CMYRACF[3tBuTyr]DDEWRPC(sequence number 167); CMYRACF[26DiMeTyr]DDEWRPC(sequence number 168); CMYRACF[3FTyr]DDEWRPC(sequence number 169); CMYRACF[2FTyr]DDEWRPC(sequence ID 170); CMYRACF[DOPA]DDEWRPC(sequence code 171); CMYRACFYDDE[1Nal]RPC(sequence ID 172); CMYRACFYDDE[2Nal]RPC(sequence number 173); CMYRACFYDDE[4FTrp]RPC(sequence ID 174); CMYRACFYDDE[5FTrp]RPC(sequence ID 175); CMYRACFYDDE[6FTrp]RPC(sequence number 176); CMYRACFYDDE[7FTrp]RPC(array_number_177); CMYRACFYDDE[Trp(Me)]RPC(Sequence ID 178); CMYRACFYDDE[2MeTrp]RPC(sequence number 179); CMYRACFYDDE[5MeTrp]RPC(sequence ID 180); CMYRACFYDDE[6MeTrp]RPC(sequence ID 181); CMYRACFYDDE[7MeTrp]RPC(sequence number 182); CMYRACFYDDEW[HArg]PC(sequence number 183); CMYRACFYDDEW[Agb]PC(sequence number 184); CMYRACFYDDEW[Cit]PC(sequence number 185); CMYRACFYDDEWR[HyP]C(sequence ID 186); CMYRACFYDDEWR[Aze]C(sequence number 187); CMYRACFYDDEWR[Pip]C(sequence ID 188); CMYRACFYDDEWR[44DFP]C(Sequence ID 189); CMYRACFYDDEWR[4FlPro]C(sequence ID 190); CMYRACFYDDEWR[trans-4FlPro]C(sequence ID 191); C[CF3Nva]YRACFYDDE[1Nal]RPC(Sequence ID 192); C[CF3Nva]YRAC[4MePhe]YDDE[1Nal]RPC(Sequence ID 193); CLYRACFYDDEWRPC(sequence number 194); CLYRAC[4MePhe]YDDE[1Nal]RPC(Sequence ID 195); CHYRACFYDDEWRPC (Sequence ID 196) Contains more selected amino acid sequences.

[0043] In one embodiment, CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -The peptide ligand for C (SEQ ID NO: 4) is as follows: CQPTPRCPFSTWPC (referred to herein as Sequence ID No. 197); CQPTPQCPYSTWPC (referred to herein as Sequence ID No. 198, and also with the following structure: [ka] When complexed with a derivative of TATB, which has the formula where * indicates a binding site of three cysteine ​​residues, it is called BCY20723); CQPT[HyP]QCPYSTWPC (referred to herein as Sequence ID No. 199); CQPT[Cis-HyP]QCPYSTWPC (referred to herein as Sequence ID No. 200); CQPT[Pip]QCPYSTWPC (referred to herein as Sequence ID No. 201); CQPTPECPYSTWPC (referred to herein as Sequence ID No. 202); CQPTPQC[HyP]YSTWPC (referred to herein as Sequence ID No. 203); CQPTPQC[Cis-HyP]YSTWPC (referred to herein as Sequence ID No. 204); CQPTPQC[Aze]YSTWPC (referred to herein as Sequence ID No. 205); CQPTPQCP[2Nal]STWPC (referred to herein as Sequence ID No. 206); CQPTPQCP[4tBuPhe]STWPC (referred to herein as Sequence ID No. 207); CQPTPQCP[4FPhe]STWPC (referred to herein as Sequence ID No. 208); CQPTPQCP[3FTyr]STWPC (referred to herein as Sequence ID No. 209); CQPTPQCP[2FTyr]STWPC (referred to herein as Sequence ID No. 210); CQPTPQCPY[Dap]TWPC (referred to herein as Sequence ID No. 211); CQPTPQCPYS[Dap]WPC (referred to herein as Sequence ID No. 212); CQPTPQCPYST[2Nal]PC (referred to herein as Sequence ID No. 213); CQPTPQCPYST[1Nal]PC (referred to herein as Sequence ID No. 214); CQPTPQCPYST[6FTrp]PC (referred to herein as Sequence ID No. 215); CQPTPQCPYST[5FTrp]PC (referred to herein as Sequence ID No. 216); CQPTPQCPYST[6ClTrp]PC (referred to herein as Sequence ID No. 217); CQPTPQCPYST[4MeoTrp]PC (referred to herein as Sequence ID No. 218); CQPTPQCPYST[5MeoTrp]PC (referred to herein as Sequence ID No. 219); CQPTPQCPYST[Trp(S)]PC (referred to herein as Sequence ID No. 220); CQPTPQCPYST[AzaTrp]PC (referred to herein as Sequence ID No. 221); CQPTPQCPYSTW[HyP]C (referred to herein as Sequence ID No. 222); CQPTPQCPYSTW[Cis-HyP]C (referred to herein as Sequence ID No. 223); CQPTPQCPYSTW[Aze]C (referred to herein as Sequence ID No. 224); CQPTPQCPYSTW[Pip]C (referred to herein as Sequence ID No. 225); and CQPTPECPYNTWPC (referred to herein as Sequence ID No. 226) Contains more selected amino acid sequences.

[0044] One embodiment, CYYX 38 -X 39 -X 40 -The peptide ligand for YACLDC (SEQ ID NO: 5) is as follows: CYYPDYYACLDC (referred to herein as Sequence ID No. 227); CYYENYYACLDC (referred to herein as Sequence ID No. 228); and CYYPDWYACLDC (referred to herein as Sequence ID No. 229) Contains more selected amino acid sequences.

[0045] One embodiment, 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 54The peptide ligand for (SEQ ID NO: 6) is as follows: CNNPVMTYWCTKGIC (referred to herein as Sequence ID No. 230); CNNPVMTYWCEKGIC (referred to herein as Sequence ID No. 231); CDNEVITYWCTKGIC (referred to herein as Sequence ID No. 232); CDNEV[tBuAla]TYWCTKGIC (referred to herein as Sequence ID No. 233); CDNEVFTYWCTKGIC (referred to herein as Sequence ID No. 234); CDNEV[Cba]TYWCTKGIC (referred to herein as Sequence ID No. 235); CDNEVITY[2Nal]CTKGIC (referred to herein as Sequence ID No. 236); CDNEVITY[1Nal]CTKGIC (referred to herein as Sequence ID No. 237); CDNEVITYWCT[Orn]GIC (referred to herein as Sequence ID No. 238); CDNEVITYWCT[HArg]GIC (referred to herein as Sequence ID No. 239); CDNEVITYWCTK[dA]IC (referred to herein as Sequence ID No. 240); CDNEVITYWCTKG[tBuGly]C (referred to herein as Sequence ID No. 241); CDNEVIT[DOPA]WCTKGIC (referred to herein as Sequence ID No. 242); CDNPVFTYWCTKGIC (referred to herein as Sequence ID No. 243); CNNPVMAYWCTKGIC (referred to herein as Sequence ID No. 244); CPNPVITYWCTKGIC (referred to herein as Sequence ID No. 245); CDNEVITYWCQMGVC (referred to herein as Sequence ID No. 246); CDNEVITYWCQRGVC (referred to herein as Sequence ID No. 247); CDNEVITYWCMRGIC (referred to herein as Sequence ID No. 248); CDNEVITYWCQRGIC (referred to herein as Sequence ID No. 249); CDNEVITY[6FTrp]CQRGIC (referred to herein as Sequence ID No. 250); CDNEVITY[5FTrp]CQRGIC (referred to herein as Sequence ID No. 251); CDNEVITY[5MeoTrp]CQRGIC (referred to herein as Sequence ID No. 252); CDNEVITY[Trp(S)]CQRGIC (referred to herein as Sequence ID No. 253); CDNEVITY[AzaTrp]CQRGIC (referred to herein as Sequence ID No. 254); CDNEVITYWCQ[HArg]GIC (referred to herein as Sequence ID No. 255); CDNEVITYWCQ[Cit]GIC (referred to herein as Sequence ID No. 256); CDNEVFEYWCTKGIC (referred to herein as Sequence ID No. 257); CDNEVITYWCERGIC (referred to herein as Sequence ID No. 258); CDNEVITYWCEMGIC (referred to herein as Sequence ID No. 259); CSNPVFAYWCSRQMC (referred to herein as Sequence ID No. 260); CSNPVFAYWCERGIC (referred to herein as Sequence ID No. 261, and also with the following structure: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21615); CSNPVFAYWCER[K(PYA)]IC (referred to herein as Sequence ID No. 262); CSNPVFAYWCER[dK(PYA)]IC (referred to herein as Sequence ID No. 263); CSNPVFAYWCER[S-aMeLys(PYA)]IC (referred to herein as Sequence ID No. 264); CSNPVFAYWCER[R-aMeLys(PYA)]IC (referred to herein as Sequence ID No. 265); C[K(PYA)]NPVFAYWCERGIC (referred to herein as Sequence ID No. 266); CSNPVFAY[5FTrp]CERGIC (referred to herein as Sequence ID No. 267); CSNPVFAYWCERGI[Cysam] (referred to herein as Sequence ID No. 268, and also having the following structure: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21623); C[K(PYA)]NPVFAYWCERGI[Cysam] (referred to herein as Sequence ID No. 269); CSNPVFAYWC[Dap]RGIC (referred to herein as Sequence ID No. 270); CKNPVFAYWC[PG]RGIC (referred to herein as Sequence ID No. 271); CENPVFAYWCERGIC (referred to herein as Sequence ID No. 272); C[dA]NPVFAYWCERGIC (referred to herein as Sequence ID No. 273); CGNPVFAYWCERGIC (referred to herein as Sequence ID No. 274); C[Aib]NPVFAYWCERGIC (referred to herein as Sequence ID No. 275); CSN[trans-4FlPro]VFAYWCERGIC (referred to herein as Sequence ID No. 276); CSN[4FlPro]VFAYWCERGIC (referred to herein as Sequence ID No. 277); CSN[HyP]VFAYWCERGIC (referred to herein as Sequence ID No. 278); CSN[Cis-HyP]VFAYWCERGIC (referred to herein as Sequence ID No. 279); CSNP[HSer]FAYWCERGIC (referred to herein as Sequence ID No. 280); CSNPV[2FPhe]AYWCERGIC (referred to herein as Sequence ID No. 281); CSNPV[4CF3Phe]AYWCERGIC (referred to herein as Sequence ID No. 282); CSNPVFSYWCERGIC (referred to herein as Sequence ID No. 283); CSNPVF[Dap]YWCERGIC (referred to herein as Sequence ID No. 284); CSNPVF[CF3Ala]YWCERGIC (referred to herein as Sequence ID No. 285); CSNPVFA[2FTyr]WCERGIC (referred to herein as Sequence ID No. 286); CSNPVFA[3FTyr]WCERGIC (referred to herein as Sequence ID No. 287); CSNPVFAY[4FTrp]CERGIC (referred to herein as Sequence ID No. 288); CSNPVFAYWCE[Cit]GIC (referred to herein as Sequence ID No. 289); CSNPVFAYWCER[dA]IC (referred to herein as Sequence ID No. 290); CSNPVFAYWCERG[Nva]C (referred to herein as Sequence ID No. 291); CSNPVFAYWCERG[Nle]C (referred to herein as Sequence ID No. 292); CSNPVFAYWCERG[EPA]C (referred to herein as Sequence ID No. 293); CSNPVFAYWCERG[tBuGly]C (referred to herein as Sequence ID No. 294); CSN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 295); C[Aib]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 296); C[dS]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 297); C[K(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 298); C[dK(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 299); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 300); CSN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to herein as Sequence ID No. 301); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to herein as Sequence ID No. 302); CSNPVFAYWCSRNLC (referred to herein as Sequence ID No. 303); CSNPVFAYWCSRGLC (referred to herein as Sequence ID No. 304); CTTDMMWKVCRTLDC (referred to herein as Sequence ID No. 305); CATDHMWKVCRTLDC (referred to herein as Sequence ID No. 306); CKTDAMWKVCRTLDC (referred to herein as Sequence ID No. 307); CSTDQMWKVCRTLDC (referred to herein as Sequence ID No. 308); CSTDYMWKVCRTLDC (referred to herein as Sequence ID No. 309, and also with the following structure: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY23141); CSTDY[Nle]WKVCRTLDC (referred to herein as Sequence ID No. 310); CATDYMWKVCRTLDC (referred to herein as Sequence ID No. 311); CSTDAMWKVCRTLDC (referred to herein as Sequence ID No. 312); CSTDYAWKVCRTLDC (referred to herein as Sequence ID No. 313); CSTDYMWKACRTLDC (referred to herein as Sequence ID No. 314); CSTDYMWKVCRALDC (referred to herein as Sequence ID No. 315); CSTDYMWKVCRTADC (referred to herein as Sequence ID No. 316); C[CF3Ala]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 317); C[HSer]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 318); CTTDYMWKVCRTLDC (referred to herein as Sequence ID No. 319); C[3HyV]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 320); CS[3HyV]DYMWKVCRTLDC (referred to herein as Sequence ID No. 321); C[Dap]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 322); CSTD[4FPhe]MWKVCRTLDC (referred to herein as Sequence ID No. 323); CSTD[1Nal]MWKVCRTLDC (referred to herein as Sequence ID No. 324); CSTD[2Nal]MWKVCRTLDC (referred to herein as Sequence ID No. 325); CSTD[26DiMeTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 326); CSTD[3FTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 327); CSTD[2FTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 328); CSTD[DOPA]MWKVCRTLDC (referred to herein as Sequence ID No. 329); CSTDY[Nva]WKVCRTLDC (referred to herein as Sequence ID No. 330); CSTDY[TfNle]WKVCRTLDC (referred to herein as Sequence ID No. 331); CSTDYEWKVCRTLDC (referred to herein as Sequence ID No. 332); CSTDY[CF3Nva]WKVCRTLDC (referred to herein as Sequence ID No. 333); CSTDYM[1Nal]KVCRTLDC (referred to herein as Sequence ID No. 334); CSTDYM[4FTrp]KVCRTLDC (referred to herein as Sequence ID No. 335); CSTDYM[5FTrp]KVCRTLDC (referred to herein as Sequence ID No. 336); CSTDYM[6FTrp]KVCRTLDC (referred to herein as Sequence ID No. 337); CSTDYM[7FTrp]KVCRTLDC (referred to herein as Sequence ID No. 338); CSTDYM[2MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 339); CSTDYM[4MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 340); CSTDYM[5MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 341); CSTDYM[6MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 342); CSTDYM[7MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 343); CSTDYM[AzaTrp]KVCRTLDC (referred to herein as Sequence ID No. 344); CSTDYMW[HArg]VCRTLDC (referred to herein as Sequence ID No. 345); CSTDYMW[Orn]VCRTLDC (referred to herein as Sequence ID No. 346); CSTDYMW[Agb]VCRTLDC (referred to herein as Sequence ID No. 347); CSTDYMWK[tBuGly]CRTLDC (referred to herein as Sequence ID No. 348); CSTDYMWK[Cbg]CRTLDC (referred to herein as Sequence ID No. 349); CSTDYMWK[C5g]CRTLDC (referred to herein as Sequence ID No. 350); CSTDYMWK[3HyV]CRTLDC (referred to herein as Sequence ID No. 351); CSTDYMWKVC[HArg]TLDC (referred to herein as Sequence ID No. 352); CSTDYMWKVC[Arg(Me)]TLDC (referred to herein as Sequence ID No. 353); CSTDYMWKVCR[3HyV]LDC (referred to herein as Sequence ID No. 354); CSTDYMWKVCRT[tBuAla]DC (referred to herein as Sequence ID No. 355); CSTDYMWKVCRT[Cba]DC (referred to herein as Sequence ID No. 356); CSTDYMWKVCRT[Nva]DC (referred to herein as Sequence ID No. 357); CSTDYMWKVCRT[Nle]DC (referred to herein as Sequence ID No. 358); CTTDMAWRDCRTLDC (referred to herein as Sequence ID No. 359); CTTDMAWRLCRTLDC (referred to herein as Sequence ID No. 360); CTTDMVWKVCRTLDC (referred to herein as Sequence ID No. 361); CVTDYMWKVCRTLDC (referred to herein as Sequence ID No. 362); CYTDSMWKVCRTLDC (referred to herein as Sequence ID No. 363); CTTDMMWKVCREPDC (referred to herein as Sequence ID No. 364); CTTDMMWKVCRSMDC (referred to herein as Sequence ID No. 365); and CTTDMMWKVCRTLDC (referred to herein as Sequence ID No. 366) Contains more selected amino acid sequences.

[0046] In some embodiments, the N-terminus of a polypeptide containing the above amino acid sequence, or a modified derivative thereof, or a salt thereof is elongated. In some embodiments, the N-terminus of the polypeptide is elongated with one or more (e.g., 1 to about 20, e.g., 1 to about 10, or 1 to about 5, e.g., 1, 2, 3, 4, or 5) further amino acids or their analogues. In some embodiments, the C-terminus of the polypeptide is elongated. In some embodiments, the C-terminus of the polypeptide is elongated with one or more (e.g., 1 to about 20, e.g., 1 to about 10, or 1 to about 5, e.g., 1, 2, 3, 4, or 5) further amino acids or their analogues. In some embodiments, both the N-terminus and C-terminus of the polypeptide are elongated. In some embodiments, both the N-terminus and C-terminus of the polypeptide are elongated with one or more (e.g., 1 to about 20, or 1 to about 10, e.g., 1 to about 5, e.g., 1, 2, 3, 4, or 5) further amino acids or their analogues.

[0047] In some embodiments, the N and / or C-terminus of the polypeptide is modified. Examples of N-terminal modification include peptide elongation by one or more amino acids or amino acid analogs, such as alanine (A) or its variants (e.g., dA), lysine (K) or its variants, guanidinoacetic acid (GuanAc), pentic acid (PYA), N-terminal acetylation (represented as Ac), or N-terminal carboxymidamidation (represented as CIA), where the N-terminal amide of the peptide is modified with a -C(=N)NH2 group to form a guanidine group. In some embodiments, the N-terminus of the polypeptide is modified by elongation with 1 to 10 amino acids, such as 1 to 5 amino acids or 3 to 5 amino acids. The amino acids may be native amino acids. In some embodiments, the N-terminus of the polypeptide is modified by elongation with an amino acid sequence selected from TVKTP, YYYEW, MRQ, EHM, EPKRQ, ANYAN, FSFHQ, AHGG, AIKP, ADST, ALNG, ALEQN, AHAGT, VNENI, and TNEGI.

[0048] Examples of C-terminal modifications include peptide elongation by 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. Another example of C-terminal modification is amidation; i.e., conversion of the C-terminal carboxylic acid group (-C(O)OH or -C(O)O - (from to amide-C(O)NH2). In some embodiments, the C-terminus of the peptide is amidated. In some embodiments, the C-terminus of the polypeptide is modified by elongation with a sequence of 1 to 10 amino acids, e.g., 1 to 8 amino acids, 1 to 6 amino acids, or 3 to 6 amino acids. The amino acids may be native amino acids. In some embodiments, the C-terminus of the polypeptide is modified by elongation with 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.

[0049] Examples of lysine variants are K(Ac) [wherein Ac represents acetyl] and KFl [wherein Fl represents fluorescein]. Another example of a lysine variant is K(PYA) or dK(PYA) [wherein PYA represents pentic acid (e.g., 4-pentic acid)]. In some embodiments, K(PYA) has the following structure (e.g., before binding to a linker, e.g., an azide group contained in the linker): [ka]

[0050] In one embodiment, the polypeptide further comprises an N-terminal addition of an alanine residue or Ac, and a C-terminal addition of an alanine residue and / or K(PYA). In one embodiment, the polypeptide further comprises an N-terminal addition of an alanine residue, and a C-terminal addition of an alanine residue and / or K(PYA) (e.g., C-terminal addition-A-[K(PYA)]). In one embodiment, the polypeptide further comprises an N-terminal addition of an alanine residue, and a C-terminal addition of an alanine residue. Typically, the C-terminus is amidated.

[0051] In one embodiment, the peptide ligand further comprises N and / or C-terminal additions, and as follows: A-(Sequence code 7)-A-[Sar6]-[KFl]; A-(Sequence No. 7)-A; A-(Sequence ID 8)-A; A-(Sequence ID 8)-A-[K(PYA)]; A-(Sequence ID 9)-A; A - (Sequence ID 10) - A; A-(Sequence ID 11)-A; A - (Sequence ID 12) - A; A-(Sequence ID 13)-A; A - (Sequence ID 14) - A); A - (Sequence No. 15) - A); A - (Sequence ID 16) - A; A-(Sequence No. 17)-A; A-(Sequence ID 18)-A; A-(Sequence ID 19)-A; A-(Sequence ID 20)-A; A-(Sequence ID 21)-A; A-(Sequence ID 22)-A; A-(Sequence No. 23)-A; A-(Sequence ID 24)-A; A-(Sequence ID 25)-A; A-(Sequence ID 25)-A-[K(PYA)]; A - (Sequence ID 25); Ac-A-(Sequence No. 25); (Sequence ID 25)-A; Ac-(Sequence ID 25)-A; Ac-(sequence number 25); Ac-A-(Sequence ID 25)-A; A-(Sequence No. 25)-DKTTV; TVKTP-(Sequence ID 25)-A; A-(Sequence ID 25)-DIHNN; A-(Sequence ID 26)-A; A-(Sequence No. 27)-A; A-(Sequence No. 28)-A; A-(Sequence ID 29)-A; A-(Sequence ID 30)-A; A-(Sequence ID 31)-A; A-(Sequence ID 32)-A; A-(Sequence No. 33)-A; A-(Sequence ID 34)-A; A-(Sequence ID 35)-A; A-(Sequence No. 36)-A; A-(Sequence No. 37)-A; A-(Sequence ID 38)-A; A-(Sequence ID 38)-A-[K(PYA)]; A - (Sequence number 38); (Sequence ID 38)-A; Ac-(sequence number 38); YYYEW-(Sequence ID 38)-A; A-(Sequence ID 39)-A; A-(Sequence ID 40)-A; A-(Sequence ID 41)-A; A-(Sequence ID 42)-A; A-(Sequence No. 43)-A; A-(Sequence ID 44)-A; A-(Sequence No. 45)-A; A-(Sequence ID 46)-A; A-(Sequence No. 47)-A; A-(Sequence ID 48)-A; A-(Sequence ID 49)-A; A-(Sequence No. 50)-A; A-(Sequence No. 51)-A; A-(Sequence ID 52)-A; A-(Sequence No. 53)-A; A-(Sequence ID 54)-A; A-(Sequence No. 55)-A; A-(Sequence ID 56)-A; A-(Sequence No. 57)-A; A-(Sequence ID 58)-A; A-(Sequence ID 59)-A; A-(Sequence ID 59)-VYNVN; A-(Sequence ID 60)-A; A-(Sequence ID 61)-A; A-(Sequence ID 62)-A; A-(Sequence No. 63)-A; A-(Sequence ID 63)-A-[K(PYA)]; A-(Sequence ID 64)-A; A-(Sequence ID 65)-A; A-(Sequence code 65)-A-[Sar6][KFl]; Ac-(Sequence ID 66)-A-[K(PYA)]; Ac-(Sequence ID 66)-[K(PYA)]; A-(Sequence ID 66)-A-[K(PYA)]; A-(Sequence No. 67)-A; A-(Sequence ID 68)-A; A-(Sequence ID 69)-A; A-(Sequence ID 70)-A; A-(Sequence ID 71)-A; A-(Sequence ID 72)-A; A-(Sequence ID 73)-A; A-(Sequence ID 74)-A; A-(Sequence ID 75)-A; A-(Sequence ID 76)-A; A-(Sequence code 76)-A-[Sar6]-[KFl]; A-(Sequence ID 76)-A-[K(PYA)]; A-(Sequence No. 77)-A; A-(Sequence ID 78)-A; A-(Sequence ID 79)-A; A-(Sequence ID 80)-A; A-(Sequence ID 80)-A-[Sar6]-[KFl]; Ac-(Sequence ID 80); A-(Sequence ID 80)-A-[Sar6]-[K(Ac)]; A-(Sequence ID 80)-AGAAAE; A-(Sequence ID 81)-A; A - (Sequence ID 82) - A); A-(Sequence ID 83)-A; A-(Sequence ID 84)-A; A-(Sequence ID 85)-A; A-(Sequence ID 86)-A; A-(Sequence No. 87)-A; A-(Sequence ID 88)-A; Ac-(sequence number 89); A - (Sequence ID 90) - A); A-(Sequence ID 91)-A; A-(Sequence code 91)-A-[Sar6]-[KFl]; A-(Sequence ID 92)-A; A-(Sequence ID 93)-A; A-(Sequence ID 94)-A; A-(Sequence ID 95)-A; A-(Sequence ID 95)-A-[Sar6]-[KFl]; A-(Sequence ID 95)-A-[K(PYA)]; Ac-(sequence number 95); A-(Sequence ID 96)-A; Ac-(sequence number 96); Ac-(sequence number 97); Ac-(sequence number 98); Ac-(sequence number 99); Ac-(sequence number 100); Ac-(sequence number 101); Ac-(sequence number 102); Ac-(sequence number 103); Ac-(sequence number 104); A-(Sequence No. 105)-A; A-(Sequence ID 105)-A-[K(PYA)]; A-(Sequence ID 106)-A-[K(PYA)]; A-(Sequence ID 107)-A; A-(Sequence ID 107)-A-[Sar6]-[KFl]; A-(Sequence ID 108)-A; A-(Sequence ID 108)-A-[K(PYA)]; Ac-(Sequence ID 108)-[K(PYA)]; Ac-A-(Sequence ID 108)-A-[K(PYA)]; A-(Sequence ID 108)-A-[Sar6]-[(K(Ac)]; A-(Sequence ID 108)-AGAAAE; A-(Sequence ID 108)-KMTHE; A-(Sequence ID 108)-NDSLN; A-(Sequence ID 108)-SVNAN; A-(Sequence ID 108)-QGHTPL; A-(Sequence ID 108)-EMEHSN; MRQ-(Sequence ID 108)-ETP; EHM-(SEQ ID NO: 108)-TQS; EPKRQ-(Sequence ID 108)-A; ANYAN-(Sequence ID 108)-A; DSFHQ-(Sequence ID 108)-A; MRQ-(Sequence ID 108)-ETP-[K(PYA)]; EPKRQ-(Sequence ID 108)-A-[K(PYA)]; Ac-(Sequence ID 108)-A-[K(PYA)]; Ac-(Sequence ID 108)-E-[K(PYA)]; A-(Sequence ID 108)-E-[K(PYA)]; A-(Sequence ID 109)-A-[K(PYA)]; A-(Sequence ID 110)-A-[K(PYA)]; A-(Sequence ID 111)-A-[K(PYA)]; A-(Sequence ID 112)-A-[K(PYA)]; A-(Sequence ID 113)-A-[K(PYA)]; A-(Sequence ID 114)-A-[K(PYA)]; A-(Sequence ID 115)-A-[K(PYA)]; A-(Sequence ID 116)-A-[K(PYA)]; A-(Sequence ID 117)-A; A-(Sequence ID 117)-A-[K(PYA)]; Ac-(Sequence ID 117)-[K(PYA)]; A-(Sequence ID 118)-A-[K(PYA)]; A-(Sequence ID 119)-A-[K(PYA)]; MRQ-(Sequence ID 119)-ETP-[K(PYA)]; EPKRQ-(Sequence ID 119)-A-[K(PYA)]; MRQ-(Sequence ID 119)-ETP; EPKRQ-(Sequence ID 119)-A; Ac-(Sequence ID 119)-[K(PYA)]; A-(Sequence ID 120)-A-[K(PYA)]; A-(Sequence ID 121)-A-[K(PYA)]; A-(Sequence ID 122)-A-[K(PYA)]; A-(Sequence ID 123)-A-[K(PYA)]; A-(Sequence ID 124)-A-[K(PYA)]; A-(Sequence ID 125)-A-[K(PYA)]; A-(Sequence ID 126)-A-[K(PYA)]; [dA]-(Sequence ID 127)-[dA]-[K(PYA)]; A-(Sequence ID 128)-A-[K(PYA)]; A-(Sequence ID 129)-A; A - (Sequence ID 129); Ac-(sequence number 129); A - (Sequence ID 130); Ac-(sequence number 130); Ac-(Sequence ID 131)-[K(PYA)]; Ac-(Sequence ID 132)-[K(PYA)]; Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl]; Ac-(Sequence ID 133)-[K(PYA)]; Ac-(Sequence ID 134)-[K(PYA)]; Ac-(Sequence ID 135)-[K(PYA)]; Ac-(Sequence ID 136)-[K(PYA)]; Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl]; A-(Sequence ID 137)-A; A-(Sequence ID 138)-A; A-(Sequence ID 138)-A-[Sar6]-[KFl]; A-(Sequence ID 138)-A-[K(PYA)]; A-(Sequence ID 139)-A; A-(Sequence ID 139)-A-[Sar6]-[KFl]; A-(Sequence ID 140)-A; A-(Sequence ID 141)-A; A-(Sequence code 141)-A-[Sar6]-[KFl]; A-(Sequence ID 142)-A; A-(Sequence ID 143)-A; A-(Sequence ID 143)-A-[K(PYA)]; A-(Sequence ID 144)-A; A-(Sequence ID 144)-A-[K(PYA)]; Ac-A-(SEQ ID NO: 144)-A; Ac-(sequence number 144); A - (Sequence ID 144); Ac-A-(sequence number 144); (Sequence ID 144)-A; Ac-(Sequence ID 144)-A; AHGG-(Sequence ID 144)-EVHA; AIKP-(Sequence ID 144)-QHEA; ADST-(SEQ ID NO: 144)-QHPA; ALNG-(SEQ ID NO: 144)-PLSA; ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)]; A-(Sequence ID 145)-A; A-(Sequence ID 146)-A; A-(Sequence ID 147)-A; A-(Sequence ID 148)-A; A-(Sequence ID 149)-A; A-(Sequence ID 150)-A; A-(Sequence ID 151)-A; A-(Sequence ID 152)-A; A-(Sequence ID 153)-A; A-(Sequence ID 154)-A; A-(Sequence ID 155)-A; A - (Sequence ID 156) - A; A-(Sequence ID 157)-A; A-(Sequence ID 158)-A; A-(Sequence ID 159)-A; A-(Sequence ID 160)-A; A - (Sequence ID 161) - A; A-(Sequence ID 162)-A; A-(Sequence ID 163)-A; A-(Sequence ID 164)-A; A-(Sequence ID 165)-A; A-(Sequence ID 166)-A; A-(Sequence ID 167)-A; A-(Sequence ID 168)-A; A-(Sequence ID 169)-A; A-(Sequence ID 170)-A; A-(Sequence ID 171)-A; A-(Sequence ID 172)-A; A-(Sequence ID 173)-A; A-(Sequence ID 174)-A; A-(Sequence ID 175)-A; A-(Sequence ID 176)-A; A-(Sequence ID 177)-A; A-(Sequence ID 178)-A; A-(Sequence ID 179)-A; A-(Sequence ID 180)-A; A-(Sequence ID 181)-A; A-(Sequence ID 182)-A; A-(Sequence ID 183)-A; A-(Sequence ID 184)-A; A-(Sequence ID 185)-A; A-(Sequence ID 186)-A; A-(Sequence ID 187)-A; A-(Sequence ID 188)-A; A-(Sequence ID 189)-A; A-(Sequence ID 190)-A; A-(Sequence ID 191)-A; ALNG-(SEQ ID NO: 192)-PLSA; ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)]; ALNG-(SEQ ID NO: 193)-PLSA; ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)]; ALEQN-(Sequence ID 194)-A; ALEQN-(Sequence ID 194)-A-[K(PYA)]; ALEQN-(SEQ ID NO: 195)-A; ALEQN-(SEQ ID NO: 195)-A-[K(PYA)]; and AHAGT-(SEQ ID NO: 196)-A; A-(Sequence ID 197)-A; A-(Sequence ID 197)-A-[K(PYA)]; A-(Sequence ID 197)-A-[Sar6]-[K(Ac)]; A-(Sequence ID 198)-A; Ac-A-(SEQ ID NO: 198)-A; A-(Sequence ID 198)-NLNLK; VNENI-(Sequence ID 198)-A; A-(SEQ ID NO: 198)-RNPHD; A-(Sequence ID 198)-IHNNG; TNEGI-(SEQ ID NO: 198)-A; VNENI-(Sequence ID 198)-A-[K(PYA)]; A-(Sequence ID 199)-A; A-(Sequence ID 200)-A; A-(Sequence ID 201)-A; A-(Sequence ID 202)-A; A-(Sequence ID 203)-A; A-(Sequence ID 204)-A; A-(Sequence ID 205)-A; A-(Sequence ID 206)-A; A-(Sequence ID 207)-A; A-(Sequence ID 208)-A; A-(Sequence ID 209)-A; A-(Sequence ID 210)-A; A-(Sequence ID 211)-A; A-(Sequence ID 212)-A; A-(Sequence ID 213)-A; A-(Sequence ID 214)-A; A-(Sequence ID 215)-A; A-(Sequence ID 216)-A; A-(Sequence ID 217)-A; A-(Sequence ID 218)-A; A-(Sequence ID 219)-A; A-(Sequence ID 220)-A; A-(Sequence ID 221)-A; A-(Sequence ID 222)-A; A-(Sequence ID 223)-A; A-(Sequence ID 224)-A; A-(Sequence ID 225)-A; A-(Sequence ID 226)-A; and A-(Sequence ID 226)-A-[K(PYA)]; A-(Sequence ID 227)-A; A-(Sequence ID 228)-A; A-(Sequence ID 229)-A; and A-(Sequence ID 229)-A-[K(PYA)]; A-(Sequence ID 230)-A; A-(Sequence ID 230)-A-[Sar6]-[KFl]; A-(Sequence ID 231)-A; A-(Sequence ID 232)-A; A-(Sequence ID 232)-A-[Sar6]-[KFl]; A-(Sequence ID 232)-A-[Sar6]-[K(Ac)]; A-(Sequence ID 232)-AGAAAE; A-(Sequence ID 233)-A; A-(Sequence ID 234)-A; A-(Sequence ID 235)-A; A-(Sequence ID 236)-A; A-(Sequence ID 237)-A; A-(Sequence ID 238)-A; A-(Sequence ID 239)-A; A-(Sequence ID 240)-A; A-(Sequence ID 241)-A; A-(Sequence ID 242)-A; A-(Sequence ID 243)-A; A-(Sequence ID 244)-A; A-(Sequence ID 245)-A; A-(Sequence ID 246)-A; A - (Sequence ID 247) - A); A-(Sequence ID 248)-A; A-(Sequence ID 249)-A; A-(Sequence code 249)-A-[Sar6]-[KFl]; Ac-A-(SEQ ID NO: 249)-A; A-(Sequence ID 250)-A; A-(Sequence ID 251)-A; A-(Sequence ID 251)-A-[K(PYA)]; A-(Sequence ID 252)-A; A-(Sequence ID 253)-A; A-(Sequence ID 254)-A; A-(Sequence ID 255)-A; A-(Sequence ID 256)-A; A-(Sequence ID 257)-A; A-(Sequence ID 258)-A; A-(Sequence ID 258)-A-[Sar6]-[KFl]; A-(Sequence ID 258)-A-[K(PYA)]; Ac-A-(SEQ ID NO: 258)-A; A-(Sequence ID 259)-A; A-(Sequence ID 260)-A; A-(Sequence ID 260)-A-[K(PYA)]; A-(Sequence ID 261)-A; A-(Sequence ID 261)-A-[K(PYA)]; [PYA]-A-(Sequence ID 261)-A; Ac-(sequence number 261); A - (Sequence ID 261); Ac-A-(Sequence ID 261); [PYA]-(Sequence ID 261); [GuanAc]-(SEQ ID NO: 261)-A; A-(Sequence ID 261)-[CF3Ala]; A-(Sequence ID 261)-S; A-(Sequence ID 262)-A; A-(Sequence ID 263)-A; A-(Sequence ID 264)-A; A-(Sequence ID 265)-A; A-(Sequence ID 266)-A; A - (Sequence ID 266); A-(Sequence ID 267)-A; A-(Sequence ID 267)-A-[K(PYA)]; Ac-(Sequence No. 268); A - (Sequence ID 268); [PYA]-(Sequence ID 268); A - (Sequence ID 269); Ac-(Sequence ID 270); Ac-(sequence number 271); A-(Sequence ID 272)-A; A-(Sequence ID 273)-A; A-(Sequence ID 274)-A; A-(Sequence ID 275)-A; A-(Sequence ID 276)-A; A-(Sequence ID 277)-A; A-(Sequence ID 278)-A; A-(Sequence ID 279)-A; A-(Sequence ID 280)-A; A-(Sequence ID 281)-A; A-(Sequence ID 282)-A; A-(Sequence ID 283)-A; A-(Sequence ID 284)-A; A-(Sequence ID 285)-A; A-(Sequence ID 286)-A; A-(Sequence No. 287)-A; A-(Sequence ID 288)-A; A-(Sequence ID 289)-A; A-(Sequence ID 290)-A; A-(Sequence ID 291)-A; A-(Sequence ID 292)-A; A-(Sequence ID 293)-A; A-(Sequence ID 294)-A; [GuanAc]-(SEQ ID NO: 295)-COOH; [GuanAc]-(Sequence ID 295); [CIA]-[K(PYA)]-(Sequence ID 295)-A; [CIA]-[dK(PYA)]-(Sequence ID 295)-A; [GuanAc]-(Sequence ID 296); [GuanAc]-(Sequence ID 297); [GuanAc]-(Sequence ID 298); [GuanAc]-(Sequence ID 299); [GuanAc]-(Sequence ID 300); [GuanAc]-(Sequence ID 301); [GuanAc]-(Sequence ID 302); A-(Sequence ID 303)-A; A-(Sequence ID 304)-A; A-(Sequence ID 305)-A-[K(PYA)]; A-(Sequence ID 306)-A; A-(Sequence ID 307)-A; A-(Sequence ID 308)-A; A-(Sequence ID 309)-A; A-(Sequence ID 309)-A-[K(PYA)]; Ac-(sequence number 309); Ac-A-(SEQ ID NO: 309)-A; [dA]-(Sequence ID 309)-A; A - (Sequence ID 309); Ac-A-(sequence number 309); (Sequence ID 309)-A; Ac-(SEQ ID NO: 309)-A; A-(Sequence ID 309)-A-[dK(PYA)]; A-(Sequence ID 309)-[K(PYA)]; A-(Sequence ID 309)-[dK(PYA)]; A-(Sequence ID 310)-A; A-(Sequence ID 310)-A-[K(PYA)]; A-(Sequence ID 311)-A; A-(Sequence ID 312)-A; A-(Sequence ID 313)-A; A-(Sequence ID 314)-A; A-(Sequence ID 315)-A; A-(Sequence ID 316)-A; A-(Sequence ID 317)-A; A-(Sequence ID 318)-A; A-(Sequence ID 319)-A; A-(Sequence ID 320)-A; A-(Sequence ID 321)-A; A-(Sequence ID 322)-A; A-(Sequence ID 323)-A; A-(Sequence ID 324)-A; A-(Sequence ID 325)-A; A-(Sequence ID 326)-A; A-(Sequence ID 327)-A; A-(Sequence ID 328)-A; A-(Sequence ID 329)-A; A-(Sequence ID 330)-A; A-(Sequence ID 331)-A; A-(Sequence ID 332)-A; A-(Sequence ID 333)-A; A-(Sequence ID 334)-A; A-(Sequence ID 335)-A; A-(Sequence No. 336)-A; A-(Sequence ID 337)-A; A-(Sequence ID 338)-A; A-(Sequence ID 339)-A; A-(Sequence ID 340)-A; A-(Sequence ID 341)-A; A-(Sequence ID 342)-A; A-(Sequence ID 343)-A; A-(Sequence ID 344)-A; A-(Sequence ID 345)-A; A-(Sequence ID 346)-A; A-(Sequence ID 347)-A; A-(Sequence ID 348)-A; A-(Sequence ID 349)-A; A-(Sequence ID 350)-A; A-(Sequence ID 351)-A; A-(Sequence ID 352)-A; A-(Sequence ID 353)-A; A-(Sequence ID 354)-A; A-(Sequence ID 355)-A; A-(Sequence ID 356)-A; A-(Sequence ID 357)-A; A-(Sequence ID 358)-A; A-(Sequence ID 359)-A; A-(Sequence ID 360)-A; A-(Sequence ID 361)-A; A-(Sequence ID 362)-A; A-(Sequence ID 363)-A; A-(Sequence ID 364)-A; A-(Sequence ID 365)-A; and A-(Sequence No. 366)-A Contains more selected amino acid sequences.

[0052] In some embodiments, the peptide ligands described herein include peptides described herein bound to a molecular scaffold. The molecular scaffold can be any molecular scaffold described in more detail herein. In some embodiments, the molecular scaffold is bound to one or more reactive groups in the peptide. In some embodiments, the molecular scaffold is bound to one or more reactive groups in the peptide, for example, one or more cysteine ​​or cysteamine groups (for example, to thiol groups contained in cysteine ​​or cysteamine side chains). In some embodiments, the peptide contains three cysteine ​​residues (L-cysteine ​​and / or D-cysteine), and the molecular scaffold is bound to the three cysteine ​​groups.

[0053] An example of a molecule suitable for use as a molecular scaffold in the peptide ligands and complexes containing them described herein is TATA (1,3,5-triacryloylhexahydro-1,3,5-triazine, available from Sigma Aldrich). TATA has the following structure: [ka] It has the following. In some embodiments, TATA reacts with the cysteinyl-thiol group of the peptide described herein to: [ka] As shown in the formula, each Cys-S represents a cysteine ​​residue (e.g., L-cysteine ​​or D-cysteine) or a cysteamine residue, forming a peptide ligand that includes a scaffold which is a derivative of TATA.

[0054] Therefore, in one embodiment, the molecular scaffold has the following structure: [ka] It has, and also, [ka] It can be represented as a derivative of TATA, where * indicates a binding site of three (e.g.) cysteine ​​residues.

[0055] In another embodiment, the molecular scaffold is 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine (TATB): [ka] TATB.

[0056] Therefore, after cyclization with the bicyclic peptide of the present invention on a cysteine ​​residue (for example), the molecular scaffold has the following structure: [ka] It has, and also, [ka] This can be represented as forming a tri-substituted 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine derivative of TATB, where * indicates a binding site of three cysteine ​​residues.

[0057] In another embodiment, the molecular scaffold is 2,4,6-tris(bromomethyl)-s-triazine (TBMT): [ka] TBMT.

[0058] Therefore, C i , C ii and C iii After cyclization with the bicyclic peptide of the present invention on a cysteine ​​residue, the molecular scaffold has the following structure: [ka] It has, and also, [ka] This can be represented as forming a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, where * indicates a binding site of (for example) three cysteine ​​residues.

[0059] In another embodiment, the molecular scaffold is 2,4,6-tris(chloromethyl)-1,3,5-triazine (TCTZ): [ka] TCTZ.

[0060] Therefore, C i , C ii and C iii After cyclization with the bicyclic peptide of the present invention on a cysteine ​​residue, the molecular scaffold has the following structure: [ka] It has the following properties, where * indicates a binding site for (for example) three cysteine ​​residues, forming a tri-substituted 2,4,6-tris(chloromethyl)-s-triazine derivative of TCTZ.

[0061] After cyclization of the bicyclic peptide of the present invention with either TBMT or TCTZ, derivatives of TBMT and TCTZ that form a molecular scaffold are understood to have the same structure as described above. Therefore, when a molecular scaffold that is a derivative of TBMT is referred to herein, the molecular scaffold may also be a derivative of TCTZ.

[0062] Therefore, according to a further aspect of the present invention, a bicyclic peptide ligand or a pharmaceutically acceptable salt thereof that can bind to TLR3 is provided, wherein the bicyclic peptide ligand comprises a peptide ligand comprising a polypeptide having three reactive groups, and the polypeptide is bound to a molecular scaffold. According to a further aspect of the present invention, a bicyclic peptide ligand that can bind to TLR3 is provided, comprising the peptide ligand and molecular scaffold described herein, 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 loop sequences.

[0063] In one embodiment, a bicyclic peptide ligand is provided comprising the peptide of SEQ ID NO: 1, or optionally a modified derivative thereof with extensions at the N and / or C terminus, or a pharmaceutically acceptable salt thereof, conjugated to a molecular scaffold which is a derivative of TATA, TATB, TBMT, or TCTZ as described herein, at each of the three reactive groups described herein (e.g., at each of the three cysteine ​​residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 7 to 61. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 7 to 23, and the molecular scaffold is a derivative of TATA as described herein. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 24 to 37, and the molecular scaffold is a derivative of TATB as described herein. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 38 to 61, and the molecular scaffold is a derivative of TBMT or TCTZ as described herein.

[0064] In one embodiment, a bicyclic peptide ligand is provided comprising the peptide of SEQ ID NO: 2, or optionally a modified derivative thereof with extensions at the N and / or C terminus, or a pharmaceutically acceptable salt thereof, which is bound to a molecular scaffold that is a derivative of TBMT or TCTZ as described herein, at each of the three reactive groups described herein (e.g., at each of the three cysteine ​​residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 62-64.

[0065] In one embodiment, a bicyclic peptide ligand is provided comprising the peptide of SEQ ID NO: 3, or optionally a modified derivative thereof with extensions at the N and / or C terminus, or a pharmaceutically acceptable salt thereof, conjugated to a molecular scaffold which is a derivative of TATA or TATB as described herein, at each of the three reactive groups described herein (e.g., at each of the three cysteine / cysteamine residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 65-196. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 65-141, and the molecular scaffold is a derivative of TATA as described herein. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 142-196, and the molecular scaffold is a derivative of TATB as described herein.

[0066] In one embodiment, a bicyclic peptide ligand is provided comprising the peptide of SEQ ID NO: 4, or optionally a modified derivative thereof with extensions at the N and / or C terminus, or a pharmaceutically acceptable salt thereof, conjugated to a molecular scaffold which is a derivative of TATB as described herein, at each of the three reactive groups described herein (e.g., at each of the three cysteine ​​residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 197-226.

[0067] In one embodiment, a bicyclic peptide ligand is provided comprising the peptide of SEQ ID NO: 5, or optionally a modified derivative thereof with extensions at the N and / or C terminus, or a pharmaceutically acceptable salt thereof, which is bound to a molecular scaffold that is a derivative of TBMT or TCTZ as described herein, at each of the three reactive groups described herein (e.g., at each of the three cysteine ​​residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 227-229.

[0068] In one embodiment, a bicyclic peptide ligand is provided comprising the peptide of SEQ ID NO: 6, or optionally a modified derivative thereof with extensions at the N and / or C terminus, or a pharmaceutically acceptable salt thereof, conjugated to a molecular scaffold which is a derivative of TATA, TBMT, or TCTZ as described herein, at each of the three reactive groups described herein (e.g., at each of the three cysteine / cysteamine residues (e.g., L-cysteine ​​or D-cysteine)). In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 230-366. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 230-259, and the molecular scaffold is a derivative of TATA as described herein. In one embodiment, the bicyclic peptide comprises the peptide sequences of SEQ ID NOs: 260-366, and the molecular scaffold is a derivative of TBMT or TCTZ as described herein.

[0069] In a further embodiment, the molecular scaffold has the following structure: [ka] A derivative of TATA having the formula where * indicates a binding site of three cysteine ​​residues, the peptide ligand C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) further includes N and / or C-terminal additions, and below: A-(Sequence ID 7)-A-[Sar6]-[KFl](referred to herein as BCY15200); A-(Sequence ID 7)-A (referred to herein as BCY15212); A-(Sequence ID 8)-A (referred to herein as BCY15747); A-(Sequence ID 8)-A-[K(PYA)] (referred to herein as BCY19281); A-(Sequence ID 9)-A (referred to herein as BCY17064); A-(Sequence ID 10)-A (referred to herein as BCY17065); A-(Sequence ID 11)-A (referred to herein as BCY17066); A-(Sequence ID 12)-A (referred to herein as BCY17067); A-(Sequence ID 13)-A (referred to herein as BCY17068); A-(Sequence ID 14)-A (referred to herein as BCY17070); A-(Sequence ID 15)-A (referred to herein as BCY17071); A-(Sequence ID 16)-A (referred to herein as BCY17072); A-(Sequence ID 17)-A (referred to herein as BCY17079); A-(Sequence ID 18)-A (referred to herein as BCY17080); A-(Sequence ID 19)-A (referred to herein as BCY17081); A-(Sequence ID 20)-A (referred to herein as BCY16675); A-(Sequence ID 21)-A (referred to herein as BCY16676); A-(Sequence ID 22)-A (referred to herein as BCY16677); and A-(Sequence ID 23)-A (referred to herein as BCY16678) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0070] In a further embodiment, the molecular scaffold has the following structure: [ka] A derivative of TATB having the formula where * indicates a binding site of three cysteine ​​residues, the peptide ligand C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) further includes N and / or C-terminal additions, and below: A-(Sequence ID 24)-A (referred to herein as BCY16997); A-(Sequence ID 25)-A (referred to herein as BCY18125); A-(Sequence ID 25)-A-[K(PYA)] (referred to herein as BCY19741); A-(Sequence ID 25) (referred to herein as BCY21538); Ac-A-(Sequence ID 25) (referred to herein as BCY21539); (Sequence ID 25)-A (referred to herein as BCY21540); Ac-(Sequence ID 25)-A (referred to herein as BCY21541); Ac-(Sequence ID 25) (referred to herein as BCY21543); Ac-A-(Sequence ID 25)-A (referred to herein as BCY21544); A-(Sequence ID 25)-DKTTV (referred to herein as BCY21769); TVKTP-(Sequence ID 25)-A (referred to herein as BCY21775); A-(Sequence ID 25)-DIHNN (referred to herein as BCY21777); A-(Sequence ID 26)-A (referred to herein as BCY21550); A-(Sequence ID 27)-A (referred to herein as BCY21551); A-(Sequence ID 28)-A (referred to herein as BCY21558); A-(Sequence ID 29)-A (referred to herein as BCY21561); A-(Sequence ID 30)-A (referred to herein as BCY21562); A-(Sequence ID 31)-A (referred to herein as BCY21564); A-(Sequence ID 32)-A (referred to herein as BCY21565); A-(Sequence ID 33)-A (referred to herein as BCY21566); A-(Sequence ID 34)-A (referred to herein as BCY21567); A-(Sequence ID 35)-A (referred to herein as BCY21568); A-(Sequence ID 36)-A (referred to herein as BCY21569); and A-(Sequence ID 37)-A (referred to herein as BCY16998) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0071] In a further embodiment, the molecular scaffold has the following structure: [ka] The peptide ligand of TBMT or TCTZ is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative having the formula where * indicates a binding site of 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 38)-A (referred to herein as BCY18251); A-(Sequence ID 38)-A-[K(PYA)] (referred to herein as BCY19587); A-(Sequence ID 38) (referred to herein as BCY21493); (Sequence ID 38)-A (referred to herein as BCY21495); Ac-(Sequence ID 38) (referred to herein as BCY21498); YYYEW-(Sequence ID 38)-A (referred to herein as BCY21773); A-(Sequence ID 39)-A (referred to herein as BCY21485); A-(Sequence ID 40)-A (referred to herein as BCY21490); A-(Sequence ID 41)-A (referred to herein as BCY21500); A-(Sequence ID 42)-A (referred to herein as BCY21502); A-(Sequence ID 43)-A (referred to herein as BCY21503); A-(Sequence ID 44)-A (referred to herein as BCY21504); A-(Sequence ID 45)-A (referred to herein as BCY21505); A-(Sequence ID 46)-A (referred to herein as BCY21506); A-(Sequence ID 47)-A (referred to herein as BCY21507); A-(Sequence ID 48)-A (referred to herein as BCY21508); A-(Sequence ID 49)-A (referred to herein as BCY21510); A-(Sequence ID 50)-A (referred to herein as BCY21515); A-(Sequence ID 51)-A (referred to herein as BCY21517); A-(Sequence ID 52)-A (referred to herein as BCY21518); A-(Sequence ID 53)-A (referred to herein as BCY21519); A-(Sequence ID 54)-A (referred to herein as BCY21521); A-(Sequence ID 55)-A (referred to herein as BCY21522); A-(Sequence ID 56)-A (referred to herein as BCY21523); A-(Sequence ID 57)-A (referred to herein as BCY21527); A-(Sequence ID 58)-A (referred to herein as BCY21528); A-(Sequence ID 59)-A (referred to herein as BCY19930); A-(Sequence ID 59)-VYNVN (referred to herein as BCY21776); A-(Sequence ID 60)-A (referred to herein as BCY19931); and A-(Sequence ID 61)-A (referred to herein as BCY19932) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0072] In a further embodiment, the molecular scaffold has the following structure: [ka] It is a trisubstituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein * in the formula indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 62)-A (referred to herein as BCY17006); A-(Sequence ID 63)-A (referred to herein as BCY18134); A-(Sequence ID 63)-A-[K(PYA)](referred to herein as BCY19746); and A-(Sequence ID 64)-A (referred to herein as BCY17012) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0073] In a further embodiment, the molecular scaffold has the following structure: [ka] A derivative of TATA having, where * indicates a binding site 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 -X25 -X 26 -X 27 -X 28 -X 29 The peptide ligand of (SEQ ID NO: 3) further includes N and / or C-terminal additions, and as follows: A-(Sequence ID 65)-A (referred to herein as BCY15206); A-(Sequence ID 65)-A-[Sar6][KFl](referred to herein as BCY15194); Ac-(Sequence ID 66)-A-[K(PYA)] (referred to herein as BCY23135); Ac-(Sequence ID 66)-[K(PYA)] (referred to herein as BCY23136); A-(Sequence ID 66)-A-[K(PYA)] (referred to herein as BCY20791); A-(Sequence ID 67)-A (referred to herein as BCY15808); A-(Sequence ID 68)-A (referred to herein as BCY15810); A-(Sequence ID 69)-A (referred to herein as BCY16655); A-(Sequence ID 70)-A (referred to herein as BCY16656); A-(Sequence ID 71)-A (referred to herein as BCY16657); A-(Sequence ID 72)-A (referred to herein as BCY16658); A-(Sequence ID 73)-A (referred to herein as BCY16659); A-(Sequence ID 74)-A (referred to herein as BCY16660); A-(Sequence ID 75)-A (referred to herein as BCY16661); A-(Sequence ID 76)-A (referred to herein as BCY15207); A-(Sequence ID 76)-A-[Sar6]-[KFl](referred to herein as BCY15195); A-(Sequence ID 76)-A-[K(PYA)] (referred to herein as BCY15750); A-(Sequence ID 77)-A (referred to herein as BCY15811); A-(Sequence ID 78)-A (referred to herein as BCY15812); A-(Sequence ID 79)-A (referred to herein as BCY15813); A-(Sequence ID 80)-A (referred to herein as BCY15814); A-(Sequence ID 80)-A-[Sar6]-[KFl](referred to herein as BCY15801); Ac-(Sequence ID 80) (referred to herein as BCY17031); A-(Sequence ID 80)-A-[Sar6]-[K(Ac)] (referred to herein as BCY19384); A-(Sequence ID 80)-AGAAAE (referred to herein as BCY19582); A-(Sequence ID 81)-A (referred to herein as BCY17032); A-(Sequence ID 82)-A (referred to herein as BCY17033); A-(Sequence ID 83)-A (referred to herein as BCY17035); A-(Sequence ID 84)-A (referred to herein as BCY17038); A-(Sequence ID 85)-A (referred to herein as BCY17040); A-(Sequence ID 86)-A (referred to herein as BCY17041); A-(Sequence ID 87)-A (referred to herein as BCY17042); A-(Sequence ID 88)-A (referred to herein as BCY17043); Ac-(Sequence ID 89) (referred to herein as BCY19197); A-(Sequence ID 90)-A (referred to herein as BCY16662); A-(Sequence ID 91)-A (referred to herein as BCY16663); A-(Sequence ID 91)-A-[Sar6]-[KFl](referred to herein as BCY16639); A-(Sequence ID 92)-A (referred to herein as BCY16664); A-(Sequence ID 93)-A (referred to herein as BCY16665); A-(Sequence ID 94)-A (referred to herein as BCY16666); A-(Sequence ID 95)-A (referred to herein as BCY16667); A-(Sequence ID 95)-A-[Sar6]-[KFl](referred to herein as BCY16643); A-(Sequence ID 95)-A-[K(PYA)] (referred to herein as BCY17238); Ac-(Sequence ID 95) (referred to herein as BCY19193); A-(Sequence ID 96)-A (referred to herein as BCY19192); Ac-(Sequence ID 96) (referred to herein as BCY19196); Ac-(Sequence ID 97) (referred to herein as BCY19194); Ac-(Sequence ID 98) (referred to herein as BCY19195); Ac-(Sequence ID 99) (referred to herein as BCY19198); Ac-(Sequence ID 100) (referred to herein as BCY19199); Ac-(Sequence ID 101) (referred to herein as BCY19200); Ac-(Sequence ID 102) (referred to herein as BCY19203); Ac-(Sequence ID 103) (referred to herein as BCY19205); Ac-(Sequence ID 104) (referred to herein as BCY19206); A-(Sequence ID 105)-A (referred to herein as BCY15208); A-(Sequence ID 105)-A-[K(PYA)] (referred to herein as BCY15751); A-(Sequence ID 106)-A-[K(PYA)] (referred to herein as BCY21608); A-(Sequence ID 107)-A (referred to herein as BCY15209); A-(Sequence ID 107)-A-[Sar6]-[KFl](referred to herein as BCY15197); A-(Sequence ID 108)-A (referred to herein as BCY15727); A-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY17452); Ac-(Sequence ID 108)-[K(PYA)] (referred to herein as BCY19157); Ac-A-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY19158); A-(Sequence ID 108)-A-[Sar6]-[(K(Ac)](referred to herein as BCY19385); A-(Sequence ID 108)-AGAAAE (referred to herein as BCY19580); A-(Sequence ID 108)-KMTHE (referred to herein as BCY21192); A-(Sequence ID 108)-NDSLN (referred to herein as BCY21193); A-(Sequence ID 108)-SVNAN (referred to herein as BCY21194); A-(Sequence ID 108)-QGHTPL (referred to herein as BCY21195); A-(Sequence ID 108)-EMEHSN (referred to herein as BCY21196); MRQ-(Sequence ID 108)-ETP (referred to herein as BCY21197); EHM-(Sequence ID 108)-TQS (referred to herein as BCY21198); EPKRQ-(Sequence ID 108)-A (referred to herein as BCY21199); ANYAN-(Sequence ID 108)-A (referred to herein as BCY21200); DSFHQ-(Sequence ID 108)-A (referred to herein as BCY21201); MRQ-(Sequence ID 108)-ETP-[K(PYA)] (referred to herein as BCY21993); EPKRQ-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY21994); Ac-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY23137); Ac-(Sequence ID 108)-E-[K(PYA)] (referred to herein as BCY23174); A-(Sequence ID 108)-E-[K(PYA)] (referred to herein as BCY23179); A-(Sequence ID 109)-A-[K(PYA)] (referred to herein as BCY19159); A-(Sequence ID 110)-A-[K(PYA)] (referred to herein as BCY19161); A-(Sequence ID 111)-A-[K(PYA)] (referred to herein as BCY19162); A-(Sequence ID 112)-A-[K(PYA)] (referred to herein as BCY19163); A-(Sequence ID 113)-A-[K(PYA)] (referred to herein as BCY19164); A-(Sequence ID 114)-A-[K(PYA)] (referred to herein as BCY19165); A-(Sequence ID 115)-A-[K(PYA)] (referred to herein as BCY19166); A-(Sequence ID 116)-A-[K(PYA)](referred to herein as BCY19167); A-(Sequence ID 117)-A (referred to herein as BCY19170); A-(Sequence ID 117)-A-[K(PYA)] (referred to herein as BCY19284); Ac-(Sequence ID 117)-[K(PYA)] (referred to herein as BCY19995); A-(Sequence ID 118)-A-[K(PYA)] (referred to herein as BCY19171); A-(Sequence ID 119)-A-[K(PYA)] (referred to herein as BCY19177); MRQ-(Sequence ID 119)-ETP-[K(PYA)] (referred to herein as BCY21995); EPKRQ-(Sequence ID 119)-A-[K(PYA)] (referred to herein as BCY21996); MRQ-(Sequence ID 119)-ETP (referred to herein as BCY21997); EPKRQ-(Sequence ID 119)-A (referred to herein as BCY21998); Ac-(Sequence ID 119)-[K(PYA)] (referred to herein as BCY22499); A-(Sequence ID 120)-A-[K(PYA)] (referred to herein as BCY19179); A-(Sequence ID 121)-A-[K(PYA)] (referred to herein as BCY19181); A-(Sequence ID 122)-A-[K(PYA)] (referred to herein as BCY19184); A-(Sequence ID 123)-A-[K(PYA)] (referred to herein as BCY19185); A-(Sequence ID 124)-A-[K(PYA)] (referred to herein as BCY19187); A-(Sequence ID 125)-A-[K(PYA)] (referred to herein as BCY19188); A-(Sequence ID 126)-A-[K(PYA)] (referred to herein as BCY19189); [dA]-(Sequence ID 127)-[dA]-[K(PYA)] (referred to herein as BCY20840); A-(Sequence ID 128)-A-[K(PYA)] (referred to herein as BCY21040); A-(Sequence ID 129)-A (referred to herein as BCY21631); A-(Sequence ID 129) (referred to herein as BCY21633); Ac-(Sequence ID 129) (referred to herein as BCY21634); A-(Sequence ID 130) (referred to herein as BCY21635); Ac-(Sequence ID 130) (referred to herein as BCY21636); Ac-(Sequence ID 131)-[K(PYA)] (referred to herein as BCY23702); Ac-(Sequence ID 132)-[K(PYA)] (referred to herein as BCY23703); Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl](referred to herein as BCY25601); Ac-(Sequence ID 133)-[K(PYA)] (referred to herein as BCY23704); Ac-(Sequence ID 134)-[K(PYA)] (referred to herein as BCY23705); Ac-(Sequence ID 135)-[K(PYA)] (referred to herein as BCY23706); Ac-(Sequence ID 136)-[K(PYA)] (referred to herein as BCY23707); Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl](referred to herein as BCY25602); A-(Sequence ID 137)-A (referred to herein as BCY15729); A-(Sequence ID 138)-A (referred to herein as BCY15210); A-(Sequence ID 138)-A-[Sar6]-[KFl](referred to herein as BCY15198); A-(Sequence ID 138)-A-[K(PYA)] (referred to herein as BCY15752); A-(Sequence ID 139)-A (referred to herein as BCY15731); A-(Sequence ID 139)-A-[Sar6]-[KFl](referred to herein as BCY15730); A-(Sequence ID 140)-A (referred to herein as BCY15733); A-(Sequence ID 141)-A (referred to herein as BCY15735); and A-(Sequence ID 141)-A-[Sar6]-[KFl](referred to herein as BCY15734) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0074] In a further embodiment, the molecular scaffold has the following structure: [ka] It is a derivative of TATB having, where * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 142)-A (referred to herein as BCY17001); A-(Sequence ID 143)-A (referred to herein as BCY18128); A-(Sequence ID 143)-A-[K(PYA)] (referred to herein as BCY19743); A-(Sequence ID 144)-A (referred to herein as BCY18129); A-(Sequence ID 144)-A-[K(PYA)] (referred to herein as BCY19744); Ac-A-(Sequence ID 144)-A (referred to herein as BCY24131); Ac-(Sequence ID 144) (referred to herein as BCY24135); A-(Sequence ID 144) (referred to herein as BCY24450); Ac-A-(Sequence ID 144) (referred to herein as BCY24451); (Sequence ID 144)-A (referred to herein as BCY24452); Ac-(Sequence ID 144)-A (referred to herein as BCY24453); AHGG-(Sequence ID 144)-EVHA (referred to herein as BCY25863); AIKP-(SEQ ID NO: 144)-QHEA (referred to herein as BCY25864); ADST-(SEQ ID NO: 144)-QHPA (referred to herein as BCY25865); ALNG-(SEQ ID NO: 144)-PLSA (referred to herein as BCY25866); ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)] (referred to herein as BCY28840); A-(Sequence ID 145)-A (referred to herein as BCY24442); A-(Sequence ID 146)-A (referred to herein as BCY24443); A-(Sequence ID 147)-A (referred to herein as BCY24444); A-(Sequence ID 148)-A (referred to herein as BCY24445); A-(Sequence ID 149)-A (referred to herein as BCY24456); A-(Sequence ID 150)-A (referred to herein as BCY24457); A-(Sequence ID 151)-A (referred to herein as BCY24458); A-(Sequence ID 152)-A (referred to herein as BCY24459); A-(Sequence ID 153)-A (referred to herein as BCY24462); A-(Sequence ID 154)-A (referred to herein as BCY24466); A-(Sequence ID 155)-A (referred to herein as BCY24467); A-(Sequence ID 156)-A (referred to herein as BCY24468); A-(Sequence ID 157)-A (referred to herein as BCY24469); A-(Sequence ID 158)-A (referred to herein as BCY24471); A-(Sequence ID 159)-A (referred to herein as BCY24472); A-(Sequence ID 160)-A (referred to herein as BCY24473); A-(Sequence ID 161)-A (referred to herein as BCY24474); A-(Sequence ID 162)-A (referred to herein as BCY24475); A-(Sequence ID 163)-A (referred to herein as BCY24477); A-(Sequence ID 164)-A (referred to herein as BCY24478); A-(Sequence ID 165)-A (referred to herein as BCY24479); A-(Sequence ID 166)-A (referred to herein as BCY24480); A-(Sequence ID 167)-A (referred to herein as BCY24481); A-(Sequence ID 168)-A (referred to herein as BCY24482); A-(Sequence ID 169)-A (referred to herein as BCY24483); A-(Sequence ID 170)-A (referred to herein as BCY24484); A-(Sequence ID 171)-A (referred to herein as BCY24485); A-(Sequence ID 172)-A (referred to herein as BCY24486); A-(Sequence ID 173)-A (referred to herein as BCY24487); A-(Sequence ID 174)-A (referred to herein as BCY24488); A-(Sequence ID 175)-A (referred to herein as BCY24489); A-(Sequence ID 176)-A (referred to herein as BCY24490); A-(Sequence ID 177)-A (referred to herein as BCY24491); A-(Sequence ID 178)-A (referred to herein as BCY24492); A-(Sequence ID 179)-A (referred to herein as BCY24493); A-(Sequence ID 180)-A (referred to herein as BCY24495); A-(Sequence ID 181)-A (referred to herein as BCY24496); A-(Sequence ID 182)-A (referred to herein as BCY24497); A-(Sequence ID 183)-A (referred to herein as BCY24498); A-(Sequence ID 184)-A (referred to herein as BCY24499); A-(Sequence ID 185)-A (referred to herein as BCY24500); A-(Sequence ID 186)-A (referred to herein as BCY24501); A-(Sequence ID 187)-A (referred to herein as BCY24503); A-(Sequence ID 188)-A (referred to herein as BCY24504); A-(Sequence ID 189)-A (referred to herein as BCY24505); A-(Sequence ID 190)-A (referred to herein as BCY24506); A-(Sequence ID 191)-A (referred to herein as BCY24509); ALNG-(SEQ ID NO: 192)-PLSA (referred to herein as BCY28838); ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)] (referred to herein as BCY28841); ALNG-(SEQ ID NO: 193)-PLSA (referred to herein as BCY28839); ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)] (referred to herein as BCY28842); ALEQN-(Sequence ID 194)-A (referred to herein as BCY25861); ALEQN-(SEQ ID NO: 194)-A-[K(PYA)] (referred to herein as BCY28843); ALEQN-(Sequence ID 195)-A (referred to herein as BCY28844); ALEQN-(SEQ ID NO: 195)-A-[K(PYA)] (referred to herein as BCY28845); and AHAGT-(SEQ ID NO: 196)-A (referred to herein as BCY25859) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0075] In a further embodiment, the molecular scaffold has the following structure: [ka] It is a derivative of TATB, having the formula where * indicates a binding site of three cysteine ​​residues, and CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4) peptide ligands further include N and / or C-terminal additions, and as follows: A-(Sequence ID 197)-A (referred to herein as BCY16999); A-(Sequence ID 197)-A-[K(PYA)] (referred to herein as BCY17693); A-(Sequence ID 197)-A-[Sar6]-[K(Ac)](referred to herein as BCY19387); A-(Sequence ID 198)-A (referred to herein as BCY18126); Ac-A-(Sequence ID 198)-A (referred to herein as BCY20725); A-(Sequence ID 198)-NLNLK (referred to herein as BCY21770); VNENI-(Sequence ID 198)-A (referred to herein as BCY21771); A-(Sequence ID 198)-RNPHD (referred to herein as BCY21772); A-(Sequence ID 198)-IHNNG (referred to herein as BCY21774); TNEGI-(Sequence ID 198)-A (referred to herein as BCY21778); VNENI-(Sequence ID 198)-A-[K(PYA)] (referred to herein as BCY23767); A-(Sequence ID 199)-A (referred to herein as BCY20731); A-(Sequence ID 200)-A (referred to herein as BCY20732); A-(Sequence ID 201)-A (referred to herein as BCY20734); A-(Sequence ID 202)-A (referred to herein as BCY20735); A-(Sequence ID 203)-A (referred to herein as BCY20736); A-(Sequence ID 204)-A (referred to herein as BCY20737); A-(Sequence ID 205)-A (referred to herein as BCY20738); A-(Sequence ID 206)-A (referred to herein as BCY20741); A-(Sequence ID 207)-A (referred to herein as BCY20742); A-(Sequence ID 208)-A (referred to herein as BCY20743); A-(Sequence ID 209)-A (referred to herein as BCY20746); A-(Sequence ID 210)-A (referred to herein as BCY20747); A-(Sequence ID 211)-A (referred to herein as BCY20748); A-(Sequence ID 212)-A (referred to herein as BCY20749); A-(Sequence ID 213)-A (referred to herein as BCY20751); A-(Sequence ID 214)-A (referred to herein as BCY20752); A-(Sequence ID 215)-A (referred to herein as BCY20756); A-(Sequence ID 216)-A (referred to herein as BCY20757); A-(Sequence ID 217)-A (referred to herein as BCY20758); A-(Sequence ID 218)-A (referred to herein as BCY20759); A-(Sequence ID 219)-A (referred to herein as BCY20760); A-(Sequence ID 220)-A (referred to herein as BCY20761); A-(Sequence ID 221)-A (referred to herein as BCY20762); A-(Sequence ID 222)-A (referred to herein as BCY20763); A-(Sequence ID 223)-A (referred to herein as BCY20764); A-(Sequence ID 224)-A (referred to herein as BCY20765); A-(Sequence ID 225)-A (referred to herein as BCY20766); A-(Sequence ID 226)-A (referred to herein as BCY18127); and A-(Sequence ID 226)-A-[K(PYA)] (referred to herein as BCY19742) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0076] In a further embodiment, the molecular scaffold has the following structure: [ka] It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein * in the formula indicates a binding site of three cysteine ​​residues, and CYYX 38 -X 39 -X 40 -The peptide ligand of YACLDC (SEQ ID NO: 5) further includes N and / or C-terminal additions, as follows: A-(Sequence ID 227)-A (referred to herein as BCY17007); A-(Sequence ID 228)-A (referred to herein as BCY18135); A-(Sequence ID 229)-A (referred to herein as BCY18136); and A-(Sequence ID 229)-A-[K(PYA)] (referred to herein as BCY19747) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0077] In a further embodiment, the molecular scaffold has the following structure: [ka] A derivative of TATA having, where * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 230)-A (referred to herein as BCY15211); A-(Sequence ID 230)-A-[Sar6]-[KFl](referred to herein as BCY15199); A-(Sequence ID 231)-A (referred to herein as BCY15737); A-(Sequence ID 232)-A (referred to herein as BCY15739); A-(Sequence ID 232)-A-[Sar6]-[KFl](referred to herein as BCY15738); A-(Sequence ID 232)-A-[Sar6]-[K(Ac)](referred to herein as BCY19386); A-(Sequence ID 232)-AGAAAE (referred to herein as BCY19581); A-(Sequence ID 233)-A (referred to herein as BCY17047); A-(Sequence ID 234)-A (referred to herein as BCY17049); A-(Sequence ID 235)-A (referred to herein as BCY17051); A-(Sequence ID 236)-A (referred to herein as BCY17055); A-(Sequence ID 237)-A (referred to herein as BCY17056); A-(Sequence ID 238)-A (referred to herein as BCY17057); A-(Sequence ID 239)-A (referred to herein as BCY17058); A-(Sequence ID 240)-A (referred to herein as BCY17059); A-(Sequence ID 241)-A (referred to herein as BCY17061); A-(Sequence ID 242)-A (referred to herein as BCY17656); A-(Sequence ID 243)-A (referred to herein as BCY15741); A-(Sequence ID 244)-A (referred to herein as BCY15743); A-(Sequence ID 245)-A (referred to herein as BCY15745); A-(Sequence ID 246)-A (referred to herein as BCY16668); A-(Sequence ID 247)-A (referred to herein as BCY16669); A-(Sequence ID 248)-A (referred to herein as BCY16670); A-(Sequence ID 249)-A (referred to herein as BCY16671); A-(Sequence ID 249)-A-[Sar6]-[KFl](referred to herein as BCY16647); Ac-A-(Sequence ID 249)-A (referred to herein as BCY19586); A-(Sequence ID 250)-A (referred to herein as BCY18510); A-(Sequence ID 251)-A (referred to herein as BCY18511); A-(Sequence ID 251)-A-[K(PYA)] (referred to herein as BCY25826); A-(Sequence ID 252)-A (referred to herein as BCY18514); A-(Sequence ID 253)-A (referred to herein as BCY18515); A-(Sequence ID 254)-A (referred to herein as BCY18518); A-(Sequence ID 255)-A (referred to herein as BCY18519); A-(Sequence ID 256)-A (referred to herein as BCY18520); A-(Sequence ID 257)-A (referred to herein as BCY16672); A-(Sequence ID 258)-A (referred to herein as BCY16673); A-(Sequence ID 258)-A-[Sar6]-[KFl](referred to herein as BCY16649); A-(Sequence ID 258)-A-[K(PYA)] (referred to herein as BCY17237); Ac-A-(Sequence ID 258)-A (referred to herein as BCY19585); and A-(Sequence ID 259)-A (referred to herein as BCY16674) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0078] In a further embodiment, the molecular scaffold has the following structure: [ka] The formula is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 260)-A (referred to herein as BCY17002); A-(Sequence ID 260)-A-[K(PYA)] (referred to herein as BCY19745); A-(Sequence ID 261)-A (referred to herein as BCY18130); A-(Sequence ID 261)-A-[K(PYA)] (referred to herein as BCY20847); [PYA]-A-(Sequence ID 261)-A (referred to herein as BCY20852); Ac-(Sequence ID 261) (referred to herein as BCY21616); A-(Sequence ID 261) (referred to herein as BCY21617); Ac-A-(Sequence ID 261) (referred to herein as BCY21618); [PYA]-(Sequence ID 261) (referred to herein as BCY21619); [GuanAc]-(SEQ ID NO: 261)-A (referred to herein as BCY23043); A-(Sequence ID 261)-[CF3Ala] (referred to herein as BCY23080); A-(Sequence ID 261)-S (referred to herein as BCY23081); A-(Sequence ID 262)-A (referred to herein as BCY20848); A-(Sequence ID 263)-A (referred to herein as BCY20849); A-(Sequence ID 264)-A (referred to herein as BCY20850); A-(Sequence ID 265)-A (referred to herein as BCY20851); A-(Sequence ID 266)-A (referred to herein as BCY20853); A-(Sequence ID 266) (referred to herein as BCY21620); A-(Sequence ID 267)-A (referred to herein as BCY21622); A-(Sequence ID 267)-A-[K(PYA)] (referred to herein as BCY21607); Ac-(Sequence ID 268) (referred to herein as BCY21624); A-(Sequence ID 268) (referred to herein as BCY21625); [PYA]-(Sequence ID 268) (referred to herein as BCY21626); A-(Sequence ID 269) (referred to herein as BCY21627); Ac-(Sequence ID 270) (referred to herein as BCY22879); Ac-(Sequence ID 271) (referred to herein as BCY22880); A-(Sequence ID 272)-A (referred to herein as BCY23044); A-(Sequence ID 273)-A (referred to herein as BCY23045); A-(Sequence ID 274)-A (referred to herein as BCY23046); A-(Sequence ID 275)-A (referred to herein as BCY23047); A-(Sequence ID 276)-A (referred to herein as BCY23050); A-(Sequence ID 277)-A (referred to herein as BCY23051); A-(Sequence ID 278)-A (referred to herein as BCY23052); A-(Sequence ID 279)-A (referred to herein as BCY23053); A-(Sequence ID 280)-A (referred to herein as BCY23054); A-(Sequence ID 281)-A (referred to herein as BCY23058); A-(Sequence ID 282)-A (referred to herein as BCY23059); A-(Sequence ID 283)-A (referred to herein as BCY23062); A-(Sequence ID 284)-A (referred to herein as BCY23063); A-(Sequence ID 285)-A (referred to herein as BCY23064); A-(Sequence ID 286)-A (referred to herein as BCY23066); A-(Sequence ID 287)-A (referred to herein as BCY23067); A-(Sequence ID 288)-A (referred to herein as BCY23068); A-(Sequence ID 289)-A (referred to herein as BCY23071); A-(Sequence ID 290)-A (referred to herein as BCY23072); A-(Sequence ID 291)-A (referred to herein as BCY23073); A-(Sequence ID 292)-A (referred to herein as BCY23074); A-(Sequence ID 293)-A (referred to herein as BCY23075); A-(Sequence ID 294)-A (referred to herein as BCY23079); [GuanAc]-(SEQ ID NO: 295)-COOH (referred to herein as BCY27058); [GuanAc]-(Sequence ID 295) (referred to herein as BCY27059); [CIA]-[K(PYA)]-(Sequence ID 295)-A (referred to herein as BCY27064); [CIA]-[dK(PYA)]-(Sequence ID 295)-A (referred to herein as BCY27065); [GuanAc]-(Sequence ID 296) (referred to herein as BCY27060); [GuanAc]-(Sequence ID 297) (referred to herein as BCY27061); [GuanAc]-(Sequence ID 298) (referred to herein as BCY27062); [GuanAc]-(Sequence ID 299) (referred to herein as BCY27063); [GuanAc]-(Sequence ID 300) (referred to herein as BCY27066); [GuanAc]-(Sequence ID 301) (referred to herein as BCY27067); [GuanAc]-(Sequence ID 302) (referred to herein as BCY27068); A-(Sequence ID 303)-A (referred to herein as BCY18131); A-(Sequence ID 304)-A (referred to herein as BCY18132); A-(Sequence ID 305)-A-[K(PYA)] (referred to herein as BCY19588); A-(Sequence ID 306)-A (referred to herein as BCY19933); A-(Sequence ID 307)-A (referred to herein as BCY19934); A-(Sequence ID 308)-A (referred to herein as BCY19935); A-(Sequence ID 309)-A (referred to herein as BCY19936); A-(Sequence ID 309)-A-[K(PYA)] (referred to herein as BCY21606); Ac-(Sequence ID 309) (referred to herein as BCY23139); Ac-A-(Sequence ID 309)-A (referred to herein as BCY23140); [dA]-(Sequence ID 309)-A (referred to herein as BCY32061); A-(Sequence ID 309) (referred to herein as BCY32074); Ac-A-(Sequence ID 309) (referred to herein as BCY32075); (Sequence ID 309)-A (referred to herein as BCY32076); Ac-(Sequence ID 309)-A (referred to herein as BCY32077); A-(Sequence ID 309)-A-[dK(PYA)] (referred to herein as BCY32126); A-(Sequence ID 309)-[K(PYA)] (referred to herein as BCY32127); A-(Sequence ID 309)-[dK(PYA)] (referred to herein as BCY32128); A-(Sequence ID 310)-A (referred to herein as BCY23138); A-(Sequence ID 310)-A-[K(PYA)] (referred to herein as BCY24613); A-(Sequence ID 311)-A (referred to herein as BCY32062); A-(Sequence ID 312)-A (referred to herein as BCY32065); A-(Sequence ID 313)-A (referred to herein as BCY32066); A-(Sequence ID 314)-A (referred to herein as BCY32069); A-(Sequence ID 315)-A (referred to herein as BCY32071); A-(Sequence ID 316)-A (referred to herein as BCY32072); A-(Sequence ID 317)-A (referred to herein as BCY32078); A-(Sequence ID 318)-A (referred to herein as BCY32079); A-(Sequence ID 319)-A (referred to herein as BCY32080); A-(Sequence ID 320)-A (referred to herein as BCY32081); A-(Sequence ID 321)-A (referred to herein as BCY32082); A-(Sequence ID 322)-A (referred to herein as BCY32083); A-(Sequence ID 323)-A (referred to herein as BCY32084); A-(Sequence ID 324)-A (referred to herein as BCY32085); A-(Sequence ID 325)-A (referred to herein as BCY32086); A-(Sequence ID 326)-A (referred to herein as BCY32087); A-(Sequence ID 327)-A (referred to herein as BCY32088); A-(Sequence ID 328)-A (referred to herein as BCY32089); A-(Sequence ID 329)-A (referred to herein as BCY32090); A-(Sequence ID 330)-A (referred to herein as BCY32091); A-(Sequence ID 331)-A (referred to herein as BCY32092); A-(Sequence ID 332)-A (referred to herein as BCY32093); A-(Sequence ID 333)-A (referred to herein as BCY32095); A-(Sequence ID 334)-A (referred to herein as BCY32096); A-(Sequence ID 335)-A (referred to herein as BCY32098); A-(Sequence ID 336)-A (referred to herein as BCY32099); A-(Sequence ID 337)-A (referred to herein as BCY32100); A-(Sequence ID 338)-A (referred to herein as BCY32101); A-(Sequence ID 339)-A (referred to herein as BCY32103); A-(Sequence ID 340)-A (referred to herein as BCY32104); A-(Sequence ID 341)-A (referred to herein as BCY32105); A-(Sequence ID 342)-A (referred to herein as BCY32106); A-(Sequence ID 343)-A (referred to herein as BCY32107); A-(Sequence ID 344)-A (referred to herein as BCY32108); A-(Sequence ID 345)-A (referred to herein as BCY32109); A-(Sequence ID 346)-A (referred to herein as BCY32110); A-(Sequence ID 347)-A (referred to herein as BCY32112); A-(Sequence ID 348)-A (referred to herein as BCY32113); A-(Sequence ID 349)-A (referred to herein as BCY32114); A-(Sequence ID 350)-A (referred to herein as BCY32115); A-(Sequence ID 351)-A (referred to herein as BCY32116); A-(Sequence ID 352)-A (referred to herein as BCY32117); A-(Sequence ID 353)-A (referred to herein as BCY32120); A-(Sequence ID 354)-A (referred to herein as BCY32121); A-(Sequence ID 355)-A (referred to herein as BCY32122); A-(Sequence ID 356)-A (referred to herein as BCY32123); A-(Sequence ID 357)-A (referred to herein as BCY32124); A-(Sequence ID 358)-A (referred to herein as BCY32125); A-(Sequence ID 359)-A (referred to herein as BCY19937); A-(Sequence ID 360)-A (referred to herein as BCY19938); A-(Sequence ID 361)-A (referred to herein as BCY19939); A-(Sequence ID 362)-A (referred to herein as BCY19940); A-(Sequence ID 363)-A (referred to herein as BCY19941); A-(Sequence ID 364)-A (referred to herein as BCY19942); A-(Sequence ID 365)-A (referred to herein as BCY19943); and A-(Sequence ID 366)-A (referred to herein as BCY18253) The more selected amino acid sequences, or modified derivatives thereof, and / or pharmaceutically acceptable salts thereof.

[0079] [Multimer-binding complex] A further aspect of the present invention provides a polymer-binding complex comprising at least two bicyclic peptide ligands (e.g., two, three, or four bicyclic peptide ligands), which may be identical or different, wherein at least one bicyclic peptide ligand is a peptide ligand described herein or a pharmaceutically acceptable salt thereof. A further aspect of the present invention provides a polymer-binding complex comprising at least two bicyclic peptide ligands described herein, wherein the peptide ligands may be identical or different, or pharmaceutically acceptable salts thereof. In some embodiments, the polymer-binding complex comprises, for example, two, three, or four bicyclic peptide ligands described herein, which may be identical or different.

[0080] In one embodiment, the multimer-binding complex comprises one or more identical bicyclic peptides (i.e., homomultimers). In another embodiment, the multimer-binding complex comprises different bicyclic peptides (i.e., heteromultimers). In one embodiment, the multimer-binding complex comprises at least two identical bicyclic peptide ligands and at least one different bicyclic peptide. In some embodiments, the multimer-binding complex comprises (a) two identical bicyclic peptide ligands and (b) one or two further bicyclic peptide ligands which may be identical or different, thereafter, the two further bicyclic peptide ligands in (b) may be identical or different from the two bicyclic peptide ligands in (a).

[0081] In one embodiment, the multimer-binding complex further comprises one or more effector groups and / or functional groups, such as one or more cytotoxic agents, radiochelators, or chromophores. The effector and / or functional groups may be those that produce a detectable signal in the presence of a second intermediate (e.g., biotin and various protein antigens). In the case of biotin, the second intermediate may be a streptavidin-enzyme conjugate or a streptavidin-dye conjugate. In one embodiment, the multimer-binding complex further comprises a fluorophore.

[0082] (Spacer) In one embodiment, the multimer-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 hold multiple bicyclic peptide ligands in an optimal arrangement for presentation to a target.

[0083] It is understood that bicyclic peptide ligands in a multimer-binding complex can be conjugated to one another via any suitable linker. The term "linker" is used herein interchangeably with spacer and hinge portions. The properties of the linker can be modified to optimize the desired functional outcome by increasing its length, stiffness, or solubility. Increasing the valence of any of the bound peptides may help increase the affinity of the heteromultimer to the target.

[0084] In one embodiment, the linker is a linear linker or a branched linker. In some embodiments, the linker is a branched linker containing three or four branches. In some embodiments, the linker can bind to three or four bicyclic peptide ligands. In some embodiments, the linker contains three branches and can bind to three bicyclic peptide ligands. In some embodiments, the linker contains four branches and can bind to four bicyclic peptide ligands. In some embodiments, the linker contains one or more repeating monomer groups.

[0085] In some embodiments, the linker is a bidentate or polydentate group having a length of about 0.3 nm to about 300 nm. In some embodiments, the linker has a length of about 0.5 nm to about 200 nm, e.g., about 1 nm to about 100 nm, e.g., about 1.5 nm to about 50 nm, e.g., about 2 nm to about 20 nm, e.g., about 3 nm to about 10 nm. In some embodiments, the linker length is the persistence length. In some embodiments, the linker length is determined when it is in an aqueous solution under physiological conditions (e.g., phosphate-buffered saline at pH 7.4, 37°C), and in some embodiments, it can be determined using an atomic force microscope.

[0086] In some embodiments, the linker comprises one or more linking portions, for example, one or more poly(alkylene glycol) groups, for example, poly(ethylene glycol) or poly(propylene glycol). In some embodiments, the linker comprises one or more groups, for example, an amine group, an amide group; an alkylene group; a carbamate group; an ether group; an ester group; a disulfide bond; a hydrazone group; a sulfonamide group; a thioether group; or a cyclic group, preferably a 4-12 membered carbocyclic or heterocyclic group, a 5-12 membered heteroaryl group, or C 6-12 The material may contain an aryl group, where the alkylene, alkenylene, alkylylene, poly(alkylene glycol), amine, and cyclic group are each independently substituted as desired.

[0087] In some embodiments, the linker contains one or more amino acids or amino acid analogs. In some embodiments, the linker contains 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 joined together. In some embodiments, the linker has the following morphological components [ka] The formula includes, and in the formula, each R 1 is H or C 1-4It is alkyl; each R 2 These are selected from the side chains of amino acids (e.g., canonical amino acids), or for example, OH, SH, SC. 1-4 Alkyl, aryl (may be substituted with OH), heteroaryl, C(O)OH, C(O)NH2, N + H3, NH(C=N) + C may be substituted with H2)NH2. 1-4 It is alkyl, for example, R 2 The link may include a side chain of arginine or homoarginine; and the link is a linker, which may optionally be terminated or substituted with one or more groups, such as an amine group, an amide group; an alkylene group; a carbamate group; an ether group; an ester group; a disulfide bond; a hydrazone group; a sulfonamide group; a thioether group; or a cyclic group as described herein. 2-8 It is a hydrocarbylene (e.g., alkylene) linker; for example, the link is terminated or interrupted at the amide group C 3-6 It may also contain an alkylene group; for example, the link is -C 1-4 Alkylene-NHC(O)-C 1-4 The morphological moiety may include alkylene-, for example, -C4alkylene-NHC(O)-C1alkylene-. In some embodiments, the moiety is conjugated to the polypeptide contained in the peptide ligand or bicyclic peptide ligand described herein, for example, at the N or C terminus of the polypeptide contained in the peptide ligand or bicyclic peptide ligand described herein.

[0088] In some embodiments, the linker comprises one or more reactants for reaction with the bicyclic peptide ligands described herein. Exemplary reactants include azide groups (for example, reacting with an alkyne group on a bicyclic peptide ligand described herein, under appropriate conditions, for example, in the presence of an azide-alkyne cycloaddition catalyst, to form, for example, a 1,2,3-triazole group); carboxylic acids and their activated derivatives (such as NHS esters) (for example, reacting with an amine group on a bicyclic peptide ligand described herein, under appropriate conditions, to form, for example, an amide bond). In the bicyclic peptide ligands described herein, the terms “azide” and “triazolyl” may be used interchangeably to describe the same structure, where “azide” refers to the structure found in the linker before conjugation to the bicyclic peptide ligand, and “triazolyl” refers to the structure found in the linker when the linker reacts with an alkynyl group on the bicyclic peptide ligand.

[0089] In some embodiments, when the linker contains poly(alkylene glycol), poly(alkylene glycol) is poly(ethylene glycol) (PEG) or poly(propylene glycol) (PPG). In some embodiments, the linker is one or more PEGs n The formula includes groups, where 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 linker includes one or more branches, for example, three branches, where each branch is a PEG n Includes the base.

[0090] In some embodiments, if the linker contains an amide group, the amide group is represented by the formula -NHC(O)- or -C(O)NH-. In some embodiments, if the linker contains an amine group, the amine group is represented by the formula N(R)3, where each R may be the same or different. In some embodiments, each R is, for example, one or more groups PEG as described herein. n The present invention comprises a bicyclic peptide ligand, which is bonded to an amine nitrogen via a linking portion containing a C6 aryl group. In some embodiments, if the linker contains a cyclic group, the cyclic group is a C6 aryl group. In some embodiments, if the linker contains an alkylene group, the alkylene group is C6 aryl group. 1-3 It is an alkylene group.

[0091] The linkers described above may also be used to conjugate bicyclic peptide ligands to effector groups and / or functional groups as described herein. Typically, the linkers that conjugate effector groups and / or functional groups to bicyclic peptide ligands are one or more PEGs. n The formula includes or consists of groups, where 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 linker conjugating the effector and / or functional group to the bicyclic peptide ligand is a covalent bond.

[0092] (dimer) In one embodiment, the multimer-binding complex contains two bicyclic peptides that are either identical (i.e., homodimers) or different (i.e., heterodimers). In one embodiment, the multimer-binding complex contains two identical bicyclic peptides (i.e., homodimers). In one embodiment, the multimer-binding complex contains two different bicyclic peptides (i.e., heterodimers).

[0093] If the multimer-binding complex contains two bicyclic peptides, it is understood that the spacer requires two binding sites.

[0094] In some embodiments of the dimer, the linker is given by formula: N3-(Alk1) m -PEG n -(Alk1) m -NHC(O)(Alk2)C(O)NH-(Alk1) m -PEG n -(Alk1) m -N3 This is shown, where each Alk1 is independently C 1-3 It is an alkylene group; 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 Alk2 is optionally substituted with a functional group that can form a linker to an effector and / or functional group described herein, such as a fluorophore. In some embodiments, Alk2 is a C5 alkylene group. In some embodiments, Alk2 is -CH2CH2CH(N*H)CH2CH2-, where * is a bonding site to an effector and / or functional group described herein, and optionally Alk2 is conjugated to the effector and / or functional group via a linker. In some embodiments, Alk2 is -CH2CH2CH(NH(fluorophore))CH2CH2-, where fluorophore is a fluorophore described herein, such as AlexaFluor488. An example of such a linker is compound 4 of Example 2, "AHDA-(PEG 10 -N3)」

[0095] In some embodiments of the dimer, the linker is given by formula: N3-(Alk1) m -PEG n -(Alk1) m -NHC(O)(Alk2)C(O)NH-(Alk1) m -PEG n -(Alk1) m -N3 This is shown, where each Alk1 is independently C 1-3It is an alkylene group; Alk2 is C 1-6 It is an alkylene group; each m is independently 0 or 1; and 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 linker is called "GTA-Peg". n It may be referred to as "-N3," for example, "GTA-PEG10-N3" as shown in Examples 5 and 6, which describe the synthesis of BCY26427 and BCY26435.

[0096] In some embodiments of the dimer, the linker is given by formula: [N3-(Alk)] m -PEG n -(Alk) m -]2-N-[-(Alk) m -PEG n -(Alk) m -Z] As shown in the formula, where each Alk is independently, optionally independently, terminated at an amide group or an -O- group C 1-3 It is an alkylene group; each m is independently 0, 1, or 2; each n is independently an integer from about 1 to about 30; and Z comprises an effector and / or functional group as described herein. In some embodiments, Z is biotin or comprises it. In some embodiments, Z is a fluorophore as described herein, e.g., Bodipy558 or comprises it. To avoid doubt, each [N3-(Alk) m -PEG n -(Alk) m The bases may be the same or different.

[0097] In some embodiments of the dimer, the linker is given by formula: N3-(Alk) m -PEG n -(Alk) m -Q As shown in the formula, where each Alk is independently, optionally independently, terminated at an amide group or an -O- group C 1-3It is an alkylene 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 its activated derivative (e.g., an NHS-ester group).

[0098] In one embodiment, the polymer-binding complex comprises two bicyclic peptides, and the polymer-binding complex is of formula (A) or formula (B): [ka] (A) [ka] (B) The motif is represented by the formula, where BCY represents a "bicyclic peptide ligand". As explained above, those skilled in the art will understand that the triazolyl group shown in the above structure arises from a reaction between the azide group in the linker and the alkyne group on the bicyclic peptide ligand (for example, the alkyne group contained in the K(PYA) moiety described herein).

[0099] In one embodiment, the polymer-binding complex includes the dimer-binding complex described in Table 1 below. [Table 2] In the formula, 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 (however, when used in a linker, the ring opens to form a -C(O)(CH2)5C(O) moiety); BDP558 represents Bodipy558; and BDP558-N3SC2 and BDP558-N3SC1 are as follows: [ka]

[0100] For example, the structure of BCY26427 is, [ka] That is the case.

[0101] In some embodiments, the polymer-binding complex is selected from BCY28218, BCY28219, BCY28220, BCY28885, BCY28887, or a pharmaceutically acceptable salt thereof. In some embodiments, the polymer-binding complex is BCY26435, or a pharmaceutically acceptable salt thereof.

[0102] (trimer) In one embodiment, the multimer-binding complex contains three bicyclic peptides that are either identical (i.e., homotrimers) or different (i.e., heterotrimers). In a further embodiment, the heterotrimer contains one bicyclic peptide in the first sequence and two bicyclic peptides in the second sequence. In another embodiment, the multimer-binding complex contains three identical bicyclic peptides.

[0103] In some embodiments of the trimer, the linker is given by the formula: [N3-(Alk)] m -PEG n -(Alk) m -]3-N As shown in the formula, where each Alk is independently, optionally independently, terminated at an amide group or an -O- group C 1-3 It is an alkylene group; each m is independently 0, 1, or 2; each n is independently an integer from about 1 to about 30. To avoid doubt, each [N3-(Alk) m -PEG n -(Alk) m -] may be the same or different.

[0104] If the multimer-binding complex contains three bicyclic peptides, it is understood that the spacer requires three binding sites. Therefore, in one embodiment, the multimer-binding complex contains three bicyclic peptides, and the multimer-binding complex is formula (C) or formula (D): [ka] (C) [ka] (D) This is the motif shown, where BCY represents a bicyclic peptide ligand.

[0105] In one embodiment, the polymer-binding complex includes the trimer-binding complex described in Table 2 below. [Table 3]

[0106] (tetramer) In one embodiment, the multimer-binding complex contains four bicyclic peptides that are either identical (i.e., homotetramer) or different (i.e., heterotetramer). In a further embodiment, the heterotetramer contains one bicyclic peptide in the first sequence and three bicyclic peptides in the second sequence. In another embodiment, the heterotetramer contains two bicyclic peptides in the first sequence and two bicyclic peptides in the second sequence. In one embodiment, the multimer-binding complex contains four identical bicyclic peptides.

[0107] In some embodiments of the tetramer, the linker is given by formula: [N3-(Alk)] m -PEG n -(Alk) m -]4-C As shown in the formula, where each Alk is independently, optionally independently, terminated at an amide group or an -O- group C 1-3 It is an alkylene group; each m is independently 0, 1, or 2; each n is independently an integer from about 1 to about 30. To avoid doubt, each [N3-(Alk) m -PEG n -(Alk) m -] may be the same or different.

[0108] If the multimer-binding complex contains four bicyclic peptides, it is understood that the spacer requires four binding sites. Therefore, in one embodiment, the multimer-binding complex contains four bicyclic peptides, and the multimer-binding complex is given by formula (E): [ka] (E) The motif shown is BCY in the formula, where BCY represents a bicyclic peptide ligand.

[0109] In one embodiment, the polymer-binding complex includes the tetramer-binding complex described in Table 3 below. [Table 4]

[0110] As described above, those skilled in the art will understand that, when conjugated with the bicyclic peptide ligands described herein, the azide group or each azide group typically reacts with an alkyne group on one of the bicyclic peptide ligands (for example, reacting with the alkyne group contained in the K(PYA) moiety described herein to form a triazolyl group).

[0111] Any of the compounds identified above may be provided, and may also be provided herein, in the form of a pharmaceutically acceptable salt.

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art, such as in the fields of peptide chemistry, cell culture and phage display, nucleic acid chemistry and biochemistry. Standard techniques are used in molecular biology, genetics and biochemical methods (Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al., Short Protocols in Molecular Biology (1999) 4). th (See ed., John Wiley & Sons, Inc.) (These are incorporated into this specification by attribution.)

[0113] [Numbering] When referring to the amino acid residue positions within the peptide of the present invention, invariant residues are omitted from the numbering, and therefore the numbering of amino acid residues within the peptide of the present invention is as follows: C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (Sequence number 1).

[0114] [Molecular format] N- or C-terminal extensions to a biring core sequence are hyphenated and appended to the left or right side of the sequence. For example, the N-terminal βAla-Sar10-Ala tail is as follows: βAla-Sar10-A-(Sequence ID X) This is shown in the formula, where Sar represents sarcosine and βAla represents β-alanine.

[0115] Unless otherwise specified, all bicyclic peptides are understood to have a C-terminal CONH2 group, with the exception of those containing a C-terminal cysam group lacking a C-terminal CONH2 group (i.e., SEQ ID NO: 130). Furthermore, in certain bicyclic peptides, the C-terminal CONH2 group may be replaced with a COOH group, as shown herein for BCY27058.

[0116] [Reverse peptide sequence] Based on the disclosures of Nair et al (2003) J Immunol 170(3), 1362-1373, it is assumed that the peptide sequences disclosed herein will also be useful in their retro-inverso form. For example, the sequences are reversed (i.e., the N-terminus becomes the C-terminus, and vice versa), and their stereochemistry is also reversed (i.e., D-amino acids become L-amino acids, and vice versa).

[0117] [Bicyclic peptide ligand] The bicyclic peptide ligands referred to herein refer to peptide ligands covalently bonded to a molecular scaffold. Typically, such bicyclic peptides are native or non-native amino acids with two or more reactive groups (e.g., cysteine, homocysteine ​​(hCys, (S)-2-amino-4-sulfanybutyrate), βCys ((R)-3-amino-3-mercaptopropanoic acid), cysteamine (Cystam), or penicillamine (Pen, (R)-2-amino-3-mercapto-3-methylbutyrate), Dap ((S)-2,3-diaminopropanoic acid), or N-alkyl-Dap (e.g., N-methyl-D). The peptide comprises a polypeptide having ap ((S)-2-amino-3-(methylamino)propanoic acid) and capable of forming a covalent bond with a scaffold, and an immanent sequence between the reaction groups, referred to as a loop sequence, because the peptide forms a loop when bound to the scaffold. In this case, the peptide typically comprises at least three cysteine ​​groups (e.g., three cysteine ​​groups), or two cysteine ​​groups and one cystam group, forming at least two loops, most typically two, on the scaffold.

[0118] Accordingly, in some embodiments, the Disclosure provides peptides, peptide ligands, or bicyclic peptide ligands described 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 with homocysteine ​​(hCys), βCys, penicillamine (Pen), Dap, or N-methyl-Dap. To avoid doubt, in a complex described herein comprising two or more peptide ligands (e.g., two or more bicyclic peptide ligands), each ligand is modified such that, optionally independently, different ligands may be modified or unmodified, and different modified ligands may contain different modifications.

[0119] [peptide pole] As described above, in some embodiments, the peptides and ligands containing them (described in more detail herein) are specific to TLR3. In some embodiments, the complexes (e.g., multimer-binding complexes) contain TLR3-specific peptides and ligands containing them (described in more detail herein).

[0120] As used herein, the term “specific” (e.g., “specific binding”) refers in its broadest sense to a peptide or peptide ligand that binds to its biological target. In some embodiments, a peptide or peptide ligand binds to its biological target in a specific manner; that is, binding to the biological target is not nonspecific. In some embodiments, a peptide exhibiting nonspecific binding is indiscriminate; that is, a peptide can typically bind to multiple different biological species, including 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, a peptide or peptide ligand selected or designed to bind specifically to its intended target does not exhibit indiscriminate binding to off-target binding sites.

[0121] In some embodiments, binding to a target is binding to a specific epitope on the target. A peptide or peptide ligand may be designed to be specific to a particular epitope, or it may be identified by a suitable screening method, such as a display technique (e.g., phage display), which can be used to develop high-affinity binders to a given target (e.g., an epitope). Alternatively, a peptide or peptide ligand may be identified by specific binding to a biological target (e.g., a cellular target) without knowledge of the specific epitope to which it binds. In some embodiments, a peptide or peptide ligand that specifically binds to a target or epitope has high affinity for that target or epitope. In some embodiments, the binding affinity of a peptide or peptide ligand to its epitope is determined by its dissociation constant (K). D It can be expressed in terms of Kd. Typically, a peptide or peptide ligand that specifically binds to a biological target has a K concentration of less than 10 μM, e.g., less than 1 μM, relative to that target. D It has. Often, peptides or peptide ligands that specifically bind to a biological target have a nanomolar K to that target. D For example, it may have a concentration of 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. Several suitable assays are described in the examples.

[0122] In some embodiments, a peptide or peptide ligand that specifically binds to a biological target has a higher affinity (lower K) for a particular biological target than other biologically binding epitopes. D) has. For example, a peptide or peptide ligand that specifically binds to TLR3 typically binds to TLR3 with higher affinity than other epitopes, e.g., other Toll-like receptors. In some embodiments, a peptide or peptide ligand that specifically binds to a biological target binds to the target with an affinity at least twice as strong as the binding of the peptide to any other off-target binding partner, e.g., at least 5 times, e.g., at least 10 times, e.g., at least 20 times, e.g., at least 50 times, e.g., at least 100 times, e.g., at least 1000 times or more.

[0123] [Advantages of bicyclic peptide ligands] The specific bicyclic peptides of the present invention possess several advantageous properties that allow them to be considered drug-like molecules suitable for injection, inhalation, nasal, ocular, oral, or topical administration. These advantageous properties include: - Species cross-reactivity. This is a typical requirement for preclinical pharmacodynamic and pharmacokinetic evaluations. - Protease stability. Ideally, bicyclic peptide ligands should exhibit stability against plasma proteases, epithelial ("membrane-anchored") proteases, gastric and intestinal proteases, lung surface proteases, and intracellular proteases. Protease stability needs to be maintained across different species so that bicyclic lead candidates can be developed in animal models and confidently administered to humans. - Desired solubility profile. This is a function of the ratio of charged hydrophilic residues to hydrophobic residues and intramolecular / intermolecular H bonds, which is important for formulation and absorption purposes. - Optimal plasma half-life in circulation. Depending on the clinical indication and treatment regimen, it may be necessary to develop bicyclic peptides for short-term exposure in acute disease management settings, or bicyclic peptides with improved retention in circulation, and therefore optimal for managing more chronic disease states. Another factor driving a desirable plasma half-life is the requirement for sustained exposure for maximum therapeutic efficiency against concomitant toxicology due to sustained exposure of the drug. - Selectivity.

[0124] [Abbreviation] Many non-natural amino acids are used in the peptide ligands of the present invention, and for clarity, these are referred to herein by the following fully defined abbreviations: Agb: 2-amino-4-guanidinobutyric acid Aio: Aminoisobutyric Acid AlloIle: Alloisoleucine Arg(Me):dN Methylarginine AzaTrp: Azatryptophan Aze: Azetidine Cba: β-cyclobutylalanine Cbg: Cyclobutylglycine CF3Ala:β-trifluoromethylalanine CF3Nva: 5,5,5-trifluoronorvaline (or (S)-2-amino-5,5,5-trifluoropentanoic acid) 4CF3Phe:4-trifluoromethylphenylalanine C5g: Cyclopentylglycine CIA: Carboxymidamide Cis-HyP:cis-L-4-hydroxyproline Cit: Citrulline 6ClTrp:6-chlorotryptophan Cysam: Cysteamine Dap: Diaminopropionic acid 44DFP: 4,4-difluoroproline 26DiMeTyr:2,6-dimethyltyrosine DOPA: 3,4-dihydroxyphenylalanine EPA: 2-amino-3-ethylpentanoic acid 4FlPro:4-Fluoro-Proline 2FPhe:2-Fluorophenylalanine 3FPhe:3-Fluorophenylalanine 4FPhe:4-Fluorophenylalanine 4FTrp:4-Fluoro-L-tryptophan 5FTrp:5-Fluoro-L-tryptophan 6FTrp:6-fluoro-L-tryptophan 7FTrp:7-fluoro-L-tryptophan 2FTyr:2-fluorotyrosine 3FTyr:3-fluorotyrosine Gla:L-γ-carboxyglutamic acid HArg: Homoarginine His1Me:N1-methyl-L-histidine His3Me:N3-methyl-L-histidine HLeu: Homoleucin HSer: Homoserine HyP: Hydroxyproline 3HyV:3-hydroxy-L-valine KFl: Lysine-Fluorescein K(PYA): Lysine, ε-4-pentinoyl 4MeOTrp:4-methoxy-tryptophan 5MeOTrp:5-Methoxytryptophan 2MePhe:2-methylphenylalanine 3MePhe:3-methylphenylalanine 4MePhe:4-methylphenylalanine 2MeTrp:2-methyl-tryptophan 4MeTrp:4-methyl-tryptophan 5MeTrp:5-methyl-tryptophan 6MeTrp:6-methyl-tryptophan 7MeTrp:7-methyl-tryptophan 1Nal:1-Naphthylalanine 2Nal:2-Naphthylalanine Nle: Norleucine Nva: Norvaline Orn: Ornithine PG: Propargylglycine Pip: Pipecolic acid PYA: Pentic acid R-aMeLys(PYA):(R)-α-methyllysine,ε-4-pentinoyl S-aMeLys(PYA):(S)-α-methyllysine,ε-4-pentinoyl tBuAla: t-butyl-alanine tBuGly: t-butyl-glycine 4tBuPhe:4-t-butyl-phenylalanine 3tBuTyr:3-t-butyl-tyrosine TfNle:6,6,6-trifluoronorleucine trans-4FlPro: trans-4-fluoropyrrolidine-2-carboxylic acid Trp(Me): Methyltryptophan Trp(S): α-amino-benzo[b]thiophene-3-propanoic acid

[0125] [Medically acceptable salts] The salt form is within the scope of the present invention, and references to peptide ligands are understood to include the salt form of said ligand.

[0126] The salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. Generally, such salts can be produced by reacting the free acidic or basic forms of these compounds with a suitable base or acid in water or an organic solvent, or a mixture thereof.

[0127] Acid addition salts (mono or disal) can be formed with a wide variety of both inorganic and organic acids. Examples of acid addition salts include 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-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, and cinnamic acid. Cramic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalogens (e.g., hydrobromic acid, hydrochloric acid, Hydroiodic acid, isethionic 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-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitin Examples include acids, monosal or disalts formed with acids selected from the group consisting of pamoic 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, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid, as well as acylated amino acids and cation exchange resins.

[0128] One particular group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. One particular salt is a hydrochloride salt. Another particular salt is an acetate salt.

[0129] The compound is anionic, or has functional groups that can be anionic (e.g., -COOH is -COO - If it has (possibly), the salt can be formed with an organic or inorganic base to produce a suitable cation. Examples of suitable inorganic cations include alkali metal ions, such as Li + na + and K + , alkaline earth metal cations, for example, Ca 2+ and Mg 2+ , and other cations, such as Al 3+ or Zn + Examples of suitable organic cations include, but are not limited to, the ammonium ion (i.e., NH4). + ) and substituted ammonium ions (e.g., NH3R + NH2R2 + NHR3 + NR4 + Examples of suitable substituted ammonium ions include, but are not limited to, methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids, such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4 + That is the case.

[0130] If the peptides of the present invention contain amine functional groups, they can be reacted with an alkylating agent, for example, according to methods well known to those skilled in the art, to form quaternary ammonium salts. Such quaternary ammonium compounds are within the scope of the peptides of the present invention.

[0131] The peptides of the present invention (including peptide ligands and their complexes) may exist as zwitterions. Such compounds may also be provided in the form of pharmaceutically acceptable salts. Suitable salts include COO - Examples include those formed with a pharmaceutically acceptable acid that provides a proton to a negatively charged group, such as a quaternary nitrogen atom, and a counterion to balance the positive charge on a positively charged group, such as a quaternary nitrogen atom. Suitable pharmaceutically acceptable acids include hydrochloric acid, sulfonic acid (including methanesulfonic acid and toluenesulfonic acid), ascorbic acid, and citric acid. Hydrochloric acid and sulfonic acid are preferred, and hydrochloric acid is particularly preferred. Alternatively, the zwitterion may 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.

[0132] [Modified derivative] The modified derivatives of peptide ligands described herein are understood to be within the scope of the present invention.

[0133] In some embodiments, the modified derivatives include functional fragments, derivatives, and variants of the sequences described herein.

[0134] As those skilled in the art will understand, a fragment of an amino acid sequence includes deletion variants of such a sequence in which one or more amino acids, for example, at least 1, 2, 3, 4, or 5 amino acids are deleted. The deletion may occur at the C-terminus or N-terminus of the reference sequence, or within the reference sequence.

[0135] Derivatives of amino acid sequences include modified sequences, including sequences modified in vivo or ex vivo. Many different protein modifications are known to those skilled in the art and include modifications to introduce novel functions to amino acid residues, modifications to protect reactive amino acid residues, or modifications to couple amino acid residues to chemical moieties such as reactive functional groups on linkers for binding to such amino acid residues. Exemplary modifications that can be made to the provided peptides, ligands, and associated complexes are described in more detail herein.

[0136] Derivatives of an amino acid sequence include addition variants of such a sequence in which one or more amino acids, for example, at least 1, 2, 3, 4, or 5 amino acids are added to or introduced into the reference sequence. The addition may occur at the C-terminus or N-terminus of the reference sequence, or within the reference sequence itself.

[0137] Amino acid sequence variants include sequences in which one or more amino acids in a reference sequence, for example, at least 1, 2, 3, 4, or 5 amino acids, are replaced by one or more other residues. Amino acid sequence variants include sequences containing naturally occurring amino acids and / or non-natural amino acids.

[0138] The variants, derivatives, and fragments of the above amino acid sequence typically retain at least some of the activity / functionality of the reference sequence. In preferred embodiments, the variants, derivatives, and fragments substantially retain their biological functions as 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 to TLR3. In such one embodiment, the variants, derivatives, and fragments bind to the same epitope 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 / functionality compared to the reference sequence.

[0139] In some embodiments, variants, derivatives, or fragments of an amino acid sequence are expressed in terms of their percentage of identity with respect to a reference sequence. Protocols for determining the percentage of identity are routine procedures within the scope of the art. Suitable methods include the CLUSTAL W (Thompson et al., Nucleic Acids Research, 22(22) 4673-4680 (1994)) and iterative modification (Gotoh, J. Mol. Biol. 264(4) 823-838 (1996)); the methods described in Altschul et al., Bull. Math. Bio. 48: 603-16, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-19, 1992. In the exemplary method, two amino acid sequences are aligned, and the alignment score is optimized using a gap start penalty of 10, a gap extension penalty of 1, and the Henikoff and Henikoff (ibid.) "blosum 62" score matrices to calculate the percentage of identity as [100 × (T / L)], where T = the total number of identical matches and L = the length of the longer sequence + the number of gaps introduced into the longer sequence to align the two sequences.

[0140] In some embodiments, a variant, derivative, or fragment of a reference sequence has at least 60% identity with respect to the reference sequence, for example, 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 more identity with respect to the reference sequence.

[0141] Examples of such appropriate modified derivatives include N-terminal and / or C-terminal modifications; substitution of one or more amino acid residues with one or more unnatural 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 isosterically and / or isoelectronic amino acids; substitution of one or more natural amino acids with one or more isosterically and / or isoelectronic unnatural amino acids or vice versa (e.g., substitution of one or more polar amino acid residues with one or more isosterically or isoelectronic amino acids; substitution of one or more nonpolar amino acid residues with other unnatural isosterically or isoelectronic amino acids); addition of spacer groups; substitution of one or more oxidation-sensitive amino acid residues with one or more oxidation-resistant amino acid residues; and substitution of one or more amino acid residues with alanine. Modifications include substitution of 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; substitution of one or more peptide bonds by surrogate bonding; modification of peptide backbone length; substitution of one or more hydrogen atoms on the α-carbon of an amino acid residue with another chemical group; modification of amino acids such as cysteine, lysine, glutamic acid / aspartic acid, and tyrosine with appropriate amine, thiol, carboxylic acid, and phenol-reactive reagents for functionalizing the amino acids; and one or more modifications selected from the introduction or substitution of amino acids having azide or alkyne groups that introduce orthogonal reactivity suitable for functionalization, for example, amino acids having azide or alkyne groups that enable functionalization by moieties having alkyne or azide groups, respectively.

[0142] Amino acid residues can typically be substituted with other amino acid residues having a similar chemical structure, similar chemical properties, or similar side-chain volume ("conservative substitutions"). The introduced amino acid may have similar polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality, or charge to the amino acid being replaced. Alternatively, a conservative substitution may involve introducing another amino acid, which is aromatic or aliphatic, in place of an existing aromatic or aliphatic amino acid. Conservative amino acid substitutions are well known in the art and can be selected according to the properties of the 20 major amino acids defined in Table A above. If the amino acids have similar polarity, this can also be determined by referring to the hydroxyl scale of the amino acid side chains, which is also well known to those skilled in the art.

[0143] In one embodiment, the modified derivative includes N-terminal and / or C-terminal modifications. In a further embodiment, the modified derivative includes N-terminal modifications using appropriate amino-reactive chemistry and / or C-terminal modifications using appropriate carboxy-reactive chemistry. In a further embodiment, the N-terminal or C-terminal modification includes the addition of an effector group, including but not limited to cytotoxic agents, radiochelating agents, or chromophores.

[0144] 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 a molecule with an acetylated N-terminus. This embodiment offers the advantage of removing a potential recognition site for aminopeptidases and avoiding the possibility of degradation of the bicyclic peptide.

[0145] In another embodiment, the N-terminal modification involves the addition of a molecular spacer group to facilitate the binding of an effector group and the retention of the bicyclic peptide's potency to its target.

[0146] 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 a molecule with an amidated C-terminus. This embodiment offers the advantage of removing a potential recognition site for carboxypeptidases, thereby reducing the potential for proteolysis of the bicyclic peptide.

[0147] In one embodiment, the modified derivative comprises the substitution of one or more amino acid residues with one or more non-natural amino acid residues. In this embodiment, the non-natural amino acids may be selected to have isosteric / isoelectronic side chains that are not recognized by degradable proteases and have no adverse effect on target efficacy.

[0148] Alternatively, non-natural amino acids with restricted amino acid side chains may be used so that proteolytic hydrolysis of nearby peptide bonds is conformally and sterically inhibited. In particular, these relate to proline analogs, bulky side chains, Cα-disubstituted derivatives (e.g., aminoisobutyric acid, Aib), and cycloamino acids, with simple derivatives being amino-cyclopropylcarboxylic acids.

[0149] In one embodiment, the modified derivative includes the addition of a spacer group. In a further embodiment, the modified derivative includes the addition of a spacer group to the N-terminal cysteine ​​and / or the C-terminal cysteine.

[0150] In one embodiment, the modified derivative includes the substitution of one or more oxidation-sensitive amino acid residues with one or more oxidation-resistant amino acid residues.

[0151] In one embodiment, the modified derivative includes the substitution of one or more charged amino acid residues with one or more hydrophobic amino acid residues. In another embodiment, the modified derivative includes the substitution of one or more hydrophobic amino acid residues with one or more charged amino acid residues. The precise balance between charged and hydrophobic amino acid residues is a crucial characteristic of bicyclic peptide ligands. For example, hydrophobic amino acid residues can affect the degree of plasma protein binding and therefore the concentration of the free, available fraction in plasma, while charged amino acid residues (particularly arginine) can affect the peptide's interaction with the phospholipid membrane on the cell surface. Two of the combinations 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 number of charged and hydrophobic amino acid residues can reduce irritation at the injection site (when the peptide drug is administered subcutaneously).

[0152] In one embodiment, the modified derivative includes the substitution of one or more L-amino acid residues with one or more D-amino acid residues. This embodiment is thought to increase proteolytic stability due to steric hindrance and the tendency of D-amino acids to stabilize the β-turn conformation (Tugyi et al (2005) PNAS, 102(2), 413-418).

[0153] In one embodiment, the modified derivative includes the removal of any amino acid residue and substitution with alanine. This embodiment offers the advantage of eliminating potential proteolytic attack sites.

[0154] It should be noted that each of the above modifications works to intentionally improve the potency or stability of the peptide. Further potency improvements based on modifications can be achieved through the following mechanisms: - By utilizing the hydrophobic effect and incorporating a hydrophobic moiety that results in a lower dissociation rate, a higher affinity can be achieved. - Incorporating charged groups that utilize long-range ionic interactions results in faster binding velocities and higher affinity (see, for example, Schreiber et al, Rapid, electrostatically assisted association of proteins (1996), Nature Struct. Biol. 3, 427-31). - For example, additional constraints can be incorporated into the peptide by precisely constraining the amino acid side chains to minimize entropy loss during target binding, constraining the torsion angle of the skeleton to minimize entropy loss during target binding, and introducing additional cyclization to the molecule for the same reasons (see Gentilucci et al, Curr. Pharmaceutical Design, (2010), 16, 3185-203 and Nestor et al, Curr. Medicinal Chem (2009), 16, 4399-418 for reviews).

[0155] [Isotope variation] The present invention comprises all peptide ligands of the present invention labeled with pharmaceutically acceptable (radioactive) isotopes, in which one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from that commonly found in nature; peptide ligands of the present invention to which a metal chelating group capable of holding the associated (radioactive) isotope is bonded (referred to as an "effector"); and peptide ligands of the present invention in which a specific functional group is covalently replaced by the associated (radioactive) isotope or an isotope-labeled functional group.

[0156] Examples of isotopes suitable for inclusion in the peptide ligand of the present invention are: 2 H(D) and 3 Hydrogen such as H(T), 11 C, 13 C and 14 Carbon such as C, 36 Chlorine such as Cl 18 Fluorine such as F 123 I, 125I and 131 Iodine such as I 13 N and 15 Nitrogen such as N, 15 O, 17 O and 18 Oxygen such as O, 32 P and other phosphorus 35 Sulfur such as S 64 Copper such as Cu 67 Ga or 68 Gallium such as Ga, 90 Yttrium such as Y and 177 Lutetium such as Lu, and 213 It contains bismuth isotopes such as Bi.

[0157] The specific isotope-labeled peptide ligands of the present invention, for example those incorporating radioisotopes, are useful in studies of the tissue distribution of drugs and / or substrates. The peptide ligands of the present invention can further possess valuable diagnostic properties in that they can be used to detect or identify the formation of complexes between labeled compounds and other molecules, peptides, proteins, enzymes, or receptors. Detection or identification methods may use compounds labeled with labeling substances such as radioisotopes, enzymes, fluorescent substances, and luminescent substances (e.g., luminol, luminol derivatives, luciferin, aequorin, and luciferase). Radioisotope tritium, i.e. 3 H(T), and carbon-14, i.e. 14 C is particularly useful for this purpose due to its ease of introduction and the ease of detection.

[0158] Deuterium, that is 2 Substitution with heavier isotopes such as H(D) may result in certain therapeutic benefits stemming from higher metabolic stability, such as an increased in vivo half-life or a reduced required dose, and therefore may be preferable in some situations.

[0159] 11 C, 18 F, 15 O and 13Substitution with positron-emitting isotopes such as 16N may be useful in positron emission tomography (PET) studies to investigate target occupancy.

[0160] The peptide ligand isotope-labeled compounds of the present invention can generally be produced by conventional techniques known to those skilled in the art, or by processes similar to those described in the attached examples, using appropriate isotope-labeling reagents instead of previously used unlabeled reagents.

[0161] [Molecular scaffolding] In some embodiments, the polypeptides disclosed herein are bound to a molecular scaffold. In one embodiment, the molecular scaffold includes a non-aromatic molecular scaffold. References herein to “non-aromatic molecular scaffold” refer to any molecular scaffold described herein that does not contain aromatic (i.e., unsaturated) carbocyclic or heterocyclic ring systems. Thus, in some embodiments, the polypeptide is bound to a non-aromatic molecular scaffold. In other embodiments, the polypeptide is bound to an aromatic molecular scaffold. Molecular scaffolds are described, for example, in WO2009 / 098450 and the references cited therein, particularly WO2004 / 077062 and WO2006 / 078161.

[0162] As described in the above literature, the molecular scaffold can be a small molecule, such as a small organic molecule.

[0163] In one embodiment, the molecular scaffold may be a macromolecule. In one embodiment, the molecular scaffold is a macromolecule composed of amino acids, nucleotides, or carbohydrates.

[0164] In one embodiment, the molecular scaffold includes reactive groups that can react with functional groups of a polypeptide to form covalent bonds.

[0165] The molecular scaffold may contain chemical groups that form links with peptides, such as amines, thiols, alcohols, ketones, aldehydes, nitriles, carboxylic acids, esters, alkenes, alkynes, azides, anhydrides, succinimides, maleimides, alkyl halides, and acyl halides.

[0166] The molecular scaffold of the present invention comprises a chemical group that enables the functional groups of polypeptides in the encoded library of the present invention to form covalent bonds with the molecular scaffold. The chemical group is selected from a broad range of functional groups, including amines, thiols, alcohols, ketones, aldehydes, nitriles, carboxylic acids, esters, alkenes, alkynes, anhydrides, succinimides, maleimides, azides, alkyl halides, and acyl halides.

[0167] The scaffolding reactants that can be used on a molecular scaffold to react with the thiol group of cysteine ​​are alkyl halides (also called halogenoalkanes or haloalkanes).

[0168] Examples include bromomethylbenzene or iodoacetamide. Other scaffold reactive groups used to selectively couple compounds to cysteine ​​in proteins include maleimides, αβ-unsaturated carbonyl-containing compounds, and α-halomethylcarbonyl-containing compounds. Examples of maleimides that can be used as molecular scaffolds in the present invention include tris-(2-maleimidoethyl)amine, tris-(2-maleimidoethyl)benzene, and tris-(maleimido)benzene.

[0169] In one embodiment, the molecular scaffold is selected from 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tripropa-2-en-1-one (triacryloylhexahydro-s-triazine; also known as 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).

[0170] In a further embodiment, the molecular scaffold is 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tripropa-2-en-1-one (also known as triacryloylhexahydro-s-triazine (TATA)): [ka] TATA.

[0171] Therefore, after cyclization with the bicyclic peptide of the present invention on the cysteine ​​residue, the molecular scaffold has the following structure: [ka] It has, and also, [ka] This can be represented as forming a tri-substituted 1,1',1''-(1,3,5-triazinan-1,3,5-triyl)tripropan-1-one derivative of TATA, where * indicates a binding site of three cysteine ​​residues.

[0172] In another embodiment, the molecular scaffold is 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine (TATB): [ka] TATB.

[0173] Therefore, after cyclization with the bicyclic peptide of the present invention on a cysteine ​​residue (for example), the molecular scaffold has the following structure: [ka] It has, and also, [ka] This can be represented as forming a tri-substituted 1,3,5-tris(bromoacetyl)hexahydro-1,3,5-triazine derivative of TATB, where * indicates a binding site of three cysteine ​​residues.

[0174] In another embodiment, the molecular scaffold is 2,4,6-tris(bromomethyl)-s-triazine (TBMT): [ka] TBMT.

[0175] Therefore, C i , C ii and C iii After cyclization with the bicyclic peptide of the present invention on a cysteine ​​residue, the molecular scaffold has the following structure: [ka] It has, and also, [ka] This can be represented as forming a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, where * indicates a binding site of (for example) three cysteine ​​residues.

[0176] Details of TBMT and its derivatization, and its use in cyclic peptides, are described in van de Langemheen et al (2016) ChemBioChem 10.1002 / cbic.201600612 (https: / / onlinelibrary.wiley.com / doi / abs / 10.1002 / cbic.201600612).

[0177] In another embodiment, the molecular scaffold is 2,4,6-tris(chloromethyl)-1,3,5-triazine (TCTZ): [ka] TCTZ.

[0178] Therefore, C i , C ii and C iii After cyclization with the bicyclic peptide of the present invention on a cysteine ​​residue, the molecular scaffold has the following structure: [ka] It has the following properties, where * indicates a binding site for (for example) three cysteine ​​residues, forming a tri-substituted 2,4,6-tris(chloromethyl)-s-triazine derivative of TCTZ.

[0179] After cyclization of the bicyclic peptide of the present invention with either TBMT or TCTZ, derivatives of TBMT and TCTZ that form a molecular scaffold are understood to have the same structure as described above. Therefore, when a molecular scaffold that is a derivative of TBMT is referred to herein, the molecular scaffold may also be a derivative of TCTZ.

[0180] [Reactive group] The molecular scaffolds of the present invention can be bonded to polypeptides via functional groups or reactive groups on the polypeptide. These are typically formed from the side chains of specific amino acids found in polypeptide polymers. Such reactive groups may be cysteine ​​side chains, homocysteine ​​side chains (hCys, (S)-2-amino-4-sulfanybutyrate), βCys side chains ((R)-3-amino-3-mercaptopropanoic acid), cysteamine side chains (Cysam, 2-aminoethanethiol), penicillamine side chains (Pen, (R)-2-amino-3-mercapto-3-methylbutyrate), Dap groups ((S)-2,3-diaminopropanoic acid), N-alkyl-Dap groups (e.g., N-methyl-Dap, (S)-2-amino-3-(methylamino)propanoic acid, [Dap(Me)] group), lysine side chains, or N-terminal amine groups or any other suitable reactive groups. Further details can be found in WO2009 / 098450. In one embodiment, all reactive groups are cysteine ​​residues.

[0181] 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 phenol group of tyrosine, or the hydroxyl group of serine. Non-natural amino acids can provide a wide range of reactive groups, including azide, keto-carbonyl, alkyne, vinyl, or aryl halide groups. The terminal amino and carboxyl groups of polypeptides can also function as reactive groups for forming covalent bonds to molecular scaffolds / molecular cores.

[0182] The polypeptide of the present invention comprises at least three reactive groups. The polypeptide may also comprise four or more reactive groups. The more reactive groups used, the more loops can be formed in the molecular scaffold.

[0183] In a preferred embodiment, a polypeptide having three reactive groups is generated. The reaction of this polypeptide with a molecular scaffold / molecular core having three-fold rotational symmetry produces a single product isomer. The generation of a single product isomer is preferred for several reasons. The nucleic acids in the compound library encode only the primary sequence of the polypeptide, but not the isomeric state of the molecule formed during the reaction of the polypeptide with the molecular core. If only one product isomer can be formed, the assignment of the nucleic acid to the product isomer is clearly defined. If multiple product isomers are formed, the nucleic acid cannot provide information about the properties of the isolated product isomer in the screening or selection process. The formation of a single product isomer is also advantageous when a particular member of the library of the present invention is synthesized. In this case, the chemical reaction between the polypeptide and the molecular scaffold produces a single product isomer rather than a mixture of isomers.

[0184] In another embodiment of the present invention, a polypeptide having four reactive groups is generated. The reaction of this polypeptide with a molecular scaffold / molecular core having tetrahedral symmetry produces two product isomers. Even if 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 both isomers, separating the two isomers, and testing both isomers for binding to a target ligand.

[0185] In one embodiment of the present invention, at least one of the reactants of the polypeptide is orthogonal to the remaining reactants. The use of orthogonal reactants makes it possible to orient the orthogonal reactant to a specific site on the molecular core. The number of product isomers formed can be limited by using a linking strategy that includes orthogonal reactants. In other words, a specific sequence for linking or orienting specific reactants of the polypeptide to specific positions on the molecular scaffold can be usefully achieved by selecting a reactant distinct from or different from those selected for one or more of the at least three bonds.

[0186] In another embodiment, the reactive group of the polypeptide of the present invention reacts with a molecular linker, which can react with a molecular scaffold, and as a result, the linker interposes between the molecular scaffold and the polypeptide in the final bonded state.

[0187] In some embodiments, amino acids in a library or set of polypeptides can be replaced by any native or non-native amino acids. These interchangeable amino acids are excluded if they have functional groups for crosslinking the polypeptide to the molecular core, so that only the loop sequence is interchangeable. The interchangeable polypeptide sequence may be a random sequence, a constant sequence, or a sequence containing both random and constant amino acids. Amino acids with reactive groups are positioned in predetermined locations within the polypeptide, as the positions of these amino acids determine the loop size.

[0188] In one embodiment, a polypeptide having three reactive groups is sequence (X) l Y(X) m Y(X) n Y(X) o The formula comprises, where Y represents an amino acid having a reactive group, X represents a random amino acid, m and n are numbers from 2 to 8 that define the length of the intervening polypeptide segment, which may be the same or different, and l and o are numbers from 0 to 20 that define the length of the adjacent polypeptide segment.

[0189] Alternatively, a molecular scaffold can be attached to a peptide via a covalent interaction using a method other than thiol-mediated bonding. Alternatively, these techniques may be used to modify or attach further portions (such as small molecules of a different purpose than the molecular scaffold) to polypeptides selected or isolated according to the present invention, and in this embodiment, obviously, the bond does not need to be covalent and may include non-covalent bonds. These methods may be used instead of (or in combination with) thiol-mediated bonding by combining them with small molecules having complementary reactive groups to produce phages that present proteins and peptides having non-natural amino acids with the required chemical reactive groups, or by incorporating non-natural amino acids into chemically or recombinantly synthesized polypeptides when the molecules are made after the selection / isolation step. Further details can be found in WO2009 / 098450 or Heinis, et al., Nat Chem Biol 2009, 5 (7), 502-7.

[0190] [Effects and functional groups] A further aspect of the present invention provides a drug conjugate comprising a peptide ligand, a bicyclic peptide ligand, or a polymer-binding complex described herein, conjugated to one or more effectors and / or functional groups.

[0191] Effectors and / or functional groups may be attached, for example, to the N and / or C terminus of a polypeptide, to amino acids within the polypeptide, or to a molecular scaffold.

[0192] A suitable effector group may include an antibody or a portion or fragment thereof. For example, an effector group may include one or more constant region domains in addition to the antibody light chain constant region (CL), antibody CH1 heavy chain domain, antibody CH2 heavy chain domain, antibody CH3 heavy chain domain, or any combination thereof. An effector group may also include the hinge region of the antibody (such a region is typically found between the CH1 and CH2 domains of an IgG molecule).

[0193] In a further embodiment of this aspect of the present invention, the effector group according to the present invention is the Fc region of an IgG molecule. Advantageously, the peptide ligand-effector group according to the present invention comprises or consists of a peptide ligand Fc fusion having a tβ half-life of 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more. Most advantageously, the peptide ligand according to the present invention comprises or consists of a peptide ligand Fc fusion having a tβ half-life of 1 day or more.

[0194] Functional groups generally include binding groups, reactive groups for the binding of drugs or other entities, and functional groups that assist in the uptake of macrocyclic peptides into cells.

[0195] The ability of peptides to penetrate cells makes them effective against intracellular targets. Targets that can be utilized by peptides with the ability to penetrate cells include transcription factors, intracellular signaling molecules such as tyrosine kinases, and molecules involved in apoptotic pathways. Functional groups that enable cell penetration include peptides, or chemical groups attached to either peptides or molecular scaffolds. For example, peptides such as VP22, HIV-Tat, and those derived from homeobox proteins of Drosophila melanogaster (Antennapedia), as described in Chen and Harrison, Biochemical Society Transactions (2007) Volume 35, part 4, p821; Gupta et al. in Advanced Drug Discovery Reviews (2004) Volume 57 9637. Examples of short peptides that have been shown to be efficient for translocation across the plasma membrane include the 16-amino acid penetratin peptide from the Drosophila Antennapedia protein (Derossi et al (1994) J Biol. Chem. Volume 269 p10444), the 18-amino acid "model amphiphilic peptide" (Oehlke et al (1998) Biochim Biophys Acts Volume 1414 p127), and the arginine-rich region of the HIV TAT protein. Non-peptidic approaches include the use of small molecule mimes or SMOCs that can be readily bound to biomolecules (Okuyama et al (2007) Nature Methods Volume 4 p153). Other chemical strategies involving the addition of guanidinium groups to molecules also enhance cell penetration (Elson-Scwab et al (2007) J Biol Chem Volume 282 p13585). Low molecular weight molecules such as steroids can be attached to molecular scaffolds to enhance uptake into cells.

[0196] One class of functional groups that can bind to peptide ligands includes antibodies and their binding fragments, such as Fab, Fv, or single-domain fragments. In particular, antibodies that bind to proteins capable of increasing the half-life of peptide ligands in vivo can be used.

[0197] In one embodiment, the peptide ligand-effector group according to the present invention has a tβ half-life selected from the group consisting of 12 hours or more, 24 hours or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 7 days or more, 8 days or more, 9 days or more, 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, or 20 days or more. Advantageously, the peptide ligand-effector group or composition according to the present invention has a tβ half-life in the range of 12 to 60 hours. In a further embodiment, it has a tβ half-life of 1 day or more. In yet another embodiment, it is in the range of 12 to 26 hours.

[0198] In one particular embodiment of the present invention, the functional group is selected from metal chelating agents suitable for complexing pharmaceutical-related metal radioisotopes.

[0199] Suitable effectors 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 (e.g., AlexaFluor 488, etc.) and Bodipy compounds (e.g., Bodipy 558). Effectors and / or functional groups may include those that produce a detectable signal in the presence of a second intermediate (e.g., biotin and various protein antigens). In the case of biotin, the second intermediate may be a streptavidin-enzyme conjugate or a streptavidin-dye conjugate.

[0200] Possible effector groups also include enzymes, such as carboxypeptidase G2 for use in enzyme / prodrug therapy, where the peptide ligand replaces the antibody in ADEPT.

[0201] In one particular embodiment of the present invention, the functional group is selected from drugs, for example, cytotoxic agents for cancer treatment. Suitable examples include alkylating agents, e.g., cisplatin and carboplatin, as well as oxaliplatin, mechloretamine, cyclophosphamide, chlorambucil, and ifosfamide; antimetabolites, e.g., purine analogs azathioprine and mercaptopurine or pyrimidine analogs; plant alkaloids and terpenoids, e.g., vinca alkaloids, e.g., vincristine, vinblastine, vinorelbine, and vindesine; podophyllotoxins and their derivatives etoposide and teniposide; taxanes, e.g., paclitaxel (originally known as taxol); topoisomerase inhibitors, e.g., camptothecin:irinotecan and topotecan; and type II inhibitors, e.g., amsacrin, etoposide, etoposide phosphate, and teniposide. Further medications include the immunosuppressant dactinomycin (used in kidney transplants), and antitumor antibiotics such as doxorubicin, epirubicin, bleomycin, and calicheamicin.

[0202] In one further specific embodiment of the present invention, the cytotoxic agent is selected from mytansinoids (e.g., DM1) or monomethyl auristatin (e.g., MMAE).

[0203] In one embodiment, the cytotoxic agent is linked to a bicyclic peptide by a cleavable bond, such as a disulfide bond or a protease-sensitive bond. In a further embodiment, a group adjacent to the disulfide bond is modified to control interference with the disulfide bond, thereby controlling the rate of cleavage and the release of the associated cytotoxic agent.

[0204] Published studies have established the possibility of modifying the sensitivity of disulfide bonds to reduction by introducing steric hindrance on either side of the disulfide bond (Kellogg et al (2011) Bioconjugate Chemistry, 22, 717). Greater steric hindrance reduces the reduction rates by intracellular glutathione and extracellular (systemic) reducing agents, consequently reducing the ease with which toxins are released both intracellularly and extracellularly. Therefore, the optimal choice of disulfide stability in circulation (minimizing undesirable side effects of toxins) for efficient release in the intracellular environment (maximizing therapeutic effects) can be achieved by carefully selecting the degree of interference on either side of the disulfide bond.

[0205] The disruption of either side of the disulfide bond is regulated by introducing one or more methyl groups to either the target entity (in this case, the bicyclic peptide) side or the toxin side of the molecular construct.

[0206] [Synthesis] The peptides of the present invention can be synthesized by standard techniques and subsequently reacted with a molecular scaffold in vitro. Standard chemistry can be used in this process. This allows for the rapid, large-scale production of soluble substances for further downstream experiments or validation. Such methods can be achieved using conventional chemistry, such as that disclosed by Timmerman et al. (above).

[0207] Accordingly, the present invention also relates to the production of polypeptides selected as described herein, wherein the production includes any further steps as described below. In one embodiment, these steps are carried out on a final product polypeptide produced by chemical synthesis.

[0208] Peptides can also be extended to incorporate, for example, another loop, thereby introducing multiple specificities.

[0209] Peptides can be simply chemically extended at their N-terminus or C-terminus, or within a loop, using orthogonally protected lysine (and analogues) with standard solid-phase or liquid-phase chemistry. Activated or activatable N-terminuses can be introduced using standard (bio)conjugation techniques. Alternatively, addition can be performed by fragment condensation or native chemical ligation (e.g., Dawson et al. 1994. Synthesis of Proteins by Native Chemical Ligation. Science 266:776-779), or enzymatically using subtilis ligases (e.g., Chang et al. Proc Natl Acad Sci US A. 1994 Dec 20; 91(26):12544-8 or Hikari et al. Bioorganic & Medicinal Chemistry Letters Volume 18, Issue 22, 15 November 2008, Pages 6000-6003).

[0210] Alternatively, the peptides may be extended or modified by further conjugation via disulfide bonds. This has the added advantage that the first and second peptides dissociate from each other in the reducing environment of the cell. In this case, a molecular scaffold (e.g., TATA, TATB, or TBMT) may be added during the chemosynthesis of the first peptide to react with three cysteine ​​groups; then, an additional cysteine ​​or thiol may be added to the N or C terminus of the first peptide, so that this cysteine ​​or thiol reacts only with the free cysteine ​​or thiol of the second peptide, forming a disulfide-bonded bicyclic peptide-peptide conjugate.

[0211] Similar techniques can be equally applied to the synthesis / coupling of two bicyclic and two-specificity macrocyclic molecules, potentially generating a tetraspecificity molecule.

[0212] Furthermore, the addition of other functional groups or effector groups can be achieved in the same manner by appropriate chemistry, either by coupling at the N or C terminus, or via the side chain. In one embodiment, the coupling is carried out in such a way as not to interfere with the activity of any of the entities.

[0213] In some embodiments, the synthesis of the peptide ligand described herein may include the solid-phase synthesis of the polypeptide described herein. In some embodiments, the solid-phase synthesis includes Fmoc solid-phase peptide synthesis (e.g., described in more detail herein). In some embodiments, the synthesized polypeptide is cyclized using the molecular scaffold described herein. In some embodiments, the cyclized ligand is purified, for example, by lyophilization. In some embodiments, the synthesis of the complex described herein includes the reaction of the cyclized polypeptide with a linker described herein. In some embodiments, the reaction of the cyclized polypeptide with a linker includes the reaction of an azide group (e.g., on the linker) with an alkyne group (e.g., on the polypeptide). In some embodiments, the reaction of the azide group with the alkyne group is carried out in the presence of a suitable azide-alkyne cyclization catalyst. In some embodiments, the suitable catalyst includes CuSO4. In some embodiments, the reaction of the azide group with the alkyne group is carried out under an inert atmosphere (e.g., N2). In some embodiments, the reaction between the cyclized polypeptide and the linker involves the reaction between an amine group (e.g., on the polypeptide) and 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 amine group and the carboxylic acid group or its activated derivative is carried out in the presence of a suitable coupling agent. In some embodiments, the suitable coupling agent includes a base.

[0214] [Pharmaceutical composition] A further aspect of the present invention provides a pharmaceutical composition comprising a peptide ligand or polymer-binding complex described herein in combination with one or more pharmaceutically acceptable additives.

[0215] Generally, this peptide ligand is used in a purified form with pharmacologically appropriate additives or carriers. Typically, these additives or carriers include aqueous or alcoholic / aqueous solutions, emulsions, or suspensions, including physiological saline and / or buffering media. Non-enteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, and Ringer's lactate solution. Appropriate physiologically acceptable adjuvants may be selected from thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin, and alginates, if necessary to maintain the polypeptide complex in suspension.

[0216] Intravenous vehicles include fluids and nutritional and electrolyte supplements, such as ringer's dextrose-based ones. 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).

[0217] The compounds of the present invention can be used alone or in combination with other drugs(s).

[0218] The compounds of the present invention can also be used in combination with nucleic acid-based therapies, antibodies, bacteriophages, or phage lysins, or other biological therapies.

[0219] The routes of administration of the pharmaceutical compositions according to the present invention may be any of those commonly known to those skilled in the art. For therapeutic purposes, the peptide ligands of the present invention may 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 (e.g., including by patches, plasters, etc.); transmucosal (e.g., including by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, for use, e.g., through the mouth or nose, e.g., by inhalation or blowing); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); and non-enteral injections, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; and implantation of depots or reservoirs, e.g., subcutaneous or intramuscular. Preferably, the pharmaceutical composition according to the present invention is administered non-enterally. The dose and frequency of administration depend on the patient's age, sex and condition, concomitant administration of other drugs, contraindications, and other parameters that the clinician should consider.

[0220] The peptide ligands of the present invention can be lyophilized for storage and reconstituted in a suitable carrier before use. This technique has been shown to be effective, and lyophilization and reconstitution techniques known in the art can be used. It will be understood by those skilled in the art that lyophilization and reconstitution may result in varying degrees of activity loss, and that these may need to be adjusted upward to compensate for the levels.

[0221] Compositions containing this peptide ligand or a cocktail thereof may be administered for therapeutic purposes. In a particular therapeutic application, the amount sufficient to achieve at least partial inhibition, suppression, modulation, death, or any other measurable parameter of a selected population of cells is defined as the "therapeutic effective dose." The amount required to achieve this dose depends on the severity of the disease and the general state of the patient's own immune system, but is generally in the range of 10 μg to 250 mg of the selected peptide ligand per kg of body weight, with administrations in the range of 100 μg to 25 mg / kg / dose being more commonly used.

[0222] Compositions containing peptide ligands according to the present invention may be used in a therapeutic setting to treat microbial infections or to provide prevention to subjects at risk of infection, such as those undergoing surgery, chemotherapy, mechanical ventilation, or other conditions or planned interventions. The peptide ligands described herein may also be used selectively in vitro or externally to kill, deplete, or otherwise effectively remove target cell populations from heterogeneous cell populations. Mammalian blood may be combined with selected peptide ligands in vitro, thereby killing or otherwise removing unwanted cells from the blood according to standard techniques for return to the mammal.

[0223] [Treatment use] A further aspect of the present invention provides peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymer-bound complexes, or drug conjugates described herein for use in preventing, suppressing, or treating TLR3-mediated diseases or disorders.

[0224] A further aspect of the present invention provides a method for preventing, suppressing or treating a TLR3-mediated disease or disorder, comprising administering a peptide ligand, bicyclic peptide ligand, pharmaceutical composition, polymer-bound complex, or drug conjugate described herein to a patient in need thereof. A further aspect of the present invention provides the use of a peptide ligand, bicyclic peptide ligand, pharmaceutical composition, polymer-bound complex, or drug conjugate described herein in the manufacture of a pharmacopoeia for preventing, suppressing or treating a TLR3-mediated disease or disorder.

[0225] Examples of diseases or disorders mediated by TLR3 include autoimmune diseases, inflammatory conditions, and cancer.

[0226] Further embodiments provide peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymer-bound complexes, or drug conjugates described herein for use in preventing, suppressing, or treating diseases or disorders selected from autoimmune diseases, inflammatory conditions, and cancer. Further embodiments provide a method for preventing, suppressing, or treating diseases or disorders selected from autoimmune diseases, inflammatory conditions, and cancer, comprising administering a peptide ligand, bicyclic peptide ligand, pharmaceutical composition, polymer-bound complex, or drug conjugate described herein to a patient in need thereof. Further embodiments provide the use of peptide ligands, bicyclic peptide ligands, pharmaceutical compositions, polymer-bound complexes, or drug conjugates described herein in the manufacture of a medicament for preventing, suppressing, or treating diseases or disorders selected from autoimmune diseases, inflammatory conditions, and cancer.

[0227] Appropriate examples of autoimmune conditions 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, Goodpasture syndrome, dermatomyositis, and sarcoidosis).

[0228] Examples of appropriate 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, inflammatory bowel disease, interstitial cystitis, lichen planus, mastocell activation syndrome, mastocytosis, otitis media, pelvic inflammatory disease, peripheral ulcerative keratitis, pneumonia, reperfusion injury, rheumatic fever, rheumatoid arthritis, rhinitis, sarcoidosis, transplant rejection, and vasculitis.

[0229] Examples of cancers (and their benign counterparts) that can be treated (or suppressed) include tumors of epithelial origin (various types of adenomas and carcinomas, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and other carcinomas), e.g., bladder cancer and urinary tract cancer, breast cancer, gastrointestinal tract (including esophageal cancer, gastric cancer, small intestine cancer, colon cancer, rectal cancer, and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder cancer and biliary tract cancer, exocrine pancreatic cancer, kidney cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, and mesothelioma), and head and neck cancers (e.g., tongue cancer, oral cancer, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, tonsil cancer, salivary gland cancer). Cancers (nasal cavity cancer and paranasal sinus cancer), ovarian cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, vulvar cancer, penile cancer, cervical cancer, myometrial cancer, endometrial cancer, thyroid cancer (e.g., follicular thyroid cancer), adrenal cancer, prostate cancer, skin cancer and adnexal cancer (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanocyte tumor, dysplastic nevus); hematological malignancies (i.e., leukemia, lymphoma) and borderline malignant disorders including premalignant hematological disorders and hematological malignancies and related conditions of the lymphatic system (e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell lymphoma, etc.). Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, T-cell lymphoma and leukemia, natural killer (NK) cell lymphoma, Hodgkin lymphoma, hairy cell leukemia, monoclonal gammaglobulinemia of unknown significance, plasmacytoma, multiple myeloma, post-transplant lymphoproliferative disorders), and myeloid hematological malignancies and related conditions (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), eosinophilia syndrome, myeloproliferative disorders, etc.) * Polycythemia vera, essential thrombocythemia and primary myelofibrosis, myeloproliferative syndromes, myelodysplastic syndromes, and promyelocytic leukemia; * Tumors of mesenchymal origin, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcoma, epithelioid sarcoma, gastrointestinal stromal tumors, benign and malignant histiocytoma and dermatofibrosarcoma protuberans, and other sarcomas of soft tissue, bone, or cartilage; * Tumors of the central or peripheral nervous system, such as astrocytoma, glioma and glioblastoma, meningioma, ependymoma, pineal tumor and Schwannoma;Endocrine tumors (e.g., pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary thyroid carcinoma); tumors of the eye and adnexa (e.g., retinoblastoma); germ cell and trophoblast tumors (e.g., teratoma, seminoma, undifferentiated germ cell tumor, hydatidiform mole, and choriocarcinoma); and pediatric and embryonic tumors (e.g., medulloblastoma, neuroblastoma, Wilms' tumor, and primitive neuroectodermal tumor); or congenital or other syndromes that make a patient more susceptible to malignant tumors (e.g., xeroderma pigmentosum).

[0230] In this specification, the term “prevention” includes the administration of a protective composition before the induction of disease. “Suppression” refers to the administration of a composition after the induction event but before the clinical manifestation of the disease. “Treatment” includes the administration of a protective composition after the appearance of disease symptoms.

[0231] Animal model systems are available that can be used to screen the efficacy of peptide ligands in the protection against or treatment of disease. The use of animal model systems is facilitated by the present invention, which enables the development of polypeptide ligands that can cross-react with human and animal targets and allows for the use of animal models.

[0232] The present invention will be further described below with reference to the following examples. [Examples]

[0233] [material and method] (Production of bicyclic peptide ligands (general method)) Bicyclic peptides were synthesized on Rink amide resin using standard Fmoc (9-fluorenylmethyloxycarbonyl) solid-phase peptide synthesis, either by manual coupling (for large-scale applications) or a Biotage SyroII automated peptide synthesizer (for small-scale applications). After cleavage of the TFA base from the resin, the peptides were 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 ammonium bicarbonate (100 mM) as the base. Completion of cyclization was determined by matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) or LC-MS. After completion, the cyclization reaction was quenched with N-acetylcysteine ​​(10 equivalents relative to the peptide), and the solution was lyophilized. The residue was dissolved in a suitable solvent and purified by RP-HPLC. Peptide fractions of sufficient purity and accurate molecular weight (confirmed by MALDI-TOF and either HPLC or LC-MS) were pooled and lyophilized. The concentration was determined by UV absorption using the extinction coefficient at 280 nm, based on the extinction coefficient of aromatic amino acids at 280 nM. Examples include Trp and Tyr, as well as unnatural amino acids such as 5FTrp.

[0234] All amino acids are used in their L-configuration unless otherwise specified. References to amino acids with the prefix "d" (i.e., dC or dA) herein refer to amino acids in their D-configuration.

[0235] (Production of multimer-bound complexes) Example 1: Manufacturing procedure for BCY15926 [ka] A mixture of compound 1 (20.0 mg, 4.21 μmol, 1.0 equivalent), compound 2 (42.6 mg, 18.5 μmol, 4.4 equivalents), and THPTA (7.30 mg, 16.8 μmol, 4.0 equivalents) was dissolved in t-BuOH / H2O (1:1, 1.0 mL, pre-degassed by purging three times with N2). Then, an aqueous solution of CuSO4 (0.4 M, 21.0 μL, 2.0 equivalents) and VcNa (3.30 mg, 16.8 μmol, 4.0 equivalents) were added under N2 conditions. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction mixture was stirred under an N2 atmosphere at 25-30°C for 1 hour. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 13904, measured m / z: 1391.3 ([M+10H]) 10+ A single main peak with )) was detected. The reaction mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY15926 (13.2 mg, 9.27 μmol, yield 29.3%, purity 97.6%) as a white solid.

[0236] Example 2: Manufacturing procedure for BCY16282 [ka] A mixture of compound 4 (15.0 mg, 23.8 μmol, 1.0 equivalent), compound 5 (39.7 mg, 33.3 μmol, 1.4 equivalents), and DIEA (12.4 μL, 71.3 μmol, 4.0 equivalents) was dissolved in DMF (0.5 mL). The reaction mixture was stirred at 25-30°C for 1 hour. LC-MS showed that compound 4 was completely consumed, and the desired m / z (MW: 1708.85, measured m / z: 854.9 ([M+2H]) was achieved. 2+ A single main peak with )) was detected. The reaction mixture was filtered to remove undissolved residue. 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 obtained as an orange solid.

[0237] [ka] A mixture of compound 6 (3.00 mg, 1.76 μmol, 1.0 equivalent), BCY15751 (8.80 mg, 3.86 μmol, 2.2 equivalents), and THPTA (1.60 mg, 3.69 μmol, 2.1 equivalents) 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, 8.80 μL, 2.0 equivalents) and VcNa (1.40 mg, 3.51 μmol, 4.0 equivalents) were added under N2 conditions. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned yellowish-green. The reaction mixture was stirred under an N2 atmosphere at 25-30°C for 1 hour. LC-MS showed that compound 6 was completely consumed, and the desired m / z (calculated MW: 6286.09, measured m / z: 1257.9 ([M+5H]) was achieved. 5+ ), 1048.6([M+6H] 6+ A single main peak with )) was detected. The reaction mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY16282 (3.40 mg, 0.54 μmol, yield 28.7%, purity 93.2%) as an orange solid.

[0238] Example 3: Manufacturing procedure for BCY25831 [ka] A mixture of compound 1 (5.0 mg, 2.03 μmol, 1.0 equivalent), compound 2 (22.1 mg, 9.15 μmol, 4.5 equivalents), and THPTA (3.50 mg, 8.13 μmol, 4.0 equivalents) 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 equivalents) and VcNa (3.20 mg, 16.3 μmol, 8.0 equivalents) were added under N2 conditions. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 12137.87, measured m / z: 1349.4 ([M+9H]) was achieved. 9+ A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY25831 (5.70 mg, 0.45 μmol, yield 22.3%, purity 96.3%) as a white solid.

[0239] Example 4: Manufacturing procedure for BCY25832 [ka] A mixture of compound 1 (5.0 mg, 2.64 μmol, 1.0 equivalent), compound 2 (21.1 mg, 8.72 μmol, 3.3 equivalents), and THPTA (3.50 mg, 7.93 μmol, 3.0 equivalents) 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, 19.8 μL, 3.0 equivalents) and VcNa (3.10 mg, 15.9 μmol, 6.0 equivalents) were added under N2 conditions. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 9150.48, measured m / z: 1307.2 ([M+7H]) was achieved. 7+A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY25832 (7.50 mg, 0.80 μmol, yield 30.3%, purity 97.9%) as a white solid.

[0240] Example 5: Manufacturing procedure for BCY26427 [ka] A mixture of compound 1 (6.0 mg, 5.22 μmol, 1.0 equivalent), compound 2 (27.7 mg, 11.5 μmol, 2.2 equivalents), and THPTA (4.5 mg, 10.4 μmol, 2.0 equivalents) was dissolved in t-BuOH / H2O (1:1, 0.3 mL, pre-degassed by purging three times with N2). Then, an aqueous solution of CuSO4 (0.4 M, 26.1 μL, 2.0 equivalents) and VcNa (4.1 mg, 20.88 μmol, 4.0 equivalents) were added under N2 conditions. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned dark blue. The reactants were stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 5988.8, measured m / z: 1198.5 ([M+5H])) was achieved. 5+ A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY26427 (13.8 mg, 2.26 μmol, yield 43.4%, purity 98.2%) as a white solid.

[0241] Example 6: Manufacturing procedure for BCY26435 [ka] A mixture of compound 1 (10.0 mg, 8.70 μmol, 1.0 equivalent), compound 2 (43.5 mg, 19.1 μmol, 2.2 equivalents), and THPTA (7.56 mg, 17.4 μmol, 2.0 equivalents) 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, 43.5 μL, 2.0 equivalents) and VcNa (6.89 mg, 34.8 μmol, 4.0 equivalents) were added under N2. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned dark blue. The reactants were stirred under an N2 atmosphere at 25°C for 0.5 hours. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 5694.57, measured m / z: 949.9 ([M+6H]) was achieved. 6+ A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY26435 (20.2 mg, 3.41 μmol, yield 39.2%, purity 96.2%) as a white solid.

[0242] Example 7: Manufacturing procedure for BCY26437 [ka] A mixture of compound 1 (11.0 mg, 5.82 μmol, 1.0 equivalent), compound 2 (43.6 mg, 19.2 μmol, 3.3 equivalents), and THPTA (7.58 mg, 17.5 μmol, 3.0 equivalents) 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 equivalents) and VcNa (6.91 mg, 34.9 μmol, 6.0 equivalents) were added under N2. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned dark blue. The reactants were stirred under an N2 atmosphere at 25°C for 0.5 hours. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 8709.05, measured m / z: 1244.9 ([M+7H])7+ A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY26437 (19.0 mg, 2.06 μmol, yield 35.5%, purity 94.6%) as a white solid.

[0243] Example 8: Manufacturing procedure for BCY26438 [ka] A mixture of compound 1 (5.00 mg, 3.17 μmol, 1.0 equivalent), compound 2 (32.4 mg, 14.3 μmol, 4.5 equivalents), and THPTA (5.50 mg, 12.7 μmol, 4.0 equivalents) was dissolved in t-BuOH / H2O (1:1, 0.4 mL, pre-degassed by purging three times with N2). Then, an aqueous solution of CuSO4 (0.4 M, 31.7 μL, 4.0 equivalents) and VcNa (5.00 mg, 25.4 μmol, 8.0 equivalents) were added under N2. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned dark blue. The reactants were stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 10668.3, measured m / z: 1334.4 ([M+8H]) was achieved. 8+ A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY26438 (3.40 mg, 0.29 μmol, yield 9.1%, purity 90.2%) as a white solid.

[0244] Example 9: Manufacturing procedure for BCY26439 [ka] A mixture of compound 1 (5.0 mg, 2.03 μmol, 1.0 equivalent), compound 2 (20.8 mg, 9.15 μmol, 4.5 equivalents), and THPTA (3.50 mg, 8.13 μmol, 4.0 equivalents) 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 equivalents) and VcNa (3.20 mg, 16.3 μmol, 8.0 equivalents) were added under N2 conditions. The pH of this solution was adjusted to 8 by the dropwise addition of 0.2 M NH4HCO3 (in 1:1 t-BuOH / H2O), and the solution turned pale yellow. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 11549.45, measured m / z: 1444.4 ([M+8H]) was achieved. 8+ A single main peak with ) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY26439 (4.0 mg, 0.30 μmol, yield 15.8%, purity 92.8%) as a white solid.

[0245] Example 10: Preparation procedure for BCY28218 (biothinyl dimer) [ka] A mixture of compound 1 (6.00 mg, 3.53 μmol, 1.0 equivalent), compound 2 (17.6 mg, 7.76 μmol, 2.2 equivalents), and THPTA (3.06 mg, 7.05 μmol, 2.0 equivalents) was dissolved in t-BuOH / H2O (1:1, 0.3 mL, pre-degassed by purging three times with N2). Subsequently, an aqueous solution of CuSO4 (0.4 M, 17.6 μL, 2.0 equivalents) and VcNa (2.79 mg, 14.1 μmol, 4.0 equivalents) were added under N2. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 6247.29, measured m / z: 1042.0 ([M+6H]) was obtained. 6+A single main peak with )) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY28218 (8.50 mg, 1.35 μmol, yield 38.2%, purity 98.9%) as a white solid.

[0246] Example 11: Preparation procedure for BCY28224 (biothinyl dimer) [ka] A mixture of compound 1 (6.00 mg, 3.44 μmol, 1.0 equivalent), compound 2 (22.1 mg, 7.56 μmol, 2.2 equivalents), and THPTA (2.99 mg, 6.87 μmol, 2.0 equivalents) was dissolved in t-BuOH / H2O (1:1, 0.3 mL, pre-degassed by purging three times with N2). Subsequently, an aqueous solution of CuSO4 (0.4 M, 17.2 μL, 2.0 equivalents) and VcNa (2.72 mg, 13.7 μmol, 4.0 equivalents) were added under N2. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. LC-MS showed that compound 1 was completely consumed, and the desired m / z (calculated MW: 7604.74, measured m / z: 1087.3 ([M+7H]) was obtained. 7+ A single main peak with )) was detected. The mixture was filtered to remove undissolved residue. The crude product was purified by preparative HPLC (TFA conditions) to obtain BCY28224 (7.20 mg, 0.907 μmol, yield 26.4%, purity 95.8%) as a white solid.

[0247] [Biological data] (SPR binding assay) TLR3 monomer SPR: Surface plasma resonance (SPR) is performed on Biacore T200 or 8K+ to determine the k-type of peptides that bind to TLR3 target proteins. a (M-1 s-1), k d (s-1), and K DThe (M) value was determined. Recombinant human TLR3-Avi[bt]-Fc-Flag-his protein was custom-produced in Hi5 insect cells at Charles River laboratories. The protein was captured on CM5 chips (GE Healthcare) using goat anti-human IgG at a surface density in the range of approximately 1100–1800 RU. Since dsRNAs that bind to TLR3 are known to be pH sensitive (Leonard et al (2008) PNAS 105(1), 258-265), standard SPR screening experiments were performed with 25 mM MES, 100 mM NaCl, and 0.05% Tween 20 acidic running buffer at pH 5.5. In some experiments, binding was confirmed in the neutral pH range using 25 mM HEPES, 100 mM NaCl, and 0.05% Tween 20 buffer at pH 7.4. An 8-fold dilution series of peptides, including a peptide at a maximum test concentration of 30 mM, was prepared in a running buffer with a final dimethyl sulfoxide (DMSO) concentration of 0.5%. Data were corrected for the DMSO exclusion volume effect. The peptides were injected onto the tip at a flow rate of 90 μL / min at 25°C. All data were double-referenced against blank injection and a reference surface using standard processing procedures. Data were fitted to a 1:1 binding model using either steady-state or kinetic methods where appropriate (in Biacore evaluation software).

[0248] Acknowledgments Charles River laboratories (Harlow and Chesterford Park) for conducting SPR analysis.

[0249] The selected monomeric bicyclic peptides of the present invention were tested in the above SPR binding assay, and the results are shown in Table 4A. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11]

[0250] The selected polymer-binding complex of the present invention was tested in the above SPR binding assay, and the results are shown in Table 4B. [Table 6]

[0251] (TLR3 reporter assay method) Null or TLR3 cells (Invivogen, hkd-htlr3ni) were added to a 96-well plate (5e4 / well) and conditioned with BCY at 37°C for 48 hours. The supernatant was collected, mixed with QUANTI-Blue solution (rep-qbs), and the absorption was read using a plate reader (Clariostar) (Dobashi et al (2022) Experimental Biology and Medicine 247(21), 917-922).

[0252] The selected peptides of the present invention were tested using the reporter assay described above, and the results are shown in Table 5. [Table 7]

[0253] (MoMac cell binding assay) 1. MoMac generation Human PBMCs were isolated from healthy blood donors by gravity gradient centrifugation on Ficoll-Pacque (GE Healthcare 1714403) and Leukosep tubes (Greiner Bio One 227290) (data shown in Table 6 were generated from a single donor designated as donor 1875 (230110)) and frozen at 5e7 cells / mL. Thawed PBMCs were fertilized in RPMI (Gibco 11875-093) 10% FBS (Corning 35-011-CV) in a T175cm flask at 37°C for at least 2 hours. The culture medium and non-adherent cells were aspirated. The remaining cells (attached monocytes) were added to 20 mL of RPMI + 10% FBS + 100 ng / mL M-CSF (Peprotech 300-25) and incubated at 37°C for 7 days for differentiation into monocyte-derived macrophages. On day 5, RPMI + 10% FBS + 100 ng / mL M-CSF was added again. From days 7 to 10, monocyte-derived macrophages (moMac) were collected by rinsing with cold PBS and gently scraping with a sponge cell scraper. The cells were plated in 96-well round-bottom plates with 100 μL of RPMI + 10% FBS at a rate of 100,000 cells per well and allowed to rest for at least 1 hour in preparation for binding or activation assays.

[0254] 2. MoMac cell binding Differentiated cultured moMac cells are plated in 100 μL of RPMI + 10% FBS medium in a 96-well round-bottom plate, with 100,000 cells per well. Cells are stained with a viability dye, incubated at room temperature for 10 minutes, and washed. Biotin-labeled bicyclic multimer compound is pre-incubated with equimolar concentrations of phycoerythrin-labeled streptavidin at room temperature for 30 minutes. After pre-incubation, the multimer complex, surface-expressed antibodies (CD206, TLR3), and antibody-controlled stains are added to the plated moMac cells and incubated on ice for 90 minutes to prevent internalization. The supernatant is gently tapped and aspirated, and the cells are resuspended in 200 μL / well of FACS buffer (PBS + 2% FBS, 0.5 M EDTA) and immediately analyzed on an Attune Nxt flow cytometer without fixation.

[0255] The selected peptides of the present invention were tested in the MoMac cell binding assay described above, and the results are shown in Table 6. [Table 8]

[0256] The results shown in Table 6 demonstrate that an increase in "maximum gMFI" relative to "untreated gMFI" indicates the binding of a multimer-binding complex. For example, a larger signal indicates the binding of more multimer-binding complexes. It should be noted that all "untreated gMFI" values ​​are the same because all multimer-binding complexes are bound to this single sample. BCY28217 and BCY28221 are unbound controls.

[0257] (Image analysis of monocyte-derived macrophages) Monocyte-derived macrophages, generated by negative magnetic bead enrichment of monocytes from human PBMCs and subsequent M-CSF differentiation, were incubated at 37°C for 90 minutes in the absence or presence of LPS (100 ng / mL), HMW Vacciggrade Poly I:C (10 μg / mL), or non-conjugated bicyclic peptide (1000 nM) (vehicle (BCY), 0.01% DMSO; vehicle (LPS / Poly-IC), 1% dH2O), and in the absence or presence of latex beads. After this time, the cells were fixed / permeabilized and labeled overnight at 4°C with phospho-NF-κB antibody, followed by labeling with AF647-conjugated secondary antibody and Hoechst. Images were acquired by confocal microscopy and are shown herein as Figure 1.

[0258] NF-κB translocation is known to be a crucial step in downstream signaling of TLR3. The data shown in Figure 1 demonstrate an increase in NF-κB translocation levels above background for the bicyclic peptide BCY26435, and importantly, no increase for the unbound bicyclic peptide control. Therefore, this data provides evidence that BCY26435 not only binds to TLR3 but also signals via TLR3. This supports the idea that BCY26435, and other TLR3-binding bicyclic peptides described herein by extrapolation, have biological function in primary cells.

[0259] The following are numbered embodiments of the present invention:

[0260] 1. A peptide ligand capable of binding to TLR3, wherein the peptide ligand is as follows: C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C(Sequence number 1); CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC(sequence_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 (Sequence ID 3); CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C(sequence 4); CYYX38 -X 39 -X 40 -YACLDC(sequence number 5); 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 (Sequence ID 6) Selected from, in the formula, X1 represents D, N, P, Y, 26 DiMeTyr, 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; X14 represents H or R; X 15 This 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 This represents C or dC; X 21 dE represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe, or dE; X 22 dY 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 27represents G, R, S, Agb, Cit, dA, dE, or HArg; X 28 This represents L, P, 44DFP, 4FlPro, Aze, Cba, dL, HyP, Pip, tBuAla, or trans-4FlPro; X 29 This represents C, dC, or Cysam; X 30 represents P, Cis-HyP, HyP, or Pip; X 31 represents E, Q, or R; X 32 This represents P, Aze, Cis-HyP, or HyP; X 33 This represents F, Y, 2FTyr, 2Nal, 3FTyr, 4FPhe, or 4tBuPhe; X 34 represents N, S, or Dap; X 35 represents T or Dap; X 36 This 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 This 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 HSer; X 46 represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, or TfNle; X 47 This 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 is represented by 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, X 54 This represents C, dC, or Cysam. A peptide ligand or a modified derivative thereof, and / or a pharmaceutically acceptable salt, containing an amino acid sequence.

[0261] 2. A bicyclic peptide ligand comprising the peptide described in Embodiment 1 and a molecular scaffold, wherein three cysteine ​​or cysam residues of the peptide ligand form covalent bonds with the molecular scaffold to form two loop sequences.

[0262] 3. The peptide ligand of C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (Sequence ID 1) is as follows: CDIACLKMYNFC(Sequence ID 7); CDIGCLRMYNFC(Sequence ID 8); CD[tBuAla]GCLRMYNFC(Sequence ID 9); CD[tBuGly]GCLRMYNFC(Sequence ID 10); CD[Cba]GCLRMYNFC(Sequence ID 11); CDI[dA]CLRMYNFC(Sequence ID 12); CDI[Aib]CLRMYNFC(Sequence ID 13); CDIGC[Cba]RMYNFC (Sequence ID 14): CDIGCL[HArg]MYNFC (Sequence ID 15): CDIGCL[Agb]MYNFC(Sequence ID 16); CDIGCLRMYN[1Nal]C(sequence ID 17); CDIGCLRMYN[2Nal]C(Sequence ID 18); CDIGCLRMYN[4tBuPhe]C(Sequence ID 19); CDIQCLRMYNFC(Sequence ID 20); CNIQCLRMYNFC(Sequence ID 21); CDIRCLRMYNFC(Sequence ID 22); CDINCLRMYNFC(Sequence ID 23); CPPGCSPRFHLC(Sequence ID 24); CPPGCSPRYHLC(Sequence ID 25; structure below: [ka] When complexed with a derivative of TATB, which has the formula where * indicates a binding site of three cysteine ​​residues, it is called BCY21542); CP[Cis-HyP]GCSPRYHLC(Sequence ID 26); CP[Aze]GCSPRYHLC(sequence number 27); CPPGCSP[HArg]YHLC(Sequence ID 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(Sequence ID 33); CPPGCSPRY[His3Me]LC(SEQ ID NO: 34); CPPGCSPRYH[tBuAla]C(sequence code 35); CPPGCSPRYH[Cba]C(Sequence ID 36); CPPGCSPRYNLC(Sequence ID 37); CYNPCLWRQVDC(SEQ ID NO: 38; structure below: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21497); CYAPCLWRQVDC(Sequence ID 39); CYNPCLWRAVDC(SEQ ID NO: 40); C[4FPhe]NPCLWRQVDC(Sequence ID 41); C[26DiMeTyr]NPCLWRQVDC(Sequence ID 42); C[3FTyr]NPCLWRQVDC(Sequence ID 43); C[2FTyr]NPCLWRQVDC(Sequence ID 44); CYN[HyP]CLWRQVDC(Sequence ID 45); CYN[Cis-HyP]CLWRQVDC(Sequence ID 46); CYN[Aze]CLWRQVDC(Sequence ID 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(Sequence ID 55); CYNPCL[Trp(Me)]RQVDC(Sequence ID 56); CYNPCLWRQ[tBuGly]DC(SEQ ID NO: 57); CYNPCLWRQ[Cbg]DC(SEQ ID NO: 58); CYNPCLWRQIDC(Sequence ID 59); CYSPCLWRQVDC(SEQ ID NO: 60); and CYTPCLWRQVDC (Sequence ID 61) Includes more selective amino acid sequences, for example: The molecular scaffold has the following structure: [ka] A derivative of TATA having the formula where * indicates a binding site of three cysteine ​​residues, and the peptide ligand C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) further includes N and / or C-terminal additions, and below: A-(Sequence ID 7)-A-[Sar6]-[KFl](referred to herein as BCY15200); A-(Sequence ID 7)-A (referred to herein as BCY15212); A-(Sequence ID 8)-A (referred to herein as BCY15747); A-(Sequence ID 8)-A-[K(PYA)] (referred to herein as BCY19281); A-(Sequence ID 9)-A (referred to herein as BCY17064); A-(Sequence ID 10)-A (referred to herein as BCY17065); A-(Sequence ID 11)-A (referred to herein as BCY17066); A-(Sequence ID 12)-A (referred to herein as BCY17067); A-(Sequence ID 13)-A (referred to herein as BCY17068); A-(Sequence ID 14)-A (referred to herein as BCY17070); A-(Sequence ID 15)-A (referred to herein as BCY17071); A-(Sequence ID 16)-A (referred to herein as BCY17072); A-(Sequence ID 17)-A (referred to herein as BCY17079); A-(Sequence ID 18)-A (referred to herein as BCY17080); A-(Sequence ID 19)-A (referred to herein as BCY17081); A-(Sequence ID 20)-A (referred to herein as BCY16675); A-(Sequence ID 21)-A (referred to herein as BCY16676); A-(Sequence ID 22)-A (referred to herein as BCY16677); and A-(Sequence ID 23)-A (referred to herein as BCY16678) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: [ka] A derivative of TATB having the formula where * indicates a binding site of three cysteine ​​residues, and the peptide ligand C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) further comprises N and / or C-terminal additions, and below: A-(Sequence ID 24)-A (referred to herein as BCY16997); A-(Sequence ID 25)-A (referred to herein as BCY18125); A-(Sequence ID 25)-A-[K(PYA)] (referred to herein as BCY19741); A-(Sequence ID 25) (referred to herein as BCY21538); Ac-A-(Sequence ID 25) (referred to herein as BCY21539); (Sequence ID 25)-A (referred to herein as BCY21540); Ac-(Sequence ID 25)-A (referred to herein as BCY21541); Ac-(Sequence ID 25) (referred to herein as BCY21543); Ac-A-(Sequence ID 25)-A (referred to herein as BCY21544); A-(Sequence ID 25)-DKTTV (referred to herein as BCY21769); TVKTP-(Sequence ID 25)-A (referred to herein as BCY21775); A-(Sequence ID 25)-DIHNN (referred to herein as BCY21777); A-(Sequence ID 26)-A (referred to herein as BCY21550); A-(Sequence ID 27)-A (referred to herein as BCY21551); A-(Sequence ID 28)-A (referred to herein as BCY21558); A-(Sequence ID 29)-A (referred to herein as BCY21561); A-(Sequence ID 30)-A (referred to herein as BCY21562); A-(Sequence ID 31)-A (referred to herein as BCY21564); A-(Sequence ID 32)-A (referred to herein as BCY21565); A-(Sequence ID 33)-A (referred to herein as BCY21566); A-(Sequence ID 34)-A (referred to herein as BCY21567); A-(Sequence ID 35)-A (referred to herein as BCY21568); A-(Sequence ID 36)-A (referred to herein as BCY21569); and A-(Sequence ID 37)-A (referred to herein as BCY16998) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: [ka] It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, wherein the formula * indicates a binding site for three cysteine ​​residues, and the peptide ligand C-X1-X2-X3-C-X4-X5-X6-X7-X8-X9-C (SEQ ID NO: 1) further comprises N and / or C-terminal additions, and is described below: A-(Sequence ID 38)-A (referred to herein as BCY18251); A-(Sequence ID 38)-A-[K(PYA)] (referred to herein as BCY19587); A-(Sequence ID 38) (referred to herein as BCY21493); (Sequence ID 38)-A (referred to herein as BCY21495); Ac-(Sequence ID 38) (referred to herein as BCY21498); YYYEW-(Sequence ID 38)-A (referred to herein as BCY21773); A-(Sequence ID 39)-A (referred to herein as BCY21485); A-(Sequence ID 40)-A (referred to herein as BCY21490); A-(Sequence ID 41)-A (referred to herein as BCY21500); A-(Sequence ID 42)-A (referred to herein as BCY21502); A-(Sequence ID 43)-A (referred to herein as BCY21503); A-(Sequence ID 44)-A (referred to herein as BCY21504); A-(Sequence ID 45)-A (referred to herein as BCY21505); A-(Sequence ID 46)-A (referred to herein as BCY21506); A-(Sequence ID 47)-A (referred to herein as BCY21507); A-(Sequence ID 48)-A (referred to herein as BCY21508); A-(Sequence ID 49)-A (referred to herein as BCY21510); A-(Sequence ID 50)-A (referred to herein as BCY21515); A-(Sequence ID 51)-A (referred to herein as BCY21517); A-(Sequence ID 52)-A (referred to herein as BCY21518); A-(Sequence ID 53)-A (referred to herein as BCY21519); A-(Sequence ID 54)-A (referred to herein as BCY21521); A-(Sequence ID 55)-A (referred to herein as BCY21522); A-(Sequence ID 56)-A (referred to herein as BCY21523); A-(Sequence ID 57)-A (referred to herein as BCY21527); A-(Sequence ID 58)-A (referred to herein as BCY21528); A-(Sequence ID 59)-A (referred to herein as BCY19930); A-(Sequence ID 59)-VYNVN (referred to herein as BCY21776); A-(Sequence ID 60)-A (referred to herein as BCY19931); and A-(Sequence ID 61)-A (referred to herein as BCY19932) A bicyclic peptide ligand according to embodiment 2, comprising a more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

[0263] 4. CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC (SEQ ID NO: 2) peptide ligand is as follows: CTSYYCEQTRHFC(Sequence ID 62); CTKYYCEQTRHFC(SEQ ID NO: 63); and CSKYYCQQTVRFC(Sequence ID 64) Includes more selective amino acid sequences, for example: The molecular scaffold has the following structure: [ka] It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 62)-A (referred to herein as BCY17006); A-(Sequence ID 63)-A (referred to herein as BCY18134); A-(Sequence ID 63)-A-[K(PYA)](referred to herein as BCY19746); and A-(Sequence ID 64)-A (referred to herein as BCY17012) A bicyclic peptide ligand according to embodiment 2, comprising a more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

[0264] 5. X 15 -X 16 -X17 -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) is as follows: CTNEVCTYWYNRGLC(Sequence ID 65); CANEVCEYWYNRGLC(Sequence ID 66); CPLDLCEYWSFRGLC(Sequence ID 67); CTNEVCRYWYNRGLC(Sequence ID 68); CDSPVCEYWSFRGLC(Sequence ID 69); CHNEVCEYWSFRGLC(Sequence ID 70); CSNEVCEYWSFRGLC(Sequence ID 71); CSNPVCEYWSFRGLC(Sequence ID 72); CNNPVCEYWSFRGLC(Sequence ID 73); CDNEVCEYWSFRGLC(Sequence ID 74); CTSEVCEYWSFRGLC(Sequence ID 75); CSTLVCQRDQLYSLC(Sequence ID 76); CHNEVCLYWYNRGLC(Sequence ID 77); CWNPVCEYWYNRGLC(Sequence ID 78); CATLQCQRDMLYGLC(Sequence ID 79); CSTLVCQRDQLYGLC(Sequence ID 80); CST[tBuAla]VCQRDQLYGLC(Sequence ID 81); CST[Cba]VCQRDQLYGLC(Sequence ID 82); CSTL[tBuAla]CQRDQLYGLC(Sequence ID 83); CSTLVCQRD[Nle]LYGLC(SEQ ID NO: 84); CSTLVCQRDQ[Cba]YGLC(SEQ ID NO: 85); CSTLVCQRDQLY[dA]LC(Sequence ID 86); CSTLVCQRDQLYG[tBuAla]C(Sequence ID 87); CSTLVCQRDQLYG[Cba]C(Sequence ID 88); CST[tBuAla]VCQRDQLY[dA]LC(Sequence ID 89); CNPLICQRDQLYGLC(Sequence ID 90); CISLACQRDQLYGLC(Sequence ID 91); CSTLECQRDQLYGLC(Sequence ID 92); CNTLVCQRDQLYGLC(Sequence ID 93); CTQLMCQRDQLYGLC(Sequence ID 94); CTELMCQRDQLYGLC(Sequence ID 95); CTE[tBuAla]MCQRDQLY[dA]LC(Sequence ID 96); CTELMCQRDQLY[dA]LC(Sequence ID 97); CTE[tBuAla]MCQRDQLYGLC(Sequence ID 98); CTELACQRDQLYGLC(Sequence ID 99); CTEL[Nle]CQRDQLYGLC(Sequence ID 100); CTEL[HLeu]CQRDQLYGLC(Sequence ID 101); CTELMCQR[Gla]QLYGLC(Sequence ID 102); CTELMCQRDQL[3FTyr]GLC(Sequence ID 103); CTELMCQRDQL[2FTyr]GLC(Sequence ID 104); CANTVCAYWETRGLC(Sequence ID 105); CANTVCAY[5FTrp]ETRGLC(sequence number 106); CPLDLCEYWSVRGLC(Sequence ID 107); CPLDLCEYWSSRGLC(Sequence ID 108); C[HyP]LDLCEYWSSRGLC(sequence number 109); CP[tBuAla]DLCEYWSSRGLC(Sequence ID 110); CP[Cba]DLCEYWSSRGLC(Sequence ID 111); CPLD[AlloIle]CEYWSSRGLC(Sequence ID 112); CPLD[tBuAla]CEYWSSRGLC(Sequence ID 113); CPLD[Cba]CEYWSSRGLC(SEQ ID NO: 114); CPLDVCEYWSSRGLC(Sequence ID 115); CPLDLCE[4FPhe]WSSRGLC(Sequence ID 116); CPLDLCEY[2Nal]SSRGLC(Sequence ID 117); CPLDLCEY[1Nal]SSRGLC(Sequence ID 118); CPLDLCEY[5FTrp]SSRGLC(Sequence ID 119); CPLDLCEY[4MeoTrp]SSRGLC(SEQ ID NO: 120); CPLDLCEY[Trp(S)]SSRGLC(Sequence ID 121); CPLDLCEYWSS[HArg]GLC(Sequence ID 122); CPLDLCEYWSS[Cit]GLC(Sequence ID 123); CPLDLCEYWSSR[dA]LC(Sequence ID 124); CPLDLCEYWSSRG[tBuAla]C(Sequence ID 125); CPLDLCEYWSSRG[Cba]C(Sequence ID 126); [dC][dP][dL][dD][dL][dC][dE][dY][dW][dS][dS][dR]G[dL][dC](Sequence ID 127); CP[Cba]DLCEY[5FTrp]SSRGLC(Sequence ID 128); CPLDLCEYW[K(PYA)]SRGLC(SEQ ID NO: 129, structure below: [ka] It has the following properties, where * indicates a binding site between three cysteine ​​residues; when complexed with a derivative of TATA, it is called BCY21632); CPLDLCEYW[K(PYA)]SRGL[Cysam](SEQ ID NO: 130, structure below: [ka] It has the following characteristics, where * indicates a binding site of three cysteine ​​residues; when complexed with a derivative of TATA, it is called BCY21637); CPLDLCEY[5FTrp]ESRGLC(Sequence ID 131); CPNDLCEY[5FTrp]SSRGLC(Sequence ID 132); CPLDLCEY[5FTrp]SSR[dA]LC(Sequence ID 133); CPLDLCEY[5FTrp]SSR[dE]LC(Sequence ID 134); CPLD[tBuAla]CEY[5FTrp]SS[HArg][dA]LC(Sequence ID 135); CP[Cba]DLCEY[5FTrp]SS[HArg][dA]LC(Sequence ID 136); CPNDLCEYWSVRGLC(Sequence ID 137); CITLQCARDMLYGLC(SEQ ID NO: 138); CSTLQCERDMLYGLC(Sequence ID 139); CISLACARDMLYGLC(SEQ ID NO: 140); CSTLQCQRDMLYGLC(Sequence ID 141); CMYRACWVAEEWRPC(sequence number 142); CMYRACYYDHEWRPC(sequence number 143); CMYRACFYDDEWRPC(sequence number 144); CMYRACAYDDEWRPC(sequence number 145); CMYRACFADDEWRPC(sequence number 146); CMYRACFYADEWRPC(sequence code 147); CMYRACFYDAEWRPC(sequence number 148); C[Nle]YRACFYDDEWRPC(sequence code 149); C[Nva]YRACFYDDEWRPC(sequence ID 150); C[TfNle]YRACFYDDEWRPC(sequence code 151); C[CF3Nva]YRACFYDDEWRPC(sequence number 152); CM[26DiMeTyr]RACFYDDEWRPC(Sequence ID 153); CMY[HArg]ACFYDDEWRPC(sequence number 154); CMY[Agb]ACFYDDEWRPC(sequence number 155); CMY[Cit]ACFYDDEWRPC(sequence number 156); CMYR[CF3Ala]CFYDDEWRPC(sequence number 157); CMYRAC[1Nal]YDDEWRPC(sequence ID 158); CMYRAC[2Nal]YDDEWRPC(sequence number 159); CMYRAC[4MePhe]YDDEWRPC(sequence ID 160); CMYRAC[3MePhe]YDDEWRPC(sequence number 161); CMYRAC[2MePhe]YDDEWRPC(sequence number 162); CMYRAC[4FPhe]YDDEWRPC(sequence number 163); CMYRAC[3FPhe]YDDEWRPC(sequence number 164); CMYRAC[2FPhe]YDDEWRPC(sequence number 165); CMYRACF[4FPhe]DDEWRPC(sequence number 166); CMYRACF[3tBuTyr]DDEWRPC(sequence number 167); CMYRACF[26DiMeTyr]DDEWRPC(sequence number 168); CMYRACF[3FTyr]DDEWRPC(sequence number 169); CMYRACF[2FTyr]DDEWRPC(sequence ID 170); CMYRACF[DOPA]DDEWRPC(sequence code 171); CMYRACFYDDE[1Nal]RPC(sequence ID 172); CMYRACFYDDE[2Nal]RPC(sequence number 173); CMYRACFYDDE[4FTrp]RPC(sequence ID 174); CMYRACFYDDE[5FTrp]RPC(sequence ID 175); CMYRACFYDDE[6FTrp]RPC(sequence number 176); CMYRACFYDDE[7FTrp]RPC(array_number_177); CMYRACFYDDE[Trp(Me)]RPC(Sequence ID 178); CMYRACFYDDE[2MeTrp]RPC(sequence number 179); CMYRACFYDDE[5MeTrp]RPC(sequence ID 180); CMYRACFYDDE[6MeTrp]RPC(sequence ID 181); CMYRACFYDDE[7MeTrp]RPC(sequence number 182); CMYRACFYDDEW[HArg]PC(sequence number 183); CMYRACFYDDEW[Agb]PC(sequence number 184); CMYRACFYDDEW[Cit]PC(sequence number 185); CMYRACFYDDEWR[HyP]C(sequence ID 186); CMYRACFYDDEWR[Aze]C(sequence number 187); CMYRACFYDDEWR[Pip]C(sequence ID 188); CMYRACFYDDEWR[44DFP]C(Sequence ID 189); CMYRACFYDDEWR[4FlPro]C(sequence ID 190); CMYRACFYDDEWR[trans-4FlPro]C(sequence ID 191); C[CF3Nva]YRACFYDDE[1Nal]RPC(Sequence ID 192); C[CF3Nva]YRAC[4MePhe]YDDE[1Nal]RPC(Sequence ID 193); CLYRACFYDDEWRPC(sequence number 194); CLYRAC[4MePhe]YDDE[1Nal]RPC(sequence code 195); and CHYRACFYDDEWRPC (Sequence ID 196) Includes more selective amino acid sequences, for example: The molecular scaffold has the following structure: [ka] A derivative of TATA having, where * indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 65)-A (referred to herein as BCY15206); A-(Sequence ID 65)-A-[Sar6][KFl](referred to herein as BCY15194); Ac-(Sequence ID 66)-A-[K(PYA)] (referred to herein as BCY23135); Ac-(Sequence ID 66)-[K(PYA)] (referred to herein as BCY23136); A-(Sequence ID 66)-A-[K(PYA)] (referred to herein as BCY20791); A-(Sequence ID 67)-A (referred to herein as BCY15808); A-(Sequence ID 68)-A (referred to herein as BCY15810); A-(Sequence ID 69)-A (referred to herein as BCY16655); A-(Sequence ID 70)-A (referred to herein as BCY16656); A-(Sequence ID 71)-A (referred to herein as BCY16657); A-(Sequence ID 72)-A (referred to herein as BCY16658); A-(Sequence ID 73)-A (referred to herein as BCY16659); A-(Sequence ID 74)-A (referred to herein as BCY16660); A-(Sequence ID 75)-A (referred to herein as BCY16661); A-(Sequence ID 76)-A (referred to herein as BCY15207); A-(Sequence ID 76)-A-[Sar6]-[KFl](referred to herein as BCY15195); A-(Sequence ID 76)-A-[K(PYA)] (referred to herein as BCY15750); A-(Sequence ID 77)-A (referred to herein as BCY15811); A-(Sequence ID 78)-A (referred to herein as BCY15812); A-(Sequence ID 79)-A (referred to herein as BCY15813); A-(Sequence ID 80)-A (referred to herein as BCY15814); A-(Sequence ID 80)-A-[Sar6]-[KFl](referred to herein as BCY15801); Ac-(Sequence ID 80) (referred to herein as BCY17031); A-(Sequence ID 80)-A-[Sar6]-[K(Ac)] (referred to herein as BCY19384); A-(Sequence ID 80)-AGAAAE (referred to herein as BCY19582); A-(Sequence ID 81)-A (referred to herein as BCY17032); A-(Sequence ID 82)-A (referred to herein as BCY17033); A-(Sequence ID 83)-A (referred to herein as BCY17035); A-(Sequence ID 84)-A (referred to herein as BCY17038); A-(Sequence ID 85)-A (referred to herein as BCY17040); A-(Sequence ID 86)-A (referred to herein as BCY17041); A-(Sequence ID 87)-A (referred to herein as BCY17042); A-(Sequence ID 88)-A (referred to herein as BCY17043); Ac-(Sequence ID 89) (referred to herein as BCY19197); A-(Sequence ID 90)-A (referred to herein as BCY16662); A-(Sequence ID 91)-A (referred to herein as BCY16663); A-(Sequence ID 91)-A-[Sar6]-[KFl](referred to herein as BCY16639); A-(Sequence ID 92)-A (referred to herein as BCY16664); A-(Sequence ID 93)-A (referred to herein as BCY16665); A-(Sequence ID 94)-A (referred to herein as BCY16666); A-(Sequence ID 95)-A (referred to herein as BCY16667); A-(Sequence ID 95)-A-[Sar6]-[KFl](referred to herein as BCY16643); A-(Sequence ID 95)-A-[K(PYA)] (referred to herein as BCY17238); Ac-(Sequence ID 95) (referred to herein as BCY19193); A-(Sequence ID 96)-A (referred to herein as BCY19192); Ac-(Sequence ID 96) (referred to herein as BCY19196); Ac-(Sequence ID 97) (referred to herein as BCY19194); Ac-(Sequence ID 98) (referred to herein as BCY19195); Ac-(Sequence ID 99) (referred to herein as BCY19198); Ac-(Sequence ID 100) (referred to herein as BCY19199); Ac-(Sequence ID 101) (referred to herein as BCY19200); Ac-(Sequence ID 102) (referred to herein as BCY19203); Ac-(Sequence ID 103) (referred to herein as BCY19205); Ac-(Sequence ID 104) (referred to herein as BCY19206); A-(Sequence ID 105)-A (referred to herein as BCY15208); A-(Sequence ID 105)-A-[K(PYA)] (referred to herein as BCY15751); A-(Sequence ID 106)-A-[K(PYA)] (referred to herein as BCY21608); A-(Sequence ID 107)-A (referred to herein as BCY15209); A-(Sequence ID 107)-A-[Sar6]-[KFl](referred to herein as BCY15197); A-(Sequence ID 108)-A (referred to herein as BCY15727); A-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY17452); Ac-(Sequence ID 108)-[K(PYA)] (referred to herein as BCY19157); Ac-A-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY19158); A-(Sequence ID 108)-A-[Sar6]-[(K(Ac)](referred to herein as BCY19385); A-(Sequence ID 108)-AGAAAE (referred to herein as BCY19580); A-(Sequence ID 108)-KMTHE (referred to herein as BCY21192); A-(Sequence ID 108)-NDSLN (referred to herein as BCY21193); A-(Sequence ID 108)-SVNAN (referred to herein as BCY21194); A-(Sequence ID 108)-QGHTPL (referred to herein as BCY21195); A-(Sequence ID 108)-EMEHSN (referred to herein as BCY21196); MRQ-(Sequence ID 108)-ETP (referred to herein as BCY21197); EHM-(Sequence ID 108)-TQS (referred to herein as BCY21198); EPKRQ-(Sequence ID 108)-A (referred to herein as BCY21199); ANYAN-(Sequence ID 108)-A (referred to herein as BCY21200); DSFHQ-(Sequence ID 108)-A (referred to herein as BCY21201); MRQ-(Sequence ID 108)-ETP-[K(PYA)] (referred to herein as BCY21993); EPKRQ-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY21994); Ac-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY23137); Ac-(Sequence ID 108)-E-[K(PYA)] (referred to herein as BCY23174); A-(Sequence ID 108)-E-[K(PYA)] (referred to herein as BCY23179); A-(Sequence ID 109)-A-[K(PYA)] (referred to herein as BCY19159); A-(Sequence ID 110)-A-[K(PYA)] (referred to herein as BCY19161); A-(Sequence ID 111)-A-[K(PYA)] (referred to herein as BCY19162); A-(Sequence ID 112)-A-[K(PYA)] (referred to herein as BCY19163); A-(Sequence ID 113)-A-[K(PYA)] (referred to herein as BCY19164); A-(Sequence ID 114)-A-[K(PYA)] (referred to herein as BCY19165); A-(Sequence ID 115)-A-[K(PYA)] (referred to herein as BCY19166); A-(Sequence ID 116)-A-[K(PYA)](referred to herein as BCY19167); A-(Sequence ID 117)-A (referred to herein as BCY19170); A-(Sequence ID 117)-A-[K(PYA)] (referred to herein as BCY19284); Ac-(Sequence ID 117)-[K(PYA)] (referred to herein as BCY19995); A-(Sequence ID 118)-A-[K(PYA)] (referred to herein as BCY19171); A-(Sequence ID 119)-A-[K(PYA)] (referred to herein as BCY19177); MRQ-(Sequence ID 119)-ETP-[K(PYA)] (referred to herein as BCY21995); EPKRQ-(Sequence ID 119)-A-[K(PYA)] (referred to herein as BCY21996); MRQ-(Sequence ID 119)-ETP (referred to herein as BCY21997); EPKRQ-(Sequence ID 119)-A (referred to herein as BCY21998); Ac-(Sequence ID 119)-[K(PYA)] (referred to herein as BCY22499); A-(Sequence ID 120)-A-[K(PYA)] (referred to herein as BCY19179); A-(Sequence ID 121)-A-[K(PYA)] (referred to herein as BCY19181); A-(Sequence ID 122)-A-[K(PYA)] (referred to herein as BCY19184); A-(Sequence ID 123)-A-[K(PYA)] (referred to herein as BCY19185); A-(Sequence ID 124)-A-[K(PYA)] (referred to herein as BCY19187); A-(Sequence ID 125)-A-[K(PYA)] (referred to herein as BCY19188); A-(Sequence ID 126)-A-[K(PYA)] (referred to herein as BCY19189); [dA]-(Sequence ID 127)-[dA]-[K(PYA)] (referred to herein as BCY20840); A-(Sequence ID 128)-A-[K(PYA)] (referred to herein as BCY21040); A-(Sequence ID 129)-A (referred to herein as BCY21631); A-(Sequence ID 129) (referred to herein as BCY21633); Ac-(Sequence ID 129) (referred to herein as BCY21634); A-(Sequence ID 130) (referred to herein as BCY21635); Ac-(Sequence ID 130) (referred to herein as BCY21636); Ac-(Sequence ID 131)-[K(PYA)] (referred to herein as BCY23702); Ac-(Sequence ID 132)-[K(PYA)] (referred to herein as BCY23703); Ac-(SEQ ID NO: 132)-[K(PYA)-(triazolyl)-(PEG)2-methyl](referred to herein as BCY25601); Ac-(Sequence ID 133)-[K(PYA)] (referred to herein as BCY23704); Ac-(Sequence ID 134)-[K(PYA)] (referred to herein as BCY23705); Ac-(Sequence ID 135)-[K(PYA)] (referred to herein as BCY23706); Ac-(Sequence ID 136)-[K(PYA)] (referred to herein as BCY23707); Ac-(SEQ ID NO: 136)-[K(PYA)-(triazolyl)-(PEG)2-methyl](referred to herein as BCY25602); A-(Sequence ID 137)-A (referred to herein as BCY15729); A-(Sequence ID 138)-A (referred to herein as BCY15210); A-(Sequence ID 138)-A-[Sar6]-[KFl](referred to herein as BCY15198); A-(Sequence ID 138)-A-[K(PYA)] (referred to herein as BCY15752); A-(Sequence ID 139)-A (referred to herein as BCY15731); A-(Sequence ID 139)-A-[Sar6]-[KFl](referred to herein as BCY15730); A-(Sequence ID 140)-A (referred to herein as BCY15733); A-(Sequence ID 141)-A (referred to herein as BCY15735); and A-(Sequence ID 141)-A-[Sar6]-[KFl](referred to herein as BCY15734) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: [ka] A derivative of TATB having, where * in the formula indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 142)-A (referred to herein as BCY17001); A-(Sequence ID 143)-A (referred to herein as BCY18128); A-(Sequence ID 143)-A-[K(PYA)] (referred to herein as BCY19743); A-(Sequence ID 144)-A (referred to herein as BCY18129); A-(Sequence ID 144)-A-[K(PYA)] (referred to herein as BCY19744); Ac-A-(Sequence ID 144)-A (referred to herein as BCY24131); Ac-(Sequence ID 144) (referred to herein as BCY24135); A-(Sequence ID 144) (referred to herein as BCY24450); Ac-A-(Sequence ID 144) (referred to herein as BCY24451); (Sequence ID 144)-A (referred to herein as BCY24452); Ac-(Sequence ID 144)-A (referred to herein as BCY24453); AHGG-(Sequence ID 144)-EVHA (referred to herein as BCY25863); AIKP-(SEQ ID NO: 144)-QHEA (referred to herein as BCY25864); ADST-(SEQ ID NO: 144)-QHPA (referred to herein as BCY25865); ALNG-(SEQ ID NO: 144)-PLSA (referred to herein as BCY25866); ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)] (referred to herein as BCY28840); A-(Sequence ID 145)-A (referred to herein as BCY24442); A-(Sequence ID 146)-A (referred to herein as BCY24443); A-(Sequence ID 147)-A (referred to herein as BCY24444); A-(Sequence ID 148)-A (referred to herein as BCY24445); A-(Sequence ID 149)-A (referred to herein as BCY24456); A-(Sequence ID 150)-A (referred to herein as BCY24457); A-(Sequence ID 151)-A (referred to herein as BCY24458); A-(Sequence ID 152)-A (referred to herein as BCY24459); A-(Sequence ID 153)-A (referred to herein as BCY24462); A-(Sequence ID 154)-A (referred to herein as BCY24466); A-(Sequence ID 155)-A (referred to herein as BCY24467); A-(Sequence ID 156)-A (referred to herein as BCY24468); A-(Sequence ID 157)-A (referred to herein as BCY24469); A-(Sequence ID 158)-A (referred to herein as BCY24471); A-(Sequence ID 159)-A (referred to herein as BCY24472); A-(Sequence ID 160)-A (referred to herein as BCY24473); A-(Sequence ID 161)-A (referred to herein as BCY24474); A-(Sequence ID 162)-A (referred to herein as BCY24475); A-(Sequence ID 163)-A (referred to herein as BCY24477); A-(Sequence ID 164)-A (referred to herein as BCY24478); A-(Sequence ID 165)-A (referred to herein as BCY24479); A-(Sequence ID 166)-A (referred to herein as BCY24480); A-(Sequence ID 167)-A (referred to herein as BCY24481); A-(Sequence ID 168)-A (referred to herein as BCY24482); A-(Sequence ID 169)-A (referred to herein as BCY24483); A-(Sequence ID 170)-A (referred to herein as BCY24484); A-(Sequence ID 171)-A (referred to herein as BCY24485); A-(Sequence ID 172)-A (referred to herein as BCY24486); A-(Sequence ID 173)-A (referred to herein as BCY24487); A-(Sequence ID 174)-A (referred to herein as BCY24488); A-(Sequence ID 175)-A (referred to herein as BCY24489); A-(Sequence ID 176)-A (referred to herein as BCY24490); A-(Sequence ID 177)-A (referred to herein as BCY24491); A-(Sequence ID 178)-A (referred to herein as BCY24492); A-(Sequence ID 179)-A (referred to herein as BCY24493); A-(Sequence ID 180)-A (referred to herein as BCY24495); A-(Sequence ID 181)-A (referred to herein as BCY24496); A-(Sequence ID 182)-A (referred to herein as BCY24497); A-(Sequence ID 183)-A (referred to herein as BCY24498); A-(Sequence ID 184)-A (referred to herein as BCY24499); A-(Sequence ID 185)-A (referred to herein as BCY24500); A-(Sequence ID 186)-A (referred to herein as BCY24501); A-(Sequence ID 187)-A (referred to herein as BCY24503); A-(Sequence ID 188)-A (referred to herein as BCY24504); A-(Sequence ID 189)-A (referred to herein as BCY24505); A-(Sequence ID 190)-A (referred to herein as BCY24506); A-(Sequence ID 191)-A (referred to herein as BCY24509); ALNG-(SEQ ID NO: 192)-PLSA (referred to herein as BCY28838); ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)] (referred to herein as BCY28841); ALNG-(SEQ ID NO: 193)-PLSA (referred to herein as BCY28839); ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)] (referred to herein as BCY28842); ALEQN-(Sequence ID 194)-A (referred to herein as BCY25861); ALEQN-(SEQ ID NO: 194)-A-[K(PYA)] (referred to herein as BCY28843); ALEQN-(Sequence ID 195)-A (referred to herein as BCY28844); ALEQN-(SEQ ID NO: 195)-A-[K(PYA)] (referred to herein as BCY28845); and AHAGT-(SEQ ID NO: 196)-A (referred to herein as BCY25859) A bicyclic peptide ligand according to embodiment 2, comprising a more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

[0265] 6. CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4) peptide ligand is as follows: CQPTPRCPFSTWPC (referred to herein as Sequence ID No. 197); CQPTPQCPYSTWPC (referred to herein as Sequence ID No. 198, with the following structure: [ka] When complexed with a derivative of TATB, which has the formula where * indicates a binding site of three cysteine ​​residues, it is called BCY20723); CQPT[HyP]QCPYSTWPC (referred to herein as Sequence ID No. 199); CQPT[Cis-HyP]QCPYSTWPC (referred to herein as Sequence ID No. 200); CQPT[Pip]QCPYSTWPC (referred to herein as Sequence ID No. 201); CQPTPECPYSTWPC (referred to herein as Sequence ID No. 202); CQPTPQC[HyP]YSTWPC (referred to herein as Sequence ID No. 203); CQPTPQC[Cis-HyP]YSTWPC (referred to herein as Sequence ID No. 204); CQPTPQC[Aze]YSTWPC (referred to herein as Sequence ID No. 205); CQPTPQCP[2Nal]STWPC (referred to herein as Sequence ID No. 206); CQPTPQCP[4tBuPhe]STWPC (referred to herein as Sequence ID No. 207); CQPTPQCP[4FPhe]STWPC (referred to herein as Sequence ID No. 208); CQPTPQCP[3FTyr]STWPC (referred to herein as Sequence ID No. 209); CQPTPQCP[2FTyr]STWPC (referred to herein as Sequence ID No. 210); CQPTPQCPY[Dap]TWPC (referred to herein as Sequence ID No. 211); CQPTPQCPYS[Dap]WPC (referred to herein as Sequence ID No. 212); CQPTPQCPYST[2Nal]PC (referred to herein as Sequence ID No. 213); CQPTPQCPYST[1Nal]PC (referred to herein as Sequence ID No. 214); CQPTPQCPYST[6FTrp]PC (referred to herein as Sequence ID No. 215); CQPTPQCPYST[5FTrp]PC (referred to herein as Sequence ID No. 216); CQPTPQCPYST[6ClTrp]PC (referred to herein as Sequence ID No. 217); CQPTPQCPYST[4MeoTrp]PC (referred to herein as Sequence ID No. 218); CQPTPQCPYST[5MeoTrp]PC (referred to herein as Sequence ID No. 219); CQPTPQCPYST[Trp(S)]PC (referred to herein as Sequence ID No. 220); CQPTPQCPYST[AzaTrp]PC (referred to herein as Sequence ID No. 221); CQPTPQCPYSTW[HyP]C (referred to herein as Sequence ID No. 222); CQPTPQCPYSTW[Cis-HyP]C (referred to herein as Sequence ID No. 223); CQPTPQCPYSTW[Aze]C (referred to herein as Sequence ID No. 224); CQPTPQCPYSTW[Pip]C (referred to herein as Sequence ID No. 225); and CQPTPECPYNTWPC (referred to herein as Sequence ID No. 226) Includes more selective amino acid sequences, for example The molecular scaffold has the following structure: [ka] It is a derivative of TATB, having the formula where * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 197)-A (referred to herein as BCY16999); A-(Sequence ID 197)-A-[K(PYA)] (referred to herein as BCY17693); A-(Sequence ID 197)-A-[Sar6]-[K(Ac)](referred to herein as BCY19387); A-(Sequence ID 198)-A (referred to herein as BCY18126); Ac-A-(Sequence ID 198)-A (referred to herein as BCY20725); A-(Sequence ID 198)-NLNLK (referred to herein as BCY21770); VNENI-(Sequence ID 198)-A (referred to herein as BCY21771); A-(Sequence ID 198)-RNPHD (referred to herein as BCY21772); A-(Sequence ID 198)-IHNNG (referred to herein as BCY21774); TNEGI-(Sequence ID 198)-A (referred to herein as BCY21778); VNENI-(Sequence ID 198)-A-[K(PYA)] (referred to herein as BCY23767); A-(Sequence ID 199)-A (referred to herein as BCY20731); A-(Sequence ID 200)-A (referred to herein as BCY20732); A-(Sequence ID 201)-A (referred to herein as BCY20734); A-(Sequence ID 202)-A (referred to herein as BCY20735); A-(Sequence ID 203)-A (referred to herein as BCY20736); A-(Sequence ID 204)-A (referred to herein as BCY20737); A-(Sequence ID 205)-A (referred to herein as BCY20738); A-(Sequence ID 206)-A (referred to herein as BCY20741); A-(Sequence ID 207)-A (referred to herein as BCY20742); A-(Sequence ID 208)-A (referred to herein as BCY20743); A-(Sequence ID 209)-A (referred to herein as BCY20746); A-(Sequence ID 210)-A (referred to herein as BCY20747); A-(Sequence ID 211)-A (referred to herein as BCY20748); A-(Sequence ID 212)-A (referred to herein as BCY20749); A-(Sequence ID 213)-A (referred to herein as BCY20751); A-(Sequence ID 214)-A (referred to herein as BCY20752); A-(Sequence ID 215)-A (referred to herein as BCY20756); A-(Sequence ID 216)-A (referred to herein as BCY20757); A-(Sequence ID 217)-A (referred to herein as BCY20758); A-(Sequence ID 218)-A (referred to herein as BCY20759); A-(Sequence ID 219)-A (referred to herein as BCY20760); A-(Sequence ID 220)-A (referred to herein as BCY20761); A-(Sequence ID 221)-A (referred to herein as BCY20762); A-(Sequence ID 222)-A (referred to herein as BCY20763); A-(Sequence ID 223)-A (referred to herein as BCY20764); A-(Sequence ID 224)-A (referred to herein as BCY20765); A-(Sequence ID 225)-A (referred to herein as BCY20766); A-(Sequence ID 226)-A (referred to herein as BCY18127); and A-(Sequence ID 226)-A-[K(PYA)] (referred to herein as BCY19742) A bicyclic peptide ligand according to embodiment 2, comprising a more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

[0266] 7. CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5) peptide ligands are as follows: CYYPDYYACLDC (referred to herein as Sequence ID No. 227); CYYENYYACLDC (referred to herein as Sequence ID No. 228); and CYYPDWYACLDC (referred to herein as Sequence ID No. 229) Includes more selective amino acid sequences, for example The molecular scaffold has the following structure: [ka] It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, and CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5) peptide ligand further includes N and / or C-terminal additions, and as follows: A-(Sequence ID 227)-A (referred to herein as BCY17007); A-(Sequence ID 228)-A (referred to herein as BCY18135); A-(Sequence ID 229)-A (referred to herein as BCY18136); and A-(Sequence ID 229)-A-[K(PYA)] (referred to herein as BCY19747) A bicyclic peptide ligand according to embodiment 2, comprising a more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

[0267] 8. 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) is as follows: CNNPVMTYWCTKGIC (referred to herein as Sequence ID No. 230); CNNPVMTYWCEKGIC (referred to herein as Sequence ID No. 231); CDNEVITYWCTKGIC (referred to herein as Sequence ID No. 232); CDNEV[tBuAla]TYWCTKGIC (referred to herein as Sequence ID No. 233); CDNEVFTYWCTKGIC (referred to herein as Sequence ID No. 234); CDNEV[Cba]TYWCTKGIC (referred to herein as Sequence ID No. 235); CDNEVITY[2Nal]CTKGIC (referred to herein as Sequence ID No. 236); CDNEVITY[1Nal]CTKGIC (referred to herein as Sequence ID No. 237); CDNEVITYWCT[Orn]GIC (referred to herein as Sequence ID No. 238); CDNEVITYWCT[HArg]GIC (referred to herein as Sequence ID No. 239); CDNEVITYWCTK[dA]IC (referred to herein as Sequence ID No. 240); CDNEVITYWCTKG[tBuGly]C (referred to herein as Sequence ID No. 241); CDNEVIT[DOPA]WCTKGIC (referred to herein as Sequence ID No. 242); CDNPVFTYWCTKGIC (referred to herein as Sequence ID No. 243); CNNPVMAYWCTKGIC (referred to herein as Sequence ID No. 244); CPNPVITYWCTKGIC (referred to herein as Sequence ID No. 245); CDNEVITYWCQMGVC (referred to herein as Sequence ID No. 246); CDNEVITYWCQRGVC (referred to herein as Sequence ID No. 247); CDNEVITYWCMRGIC (referred to herein as Sequence ID No. 248); CDNEVITYWCQRGIC (referred to herein as Sequence ID No. 249); CDNEVITY[6FTrp]CQRGIC (referred to herein as Sequence ID No. 250); CDNEVITY[5FTrp]CQRGIC (referred to herein as Sequence ID No. 251); CDNEVITY[5MeoTrp]CQRGIC (referred to herein as Sequence ID No. 252); CDNEVITY[Trp(S)]CQRGIC (referred to herein as Sequence ID No. 253); CDNEVITY[AzaTrp]CQRGIC (referred to herein as Sequence ID No. 254); CDNEVITYWCQ[HArg]GIC (referred to herein as Sequence ID No. 255); CDNEVITYWCQ[Cit]GIC (referred to herein as Sequence ID No. 256); CDNEVFEYWCTKGIC (referred to herein as Sequence ID No. 257); CDNEVITYWCERGIC (referred to herein as Sequence ID No. 258); CDNEVITYWCEMGIC (referred to herein as Sequence ID No. 259); CSNPVFAYWCSRQMC (referred to herein as Sequence ID No. 260); CSNPVFAYWCERGIC (referred to herein as Sequence ID No. 261, and also with the following structure: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21615); CSNPVFAYWCER[K(PYA)]IC (referred to herein as Sequence ID No. 262); CSNPVFAYWCER[dK(PYA)]IC (referred to herein as Sequence ID No. 263); CSNPVFAYWCER[S-aMeLys(PYA)]IC (referred to herein as Sequence ID No. 264); CSNPVFAYWCER[R-aMeLys(PYA)]IC (referred to herein as Sequence ID No. 265); C[K(PYA)]NPVFAYWCERGIC (referred to herein as Sequence ID No. 266); CSNPVFAY[5FTrp]CERGIC (referred to herein as Sequence ID No. 267); CSNPVFAYWCERGI[Cysam] (referred to herein as Sequence ID No. 268, and also having the following structure: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21623); C[K(PYA)]NPVFAYWCERGI[Cysam] (referred to herein as Sequence ID No. 269); CSNPVFAYWC[Dap]RGIC (referred to herein as Sequence ID No. 270); CKNPVFAYWC[PG]RGIC (referred to herein as Sequence ID No. 271); CENPVFAYWCERGIC (referred to herein as Sequence ID No. 272); C[dA]NPVFAYWCERGIC (referred to herein as Sequence ID No. 273); CGNPVFAYWCERGIC (referred to herein as Sequence ID No. 274); C[Aib]NPVFAYWCERGIC (referred to herein as Sequence ID No. 275); CSN[trans-4FlPro]VFAYWCERGIC (referred to herein as Sequence ID No. 276); CSN[4FlPro]VFAYWCERGIC (referred to herein as Sequence ID No. 277); CSN[HyP]VFAYWCERGIC (referred to herein as Sequence ID No. 278); CSN[Cis-HyP]VFAYWCERGIC (referred to herein as Sequence ID No. 279); CSNP[HSer]FAYWCERGIC (referred to herein as Sequence ID No. 280); CSNPV[2FPhe]AYWCERGIC (referred to herein as Sequence ID No. 281); CSNPV[4CF3Phe]AYWCERGIC (referred to herein as Sequence ID No. 282); CSNPVFSYWCERGIC (referred to herein as Sequence ID No. 283); CSNPVF[Dap]YWCERGIC (referred to herein as Sequence ID No. 284); CSNPVF[CF3Ala]YWCERGIC (referred to herein as Sequence ID No. 285); CSNPVFA[2FTyr]WCERGIC (referred to herein as Sequence ID No. 286); CSNPVFA[3FTyr]WCERGIC (referred to herein as Sequence ID No. 287); CSNPVFAY[4FTrp]CERGIC (referred to herein as Sequence ID No. 288); CSNPVFAYWCE[Cit]GIC (referred to herein as Sequence ID No. 289); CSNPVFAYWCER[dA]IC (referred to herein as Sequence ID No. 290); CSNPVFAYWCERG[Nva]C (referred to herein as Sequence ID No. 291); CSNPVFAYWCERG[Nle]C (referred to herein as Sequence ID No. 292); CSNPVFAYWCERG[EPA]C (referred to herein as Sequence ID No. 293); CSNPVFAYWCERG[tBuGly]C (referred to herein as Sequence ID No. 294); CSN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 295); C[Aib]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 296); C[dS]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 297); C[K(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 298); C[dK(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 299); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 300); CSN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to herein as Sequence ID No. 301); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to herein as Sequence ID No. 302); CSNPVFAYWCSRNLC (referred to herein as Sequence ID No. 303); CSNPVFAYWCSRGLC (referred to herein as Sequence ID No. 304); CTTDMMWKVCRTLDC (referred to herein as Sequence ID No. 305); CATDHMWKVCRTLDC (referred to herein as Sequence ID No. 306); CKTDAMWKVCRTLDC (referred to herein as Sequence ID No. 307); CSTDQMWKVCRTLDC (referred to herein as Sequence ID No. 308); CSTDYMWKVCRTLDC (referred to herein as Sequence ID No. 309, and also with the following structure: [ka] When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY23141); CSTDY[Nle]WKVCRTLDC (referred to herein as Sequence ID No. 310); CATDYMWKVCRTLDC (referred to herein as Sequence ID No. 311); CSTDAMWKVCRTLDC (referred to herein as Sequence ID No. 312); CSTDYAWKVCRTLDC (referred to herein as Sequence ID No. 313); CSTDYMWKACRTLDC (referred to herein as Sequence ID No. 314); CSTDYMWKVCRALDC (referred to herein as Sequence ID No. 315); CSTDYMWKVCRTADC (referred to herein as Sequence ID No. 316); C[CF3Ala]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 317); C[HSer]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 318); CTTDYMWKVCRTLDC (referred to herein as Sequence ID No. 319); C[3HyV]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 320); CS[3HyV]DYMWKVCRTLDC (referred to herein as Sequence ID No. 321); C[Dap]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 322); CSTD[4FPhe]MWKVCRTLDC (referred to herein as Sequence ID No. 323); CSTD[1Nal]MWKVCRTLDC (referred to herein as Sequence ID No. 324); CSTD[2Nal]MWKVCRTLDC (referred to herein as Sequence ID No. 325); CSTD[26DiMeTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 326); CSTD[3FTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 327); CSTD[2FTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 328); CSTD[DOPA]MWKVCRTLDC (referred to herein as Sequence ID No. 329); CSTDY[Nva]WKVCRTLDC (referred to herein as Sequence ID No. 330); CSTDY[TfNle]WKVCRTLDC (referred to herein as Sequence ID No. 331); CSTDYEWKVCRTLDC (referred to herein as Sequence ID No. 332); CSTDY[CF3Nva]WKVCRTLDC (referred to herein as Sequence ID No. 333); CSTDYM[1Nal]KVCRTLDC (referred to herein as Sequence ID No. 334); CSTDYM[4FTrp]KVCRTLDC (referred to herein as Sequence ID No. 335); CSTDYM[5FTrp]KVCRTLDC (referred to herein as Sequence ID No. 336); CSTDYM[6FTrp]KVCRTLDC (referred to herein as Sequence ID No. 337); CSTDYM[7FTrp]KVCRTLDC (referred to herein as Sequence ID No. 338); CSTDYM[2MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 339); CSTDYM[4MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 340); CSTDYM[5MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 341); CSTDYM[6MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 342); CSTDYM[7MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 343); CSTDYM[AzaTrp]KVCRTLDC (referred to herein as Sequence ID No. 344); CSTDYMW[HArg]VCRTLDC (referred to herein as Sequence ID No. 345); CSTDYMW[Orn]VCRTLDC (referred to herein as Sequence ID No. 346); CSTDYMW[Agb]VCRTLDC (referred to herein as Sequence ID No. 347); CSTDYMWK[tBuGly]CRTLDC (referred to herein as Sequence ID No. 348); CSTDYMWK[Cbg]CRTLDC (referred to herein as Sequence ID No. 349); CSTDYMWK[C5g]CRTLDC (referred to herein as Sequence ID No. 350); CSTDYMWK[3HyV]CRTLDC (referred to herein as Sequence ID No. 351); CSTDYMWKVC[HArg]TLDC (referred to herein as Sequence ID No. 352); CSTDYMWKVC[Arg(Me)]TLDC (referred to herein as Sequence ID No. 353); CSTDYMWKVCR[3HyV]LDC (referred to herein as Sequence ID No. 354); CSTDYMWKVCRT[tBuAla]DC (referred to herein as Sequence ID No. 355); CSTDYMWKVCRT[Cba]DC (referred to herein as Sequence ID No. 356); CSTDYMWKVCRT[Nva]DC (referred to herein as Sequence ID No. 357); CSTDYMWKVCRT[Nle]DC (referred to herein as Sequence ID No. 358); CTTDMAWRDCRTLDC (referred to herein as Sequence ID No. 359); CTTDMAWRLCRTLDC (referred to herein as Sequence ID No. 360); CTTDMVWKVCRTLDC (referred to herein as Sequence ID No. 361); CVTDYMWKVCRTLDC (referred to herein as Sequence ID No. 362); CYTDSMWKVCRTLDC (referred to herein as Sequence ID No. 363); CTTDMMWKVCREPDC (referred to herein as Sequence ID No. 364); CTTDMMWKVCRSMDC (referred to herein as Sequence ID No. 365); and CTTDMMWKVCRTLDC (referred to herein as Sequence ID No. 366) Includes more selective amino acid sequences, for example The molecular scaffold has the following structure: [ka] A derivative of TATA having, where * indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 230)-A (referred to herein as BCY15211); A-(Sequence ID 230)-A-[Sar6]-[KFl](referred to herein as BCY15199); A-(Sequence ID 231)-A (referred to herein as BCY15737); A-(Sequence ID 232)-A (referred to herein as BCY15739); A-(Sequence ID 232)-A-[Sar6]-[KFl](referred to herein as BCY15738); A-(Sequence ID 232)-A-[Sar6]-[K(Ac)](referred to herein as BCY19386); A-(Sequence ID 232)-AGAAAE (referred to herein as BCY19581); A-(Sequence ID 233)-A (referred to herein as BCY17047); A-(Sequence ID 234)-A (referred to herein as BCY17049); A-(Sequence ID 235)-A (referred to herein as BCY17051); A-(Sequence ID 236)-A (referred to herein as BCY17055); A-(Sequence ID 237)-A (referred to herein as BCY17056); A-(Sequence ID 238)-A (referred to herein as BCY17057); A-(Sequence ID 239)-A (referred to herein as BCY17058); A-(Sequence ID 240)-A (referred to herein as BCY17059); A-(Sequence ID 241)-A (referred to herein as BCY17061); A-(Sequence ID 242)-A (referred to herein as BCY17656); A-(Sequence ID 243)-A (referred to herein as BCY15741); A-(Sequence ID 244)-A (referred to herein as BCY15743); A-(Sequence ID 245)-A (referred to herein as BCY15745); A-(Sequence ID 246)-A (referred to herein as BCY16668); A-(Sequence ID 247)-A (referred to herein as BCY16669); A-(Sequence ID 248)-A (referred to herein as BCY16670); A-(Sequence ID 249)-A (referred to herein as BCY16671); A-(Sequence ID 249)-A-[Sar6]-[KFl](referred to herein as BCY16647); Ac-A-(Sequence ID 249)-A (referred to herein as BCY19586); A-(Sequence ID 250)-A (referred to herein as BCY18510); A-(Sequence ID 251)-A (referred to herein as BCY18511); A-(Sequence ID 251)-A-[K(PYA)] (referred to herein as BCY25826); A-(Sequence ID 252)-A (referred to herein as BCY18514); A-(Sequence ID 253)-A (referred to herein as BCY18515); A-(Sequence ID 254)-A (referred to herein as BCY18518); A-(Sequence ID 255)-A (referred to herein as BCY18519); A-(Sequence ID 256)-A (referred to herein as BCY18520); A-(Sequence ID 257)-A (referred to herein as BCY16672); A-(Sequence ID 258)-A (referred to herein as BCY16673); A-(Sequence ID 258)-A-[Sar6]-[KFl](referred to herein as BCY16649); A-(Sequence ID 258)-A-[K(PYA)] (referred to herein as BCY17237); Ac-A-(Sequence ID 258)-A (referred to herein as BCY19585); and A-(Sequence ID 259)-A (referred to herein as BCY16674) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: [ka] It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, wherein * in the formula indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 260)-A (referred to herein as BCY17002); A-(Sequence ID 260)-A-[K(PYA)] (referred to herein as BCY19745); A-(Sequence ID 261)-A (referred to herein as BCY18130); A-(Sequence ID 261)-A-[K(PYA)] (referred to herein as BCY20847); [PYA]-A-(Sequence ID 261)-A (referred to herein as BCY20852); Ac-(Sequence ID 261) (referred to herein as BCY21616); A-(Sequence ID 261) (referred to herein as BCY21617); Ac-A-(Sequence ID 261) (referred to herein as BCY21618); [PYA]-(Sequence ID 261) (referred to herein as BCY21619); [GuanAc]-(SEQ ID NO: 261)-A (referred to herein as BCY23043); A-(Sequence ID 261)-[CF3Ala] (referred to herein as BCY23080); A-(Sequence ID 261)-S (referred to herein as BCY23081); A-(Sequence ID 262)-A (referred to herein as BCY20848); A-(Sequence ID 263)-A (referred to herein as BCY20849); A-(Sequence ID 264)-A (referred to herein as BCY20850); A-(Sequence ID 265)-A (referred to herein as BCY20851); A-(Sequence ID 266)-A (referred to herein as BCY20853); A-(Sequence ID 266) (referred to herein as BCY21620); A-(Sequence ID 267)-A (referred to herein as BCY21622); A-(Sequence ID 267)-A-[K(PYA)] (referred to herein as BCY21607); Ac-(Sequence ID 268) (referred to herein as BCY21624); A-(Sequence ID 268) (referred to herein as BCY21625); [PYA]-(Sequence ID 268) (referred to herein as BCY21626); A-(Sequence ID 269) (referred to herein as BCY21627); Ac-(Sequence ID 270) (referred to herein as BCY22879); Ac-(Sequence ID 271) (referred to herein as BCY22880); A-(Sequence ID 272)-A (referred to herein as BCY23044); A-(Sequence ID 273)-A (referred to herein as BCY23045); A-(Sequence ID 274)-A (referred to herein as BCY23046); A-(Sequence ID 275)-A (referred to herein as BCY23047); A-(Sequence ID 276)-A (referred to herein as BCY23050); A-(Sequence ID 277)-A (referred to herein as BCY23051); A-(Sequence ID 278)-A (referred to herein as BCY23052); A-(Sequence ID 279)-A (referred to herein as BCY23053); A-(Sequence ID 280)-A (referred to herein as BCY23054); A-(Sequence ID 281)-A (referred to herein as BCY23058); A-(Sequence ID 282)-A (referred to herein as BCY23059); A-(Sequence ID 283)-A (referred to herein as BCY23062); A-(Sequence ID 284)-A (referred to herein as BCY23063); A-(Sequence ID 285)-A (referred to herein as BCY23064); A-(Sequence ID 286)-A (referred to herein as BCY23066); A-(Sequence ID 287)-A (referred to herein as BCY23067); A-(Sequence ID 288)-A (referred to herein as BCY23068); A-(Sequence ID 289)-A (referred to herein as BCY23071); A-(Sequence ID 290)-A (referred to herein as BCY23072); A-(Sequence ID 291)-A (referred to herein as BCY23073); A-(Sequence ID 292)-A (referred to herein as BCY23074); A-(Sequence ID 293)-A (referred to herein as BCY23075); A-(Sequence ID 294)-A (referred to herein as BCY23079); [GuanAc]-(SEQ ID NO: 295)-COOH (referred to herein as BCY27058); [GuanAc]-(Sequence ID 295) (referred to herein as BCY27059); [CIA]-[K(PYA)]-(Sequence ID 295)-A (referred to herein as BCY27064); [CIA]-[dK(PYA)]-(Sequence ID 295)-A (referred to herein as BCY27065); [GuanAc]-(Sequence ID 296) (referred to herein as BCY27060); [GuanAc]-(Sequence ID 297) (referred to herein as BCY27061); [GuanAc]-(Sequence ID 298) (referred to herein as BCY27062); [GuanAc]-(Sequence ID 299) (referred to herein as BCY27063); [GuanAc]-(Sequence ID 300) (referred to herein as BCY27066); [GuanAc]-(Sequence ID 301) (referred to herein as BCY27067); [GuanAc]-(Sequence ID 302) (referred to herein as BCY27068); A-(Sequence ID 303)-A (referred to herein as BCY18131); A-(Sequence ID 304)-A (referred to herein as BCY18132); A-(Sequence ID 305)-A-[K(PYA)] (referred to herein as BCY19588); A-(Sequence ID 306)-A (referred to herein as BCY19933); A-(Sequence ID 307)-A (referred to herein as BCY19934); A-(Sequence ID 308)-A (referred to herein as BCY19935); A-(Sequence ID 309)-A (referred to herein as BCY19936); A-(Sequence ID 309)-A-[K(PYA)] (referred to herein as BCY21606); Ac-(Sequence ID 309) (referred to herein as BCY23139); Ac-A-(Sequence ID 309)-A (referred to herein as BCY23140); [dA]-(Sequence ID 309)-A (referred to herein as BCY32061); A-(Sequence ID 309) (referred to herein as BCY32074); Ac-A-(Sequence ID 309) (referred to herein as BCY32075); (Sequence ID 309)-A (referred to herein as BCY32076); Ac-(Sequence ID 309)-A (referred to herein as BCY32077); A-(Sequence ID 309)-A-[dK(PYA)] (referred to herein as BCY32126); A-(Sequence ID 309)-[K(PYA)] (referred to herein as BCY32127); A-(Sequence ID 309)-[dK(PYA)] (referred to herein as BCY32128); A-(Sequence ID 310)-A (referred to herein as BCY23138); A-(Sequence ID 310)-A-[K(PYA)] (referred to herein as BCY24613); A-(Sequence ID 311)-A (referred to herein as BCY32062); A-(Sequence ID 312)-A (referred to herein as BCY32065); A-(Sequence ID 313)-A (referred to herein as BCY32066); A-(Sequence ID 314)-A (referred to herein as BCY32069); A-(Sequence ID 315)-A (referred to herein as BCY32071); A-(Sequence ID 316)-A (referred to herein as BCY32072); A-(Sequence ID 317)-A (referred to herein as BCY32078); A-(Sequence ID 318)-A (referred to herein as BCY32079); A-(Sequence ID 319)-A (referred to herein as BCY32080); A-(Sequence ID 320)-A (referred to herein as BCY32081); A-(Sequence ID 321)-A (referred to herein as BCY32082); A-(Sequence ID 322)-A (referred to herein as BCY32083); A-(Sequence ID 323)-A (referred to herein as BCY32084); A-(Sequence ID 324)-A (referred to herein as BCY32085); A-(Sequence ID 325)-A (referred to herein as BCY32086); A-(Sequence ID 326)-A (referred to herein as BCY32087); A-(Sequence ID 327)-A (referred to herein as BCY32088); A-(Sequence ID 328)-A (referred to herein as BCY32089); A-(Sequence ID 329)-A (referred to herein as BCY32090); A-(Sequence ID 330)-A (referred to herein as BCY32091); A-(Sequence ID 331)-A (referred to herein as BCY32092); A-(Sequence ID 332)-A (referred to herein as BCY32093); A-(Sequence ID 333)-A (referred to herein as BCY32095); A-(Sequence ID 334)-A (referred to herein as BCY32096); A-(Sequence ID 335)-A (referred to herein as BCY32098); A-(Sequence ID 336)-A (referred to herein as BCY32099); A-(Sequence ID 337)-A (referred to herein as BCY32100); A-(Sequence ID 338)-A (referred to herein as BCY32101); A-(Sequence ID 339)-A (referred to herein as BCY32103); A-(Sequence ID 340)-A (referred to herein as BCY32104); A-(Sequence ID 341)-A (referred to herein as BCY32105); A-(Sequence ID 342)-A (referred to herein as BCY32106); A-(Sequence ID 343)-A (referred to herein as BCY32107); A-(Sequence ID 344)-A (referred to herein as BCY32108); A-(Sequence ID 345)-A (referred to herein as BCY32109); A-(Sequence ID 346)-A (referred to herein as BCY32110); A-(Sequence ID 347)-A (referred to herein as BCY32112); A-(Sequence ID 348)-A (referred to herein as BCY32113); A-(Sequence ID 349)-A (referred to herein as BCY32114); A-(Sequence ID 350)-A (referred to herein as BCY32115); A-(Sequence ID 351)-A (referred to herein as BCY32116); A-(Sequence ID 352)-A (referred to herein as BCY32117); A-(Sequence ID 353)-A (referred to herein as BCY32120); A-(Sequence ID 354)-A (referred to herein as BCY32121); A-(Sequence ID 355)-A (referred to herein as BCY32122); A-(Sequence ID 356)-A (referred to herein as BCY32123); A-(Sequence ID 357)-A (referred to herein as BCY32124); A-(Sequence ID 358)-A (referred to herein as BCY32125); A-(Sequence ID 359)-A (referred to herein as BCY19937); A-(Sequence ID 360)-A (referred to herein as BCY19938); A-(Sequence ID 361)-A (referred to herein as BCY19939); A-(Sequence ID 362)-A (referred to herein as BCY19940); A-(Sequence ID 363)-A (referred to herein as BCY19941); A-(Sequence ID 364)-A (referred to herein as BCY19942); A-(Sequence ID 365)-A (referred to herein as BCY19943); and A-(Sequence ID 366)-A (referred to herein as BCY18253) A bicyclic peptide ligand according to embodiment 2, comprising a more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

[0268] 9. A multimer-binding complex comprising at least two bicyclic peptide ligands according to any one of embodiments 2 to 8, wherein the peptide ligands may be the same or different.

[0269] 10. The polymer-binding complex according to embodiment 9, comprising one or more identical bicyclic peptides (i.e., homomultimers).

[0270] 11. A polymer-binding complex according to embodiment 9, comprising different bicyclic peptides (i.e., heteromultimers).

[0271] 12. Containing two bicyclic peptides that are either identical (i.e., homodimers) or different (i.e., heterodimers), for example: [Table 9] A polymer-binding complex according to embodiment 9, comprising:

[0272] 13. The multimer-binding complex contains three bicyclic peptides that are either identical (i.e., homotrimer) or different (i.e., heterotrimer), for example, the heterotrimer contains one bicyclic peptide in the first sequence and two bicyclic peptides in the second sequence, in particular: [Table 10] A polymer-binding complex according to embodiment 9, comprising:

[0273] 14. The multimer-binding complex contains four bicyclic peptides that are either identical (i.e., homotetramer) or different (i.e., heterotetramer), for example, the heterotetramer contains one bicyclic peptide in the first sequence and three bicyclic peptides in the second sequence, or the heterotetramer contains two bicyclic peptides in the first sequence and two bicyclic peptides in the second sequence, in particular: [Table 11] A polymer-binding complex according to embodiment 9, comprising:

[0274] 15. A pharmaceutical composition comprising a peptide ligand according to Embodiment 1, or a bicyclic peptide ligand according to any one of Embodiments 2 to 8, or a polymer-binding complex according to any one of Embodiments 9 to 14, in combination with one or more pharmaceutically acceptable additives.

[0275] 16. A peptide ligand according to Embodiment 1, or a bicyclic peptide ligand according to any one of Embodiments 2 to 8, or a multimer-bound complex according to any one of Embodiments 9 to 14, or a pharmaceutical composition according to Embodiment 15, for use in preventing, suppressing, or treating a disease or disorder mediated by TLR3.

Claims

1. Peptide ligands, as follows: C-X 1 -X 2 -X 3 -C-X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -C (SEQ ID NO: 1); CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC(array number 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 (Sequence ID 3); CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (array number 4); CYYX 38 -X 39 -X 40 -YACLDC(SEQ ID NO: 5); 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 (Sequence ID 6) Selected from, in the formula, X 1 represents D, N, P, Y, 26 DiMeTyr, 2FTyr, 3FTyr, or 4FPhe; X 2 represents A, I, N, P, S, T, Aze, Cba, Cis-HyP, tBuAla, or tBuGly; X 3 represents A, G, N, P, Q, R, Aib, Aze, Cis-HyP, dA, HyP, or Pip; X 4 represents L, S, or Cba; X 5 represents K, P, R, W, 5FTrp, 5MeOTrp, 6ClTrp, 6FTrp, 6MeTrp, Agb, HArg, Trp(Me), or Trp(S); X 6 represents M, R, or HArg; X 7 represents A, F, Q, Y, 2FTyr, 3FTyr, 3tBuTyr, or 4FPhe; X 8 represents H, I, N, V, Cbg, His1Me, His3Me, or tBuGly; X 9 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 This 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 This represents C or dC; X 21 dE represents A, E, F, L, Q, R, T, W, Y, 1Nal, 2FPhe, 2MePhe, 2Nal, 3FPhe, 3MePhe, 4FPhe, 4MePhe, or dE; X 22 dY 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 This 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 This 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 is represented by A, H, M, Q, S, V, Y, 1Nal, 26DiMeTyr, 2FTyr, 2Nal, 3FTyr, 4FPhe, DOPA, or HSer; X 46 represents A, E, F, I, M, V, 2FPhe, 4CF3Phe, Cba, CF3Nva, Nle, Nva, tBuAla, or TfNle; X 47 This 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 is represented by 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 This represents C, dC, or Cysam. A peptide ligand or a modified derivative thereof, and / or a pharmaceutically acceptable salt, comprising a polypeptide having an amino acid sequence.

2. A bicyclic peptide ligand or a pharmaceutically acceptable salt thereof that can bind to TLR3, wherein the bicyclic peptide ligand comprises a peptide ligand comprising a polypeptide having three reactive groups, and the polypeptide is bound 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 three cysteine ​​or cysam residues of the peptide ligand form covalent bonds with a molecular scaffold to form two loop sequences.

4. CX 1 -X 2 -X 3 -CX 4 -X 5 -X 6 -X 7 -X 8 -X 9 -C (SEQ ID NO: 1) peptide ligand is as follows: CDIACLKMYNFC(Sequence ID 7); CDIGCLRMYNFC(Sequence ID 8); CD[tBuAla]GCLRMYNFC(Sequence ID 9); CD[tBuGly]GCLRMYNFC(Sequence ID 10); CD[Cba]GCLRMYNFC (Sequence ID 11); CDI[dA]CLRMYNFC(SEQ ID NO: 12); CDI[Aib]CLRMYNFC (Sequence ID 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 (Sequence ID 20); CNIQCLRMYNFC (Sequence ID 21); CDIRCLRMYNFC (Sequence ID 22); CDINCLRMYNFC(Sequence ID 23); CPPGCSPRFHLC (Sequence ID 24); CPPGCSPRYHLC (Sequence ID 25; structure below: 【Chemistry 1】 (It has the formula, where * indicates a binding site of three cysteine ​​residues, and when complexed with a derivative of TATB, it is called BCY21542); 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 (Sequence ID 37); CYNPCLWRQVDC (SEQ ID NO: 38; structure below: 【Chemistry 2】 (When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21497); 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 (Sequence ID 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 (Sequence ID 59); CYSPCLWRQVDC(SEQ ID NO: 60); and CYTPCLWRQVDC (Sequence ID 61) This includes polypeptides having more selectable amino acid sequences, for example: The molecular scaffold has the following structure: 【Transformation 3】 It is a derivative of TATA, in which * in the formula indicates a binding site of three cysteine ​​residues, and CX 1 -X 2 -X 3 -CX 4 -X 5 -X 6 -X 7 -X 8 -X 9 - The peptide ligand of C (SEQ ID NO: 1) further includes N and / or C-terminal additions, and as follows: A-(Sequence No. 7)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15200); A-(Sequence ID 7)-A (referred to herein as BCY15212); A-(Sequence ID 8)-A (referred to herein as BCY15747); A-(Sequence ID 8)-A-[K(PYA)] (referred to herein as BCY19281); A-(Sequence ID 9)-A (referred to herein as BCY17064); A-(Sequence ID 10)-A (referred to herein as BCY17065); A-(Sequence ID 11)-A (referred to herein as BCY17066); A-(Sequence ID 12)-A (referred to herein as BCY17067); A-(Sequence ID 13)-A (referred to herein as BCY17068); A-(Sequence ID 14)-A (referred to herein as BCY17070); A-(Sequence ID 15)-A (referred to herein as BCY17071); A-(Sequence ID 16)-A (referred to herein as BCY17072); A-(Sequence ID 17)-A (referred to herein as BCY17079); A-(Sequence ID 18)-A (referred to herein as BCY17080); A-(Sequence ID 19)-A (referred to herein as BCY17081); A-(Sequence ID 20)-A (referred to herein as BCY16675); A-(Sequence ID 21)-A (referred to herein as BCY16676); A-(Sequence ID 22)-A (referred to herein as BCY16677); and A-(Sequence ID 23)-A (referred to herein as BCY16678) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: 【Chemistry 4】 It is a derivative of TATB, wherein * in the formula indicates a binding site of three cysteine ​​residues, and CX 1 -X 2 -X 3 -CX 4 -X 5 -X 6 -X 7 -X 8 -X 9 - The peptide ligand of C (SEQ ID NO: 1) further includes N and / or C-terminal additions, and as follows: A-(Sequence ID 24)-A (referred to herein as BCY16997); A-(Sequence ID 25)-A (referred to herein as BCY18125); A-(Sequence ID 25)-A-[K(PYA)] (referred to herein as BCY19741); A-(Sequence ID 25) (referred to herein as BCY21538); Ac-A-(Sequence ID 25) (referred to herein as BCY21539); (Sequence ID 25)-A (referred to herein as BCY21540); Ac-(Sequence ID 25)-A (referred to herein as BCY21541); Ac-(Sequence ID 25) (referred to herein as BCY21543); Ac-A-(SEQ ID NO: 25)-A (referred to herein as BCY21544); A-(Sequence ID 25)-DKTTV (referred to herein as BCY21769); TVKTP-(Sequence ID 25)-A (referred to herein as BCY21775); A-(Sequence ID 25)-DIHNN (referred to herein as BCY21777); A-(Sequence ID 26)-A (referred to herein as BCY21550); A-(Sequence ID 27)-A (referred to herein as BCY21551); A-(Sequence ID 28)-A (referred to herein as BCY21558); A-(Sequence ID 29)-A (referred to herein as BCY21561); A-(Sequence ID 30)-A (referred to herein as BCY21562); A-(Sequence ID 31)-A (referred to herein as BCY21564); A-(Sequence ID 32)-A (referred to herein as BCY21565); A-(Sequence ID 33)-A (referred to herein as BCY21566); A-(Sequence ID 34)-A (referred to herein as BCY21567); A-(Sequence ID 35)-A (referred to herein as BCY21568); A-(Sequence ID 36)-A (referred to herein as BCY21569); and A-(Sequence ID 37)-A (referred to herein as BCY16998) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: 【Transformation 5】 It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein the formula * indicates a binding site of three cysteine ​​residues, and CX 1 -X 2 -X 3 -CX 4 -X 5 -X 6 -X 7 -X 8 -X 9 - The peptide ligand of C (SEQ ID NO: 1) further includes N and / or C-terminal additions, and as follows: A-(Sequence ID 38)-A (referred to herein as BCY18251); A-(Sequence ID 38)-A-[K(PYA)] (referred to herein as BCY19587); A-(Sequence ID 38) (referred to herein as BCY21493); (Sequence ID 38)-A (referred to herein as BCY21495); Ac-(Sequence ID 38) (referred to herein as BCY21498); YYYEW-(Sequence ID 38)-A (referred to herein as BCY21773); A-(Sequence ID 39)-A (referred to herein as BCY21485); A-(Sequence ID 40)-A (referred to herein as BCY21490); A-(Sequence ID 41)-A (referred to herein as BCY21500); A-(Sequence ID 42)-A (referred to herein as BCY21502); A-(Sequence ID 43)-A (referred to herein as BCY21503); A-(Sequence ID 44)-A (referred to herein as BCY21504); A-(Sequence ID 45)-A (referred to herein as BCY21505); A-(Sequence ID 46)-A (referred to herein as BCY21506); A-(Sequence ID 47)-A (referred to herein as BCY21507); A-(Sequence ID 48)-A (referred to herein as BCY21508); A-(Sequence ID 49)-A (referred to herein as BCY21510); A-(Sequence ID 50)-A (referred to herein as BCY21515); A-(Sequence ID 51)-A (referred to herein as BCY21517); A-(Sequence ID 52)-A (referred to herein as BCY21518); A-(Sequence ID 53)-A (referred to herein as BCY21519); A-(Sequence ID 54)-A (referred to herein as BCY21521); A-(Sequence ID 55)-A (referred to herein as BCY21522); A-(Sequence ID 56)-A (referred to herein as BCY21523); A-(Sequence ID 57)-A (referred to herein as BCY21527); A-(Sequence ID 58)-A (referred to herein as BCY21528); A-(Sequence ID 59)-A (referred to herein as BCY19930); A-(Sequence ID 59)-VYNVN (referred to herein as BCY21776); A-(Sequence ID 60)-A (referred to herein as BCY19931); and A-(Sequence ID 61)-A (referred to herein as BCY19932) The bicyclic peptide ligand according to claim 3, comprising a more selected amino acid sequence, a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

5. CX 10 -X 11 -YYCX 12 -QTX 13 -X 14 -FC (SEQ ID NO: 2) peptide ligand is as follows: CTSYYCEQTRHFC (Sequence ID 62); CTKYYCEQTRHFC (Sequence ID 63); and CSKYYCQQTVRFC(Sequence ID 64) Includes more selective amino acid sequences, for example: The molecular scaffold has the following structure: 【Transformation 6】 It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein the formula * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 62)-A (referred to herein as BCY17006); A-(Sequence ID 63)-A (referred to herein as BCY18134); A-(SEQ ID NO: 63)-A-[K(PYA)](referred to herein as BCY19746); and A-(Sequence ID 64)-A (referred to herein as BCY17012) The bicyclic peptide ligand according to claim 3, comprising a more selected amino acid sequence, a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

6. 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) is as follows: CTNEVCTYWYNRGLC (Sequence ID 65); CANEVCEYWYNRGLC (Sequence ID 66); CPLDLCEYWSFRGLC (Sequence ID 67); CTNEVCRYWYNRGLC (Sequence ID 68); CDSPVCEYWSFRGLC (Sequence ID 69); CHNEVCEYWSFRGLC (Sequence ID 70); CSNEVCEYWSFRGLC (Sequence ID 71); CSNPVCEYWSFRGLC (Sequence ID 72); CNNPVCEYWSFRGLC (Sequence ID 73); CDNEVCEYWSFRGLC (Sequence ID 74); CTSEVCEYWSFRGLC (Sequence ID 75); CSTLVCQRDQLYSLC (Sequence ID 76); CHNEVCLYWYNRGLC (Sequence ID 77); CWNPVCEYWYNRGLC (Sequence ID 78); CATLQCQRDMLYGLC (Sequence ID 79); CSTLVCQRDQLYGLC (Sequence ID 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 (Sequence ID 86); CSTLVCQRDQLYG[tBuAla]C (Sequence ID 87); CSTLVCQRDQLYG[Cba]C (Sequence ID 88); CST[tBuAla]VCQRDQLY[dA]LC (Sequence ID 89); CNPLICQRDQLYGLC(SEQ ID NO: 90); CISLACQRDQLYGLC (Sequence ID 91); CSTLECQRDQLYGLC (Sequence ID 92); CNTLVCQRDQLYGLC (Sequence ID 93); CTQLMCQRDQLYGLC (Sequence ID 94); CTELMCQRDQLYGLC (Sequence ID 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 (Sequence ID 99); CTEL[Nle]CQRDQLYGLC(SEQ ID NO: 100); CTEL[HLeu]CQRDQLYGLC (Sequence ID 101); CTELMCQR[Gla]QLYGLC (Sequence ID 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 (Sequence ID 107); CPLDLCEYWSSRGLC (Sequence ID 108); C[HyP]LDLCEYWSSRGLC(SEQ ID NO: 109); CP[tBuAla]DLCEYWSSRGLC(SEQ ID NO: 110); CP[Cba]DLCEYWSSRGLC (Sequence ID 111); CPLD[AlloIle]CEYWSSRGLC (Sequence ID 112); CPLD[tBuAla]CEYWSSRGLC (SEQ ID NO: 113); CPLD[Cba]CEYWSSRGLC (SEQ ID NO: 114); CPLDVCEYWSSRGLC (Sequence ID 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 (Sequence ID 119); CPLDLCEY[4MeoTrp]SSRGLC(SEQ ID NO: 120); CPLDLCEY[Trp(S)]SSRGLC(SEQ ID NO: 121); CPLDLCEYWSS[HArg]GLC (Sequence ID 122); CPLDLCEYWSS[Cit]GLC(SEQ ID NO: 123); CPLDLCEYWSSR[dA]LC (SEQ ID NO: 124); CPLDLCEYWSSRG[tBuAla]C (Sequence ID 125); CPLDLCEYWSSRG[Cba]C (Sequence ID 126); [dC][dP][dL][dD][dL][dC][dE][dY][dW][dS][dS][dR]G[dL][dC](Sequence ID 127); CP[Cba]DLCEY[5FTrp]SSRGLC (Sequence ID 128); CPLDLCEYW[K(PYA)]SRGLC(SEQ ID NO: 129, structure below: 【Transformation 7】 (It has the formula, where * indicates a binding site of three cysteine ​​residues, and when complexed with a TATA derivative, it is called BCY21632); CPLDLCEYW[K(PYA)]SRGL[Cysam](SEQ ID NO: 130, structure below: 【Transformation 8】 (It has the formula, where * indicates a binding site of three cysteine ​​residues, and when complexed with a TATA derivative, it is called BCY21637); CPLDLCEY[5FTrp]ESRGLC (Sequence ID 131); CPNDLCEY[5FTrp]SSRGLC (Sequence ID 132); CPLDLCEY[5FTrp]SSR[dA]LC (Sequence ID 133); CPLDLCEY[5FTrp]SSR[dE]LC (Sequence ID 134); CPLD[tBuAla]CEY[5FTrp]SS[HArg][dA]LC (Sequence ID 135); CP[Cba]DLCEY[5FTrp]SS[HArg][dA]LC (Sequence ID 136); CPNDLCEYWSVRGLC (Sequence ID 137); CITLQCARDMLYGLC (SEQ ID NO: 138); CSTLQCERDMLYGLC (Sequence ID 139); CISLACARDMLYGLC (SEQ ID NO: 140); CSTLQCQRDMLYGLC (Sequence ID 141); CMYRACWVAEEWRPC(Sequence ID 142); CMYRACYYDHEWRPC(Sequence ID 143); CMYRACFYDDEWRPC(sequence number 144); CMYRACAYDDEWRPC(sequence number 145); CMYRACFADDEWRPC(sequence number 146); CMYRACFYADEWRPC(SEQ ID NO: 147); CMYRACFYDAEWRPC(sequence number 148); C[Nle]YRACFYDDEWRPC(sequence number 149); C[Nva]YRACFYDDEWRPC(sequence ID 150); C[TfNle]YRACFYDDEWRPC(sequence ID 151); C[CF3Nva]YRACFYDDEWRPC(Sequence ID 152); CM[26DiMeTyr]RACFYDDEWRPC(SEQ ID NO: 153); CMY[HArg]ACFYDDEWRPC(SEQ ID NO: 154); CMY[Agb]ACFYDDEWRPC (Sequence ID 155); CMY[Cit]ACFYDDEWRPC(sequence number 156); CMYR[CF3Ala]CFYDDEWRPC(Sequence ID 157); CMYRAC[1Nal]YDDEWRPC(sequence ID 158); CMYRAC[2Nal]YDDEWRPC(SEQ ID NO: 159); CMYRAC[4MePhe]YDDEWRPC(SEQ ID NO: 160); CMYRAC[3MePhe]YDDEWRPC(SEQ ID NO: 161); CMYRAC[2MePhe]YDDEWRPC(SEQ ID NO: 162); CMYRAC[4FPhe]YDDEWRPC(SEQ ID NO: 163); CMYRAC[3FPhe]YDDEWRPC(SEQ ID NO: 164); CMYRAC[2FPhe]YDDEWRPC(SEQ ID NO: 165); CMYRACF[4FPhe]DDEWRPC(sequence ID 166); CMYRACF[3tBuTyr]DDEWRPC(SEQ ID NO: 167); CMYRACF[26DiMeTyr]DDEWRPC(SEQ ID NO: 168); CMYRACF[3FTyr]DDEWRPC(SEQ ID NO: 169); CMYRACF[2FTyr]DDEWRPC(SEQ ID NO: 170); CMYRACF[DOPA]DDEWRPC(SEQ ID NO: 171); CMYRACFYDDE[1Nal]RPC(sequence ID 172); CMYRACFYDDE[2Nal]RPC(sequence ID 173); CMYRACFYDDE[4FTrp]RPC(SEQ ID NO: 174); CMYRACFYDDE[5FTrp]RPC(SEQ ID NO: 175); CMYRACFYDDE[6FTrp]RPC(sequence ID 176); CMYRACFYDDE[7FTrp]RPC(sequence ID 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(sequence ID 182); CMYRACFYDDEW[HArg]PC (Sequence ID 183); CMYRACFYDDEW[Agb]PC (Sequence ID 184); CMYRACFYDDEW[Cit]PC(Sequence ID 185); CMYRACFYDDEWR[HyP]C (SEQ ID NO: 186); CMYRACFYDDEWR[Aze]C (Sequence ID 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(Sequence ID 192); C[CF3Nva]YRAC[4MePhe]YDDE[1Nal]RPC(Sequence ID 193); CLYRACFYDDEWRPC(SEQ ID NO: 194); CLYRAC[4MePhe]YDDE[1Nal]RPC(SEQ ID NO: 195); and CHYRACFYDDEWRPC (Sequence ID 196) Includes more selective amino acid sequences, for example: The molecular scaffold has the following structure: 【Chemistry 9】 A derivative of TATA having, where * indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 65)-A (referred to herein as BCY15206); A-(Sequence No. 65)-A-[Sar 6 [KFl] (referred to herein as BCY15194); Ac-(Sequence ID 66)-A-[K(PYA)] (referred to herein as BCY23135); Ac-(SEQ ID NO: 66)-[K(PYA)] (referred to herein as BCY23136); A-(Sequence ID 66)-A-[K(PYA)] (referred to herein as BCY20791); A-(Sequence ID 67)-A (referred to herein as BCY15808); A-(Sequence ID 68)-A (referred to herein as BCY15810); A-(Sequence ID 69)-A (referred to herein as BCY16655); A-(Sequence ID 70)-A (referred to herein as BCY16656); A-(Sequence ID 71)-A (referred to herein as BCY16657); A-(Sequence ID 72)-A (referred to herein as BCY16658); A-(Sequence ID 73)-A (referred to herein as BCY16659); A-(Sequence ID 74)-A (referred to herein as BCY16660); A-(Sequence ID 75)-A (referred to herein as BCY16661); A-(Sequence ID 76)-A (referred to herein as BCY15207); A-(Sequence No. 76)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15195); A-(Sequence ID 76)-A-[K(PYA)] (referred to herein as BCY15750); A-(Sequence ID 77)-A (referred to herein as BCY15811); A-(Sequence ID 78)-A (referred to herein as BCY15812); A-(Sequence ID 79)-A (referred to herein as BCY15813); A-(Sequence ID 80)-A (referred to herein as BCY15814); A-(Sequence No. 80)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15801); Ac-(Sequence ID 80) (referred to herein as BCY17031); A-(Sequence No. 80)-A-[Sar 6 ]-[K(Ac)] (referred to herein as BCY19384); A-(Sequence ID 80)-AGAAAE (referred to herein as BCY19582); A-(Sequence ID 81)-A (referred to herein as BCY17032); A-(Sequence ID 82)-A (referred to herein as BCY17033); A-(Sequence ID 83)-A (referred to herein as BCY17035); A-(Sequence ID 84)-A (referred to herein as BCY17038); A-(Sequence ID 85)-A (referred to herein as BCY17040); A-(Sequence ID 86)-A (referred to herein as BCY17041); A-(Sequence ID 87)-A (referred to herein as BCY17042); A-(Sequence ID 88)-A (referred to herein as BCY17043); Ac-(Sequence ID 89) (referred to as BCY19197 in this specification); A-(Sequence ID 90)-A (referred to herein as BCY16662); A-(Sequence ID 91)-A (referred to herein as BCY16663); A-(Sequence No. 91)-A-[Sar 6 ]-[KFl] (referred to herein as BCY16639); A-(Sequence ID 92)-A (referred to herein as BCY16664); A-(Sequence ID 93)-A (referred to herein as BCY16665); A-(Sequence ID 94)-A (referred to herein as BCY16666); A-(Sequence ID 95)-A (referred to herein as BCY16667); A-(Sequence ID 95)-A-[Sar 6 ]-[KFl] (referred to herein as BCY16643); A-(Sequence ID 95)-A-[K(PYA)] (referred to herein as BCY17238); Ac-(Sequence ID 95) (referred to herein as BCY19193); A-(Sequence ID 96)-A (referred to herein as BCY19192); Ac-(Sequence ID 96) (referred to as BCY19196 herein); Ac-(Sequence ID 97) (referred to herein as BCY19194); Ac-(Sequence ID 98) (referred to as BCY19195 in this specification); Ac-(Sequence ID 99) (referred to as BCY19198 in this specification); Ac-(Sequence ID 100) (referred to as BCY19199 in this specification); Ac-(Sequence ID 101) (referred to herein as BCY19200); Ac-(Sequence ID 102) (referred to herein as BCY19203); Ac-(Sequence ID 103) (referred to herein as BCY19205); Ac-(Sequence ID 104) (referred to herein as BCY19206); A-(Sequence ID 105)-A (referred to herein as BCY15208); A-(Sequence ID 105)-A-[K(PYA)] (referred to herein as BCY15751); A-(Sequence ID 106)-A-[K(PYA)] (referred to herein as BCY21608); A-(Sequence ID 107)-A (referred to herein as BCY15209); A-(Sequence No. 107)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15197); A-(Sequence ID 108)-A (referred to herein as BCY15727); A-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY17452); Ac-(Sequence ID 108)-[K(PYA)] (referred to herein as BCY19157); Ac-A-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY19158); A-(Sequence No. 108)-A-[Sar 6 ]-[(K(Ac)] (referred to herein as BCY19385); A-(Sequence ID 108)-AGAAAE (referred to herein as BCY19580); A-(Sequence ID 108)-KMTHE (referred to herein as BCY21192); A-(Sequence ID 108)-NDSLN (referred to herein as BCY21193); A-(Sequence ID 108)-SVNAN (referred to herein as BCY21194); A-(Sequence ID 108)-QGHTPL (referred to herein as BCY21195); A-(Sequence ID 108)-EMEHSN (referred to herein as BCY21196); MRQ-(Sequence ID 108)-ETP (referred to herein as BCY21197); EHM-(SEQ ID NO: 108)-TQS (referred to herein as BCY21198); EPKRQ-(Sequence ID 108)-A (referred to herein as BCY21199); ANYAN-(Sequence ID 108)-A (referred to herein as BCY21200); DSFHQ-(Sequence ID 108)-A (referred to herein as BCY21201); MRQ-(Sequence ID 108)-ETP-[K(PYA)] (referred to herein as BCY21993); EPKRQ-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY21994); Ac-(Sequence ID 108)-A-[K(PYA)] (referred to herein as BCY23137); Ac-(Sequence ID 108)-E-[K(PYA)] (referred to herein as BCY23174); A-(Sequence ID 108)-E-[K(PYA)] (referred to herein as BCY23179); A-(Sequence ID 109)-A-[K(PYA)] (referred to herein as BCY19159); A-(Sequence ID 110)-A-[K(PYA)] (referred to herein as BCY19161); A-(Sequence ID 111)-A-[K(PYA)] (referred to herein as BCY19162); A-(Sequence ID 112)-A-[K(PYA)] (referred to herein as BCY19163); A-(Sequence ID 113)-A-[K(PYA)] (referred to herein as BCY19164); A-(Sequence ID 114)-A-[K(PYA)] (referred to herein as BCY19165); A-(Sequence ID 115)-A-[K(PYA)] (referred to herein as BCY19166); A-(Sequence ID 116)-A-[K(PYA)] (referred to herein as BCY19167); A-(Sequence ID 117)-A (referred to herein as BCY19170); A-(Sequence ID 117)-A-[K(PYA)] (referred to herein as BCY19284); Ac-(Sequence ID 117)-[K(PYA)] (referred to herein as BCY19995); A-(Sequence ID 118)-A-[K(PYA)] (referred to herein as BCY19171); A-(Sequence ID 119)-A-[K(PYA)] (referred to herein as BCY19177); MRQ-(Sequence ID 119)-ETP-[K(PYA)] (referred to herein as BCY21995); EPKRQ-(Sequence ID 119)-A-[K(PYA)] (referred to herein as BCY21996); MRQ-(Sequence ID 119)-ETP (referred to herein as BCY21997); EPKRQ-(Sequence ID 119)-A (referred to herein as BCY21998); Ac-(Sequence ID 119)-[K(PYA)] (referred to herein as BCY22499); A-(Sequence ID 120)-A-[K(PYA)] (referred to herein as BCY19179); A-(Sequence ID 121)-A-[K(PYA)] (referred to herein as BCY19181); A-(Sequence ID 122)-A-[K(PYA)] (referred to herein as BCY19184); A-(Sequence ID 123)-A-[K(PYA)] (referred to herein as BCY19185); A-(Sequence ID 124)-A-[K(PYA)] (referred to herein as BCY19187); A-(Sequence ID 125)-A-[K(PYA)] (referred to herein as BCY19188); A-(Sequence ID 126)-A-[K(PYA)] (referred to herein as BCY19189); [dA]-(SEQ ID NO: 127)-[dA]-[K(PYA)] (referred to herein as BCY20840); A-(Sequence ID 128)-A-[K(PYA)] (referred to herein as BCY21040); A-(Sequence ID 129)-A (referred to herein as BCY21631); A-(Sequence ID 129) (referred to herein as BCY21633); Ac-(Sequence ID 129) (referred to herein as BCY21634); A-(Sequence ID 130) (referred to herein as BCY21635); Ac-(Sequence ID 130) (referred to herein as BCY21636); Ac-(Sequence ID 131)-[K(PYA)] (referred to herein as BCY23702); Ac-(Sequence ID 132)-[K(PYA)] (referred to herein as BCY23703); Ac-(Sequence ID 132)-[K(PYA)-(Triazolyl)-(PEG) 2 -methyl] (referred to herein as BCY25601); Ac-(Sequence ID 133)-[K(PYA)] (referred to herein as BCY23704); Ac-(Sequence ID 134)-[K(PYA)] (referred to herein as BCY23705); Ac-(Sequence ID 135)-[K(PYA)] (referred to herein as BCY23706); Ac-(Sequence ID 136)-[K(PYA)] (referred to herein as BCY23707); Ac-(SEQ ID NO: 136)-[K(PYA)-(Triazolyl)-(PEG) 2 -methyl] (referred to herein as BCY25602); A-(Sequence ID 137)-A (referred to herein as BCY15729); A-(Sequence ID 138)-A (referred to herein as BCY15210); A-(Sequence No. 138)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15198); A-(Sequence ID 138)-A-[K(PYA)] (referred to herein as BCY15752); A-(Sequence ID 139)-A (referred to herein as BCY15731); A-(Sequence No. 139)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15730); A-(Sequence ID 140)-A (referred to herein as BCY15733); A-(Sequence ID 141)-A (referred to herein as BCY15735); and A-(Sequence No. 141)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15734) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: 【Chemistry 10】 A derivative of TATB having, where * in the formula indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 142)-A (referred to herein as BCY17001); A-(Sequence ID 143)-A (referred to herein as BCY18128); A-(Sequence ID 143)-A-[K(PYA)] (referred to herein as BCY19743); A-(Sequence ID 144)-A (referred to herein as BCY18129); A-(Sequence ID 144)-A-[K(PYA)] (referred to herein as BCY19744); Ac-A-(SEQ ID NO: 144)-A (referred to herein as BCY24131); Ac-(Sequence ID 144) (referred to herein as BCY24135); A-(Sequence ID 144) (referred to herein as BCY24450); Ac-A-(Sequence ID 144) (referred to herein as BCY24451); (Sequence ID 144)-A (referred to herein as BCY24452); Ac-(Sequence ID 144)-A (referred to herein as BCY24453); AHGG-(Sequence ID 144)-EVHA (referred to herein as BCY25863); AIKP-(SEQ ID NO: 144)-QHEA (referred to herein as BCY25864); ADST-(SEQ ID NO: 144)-QHPA (referred to herein as BCY25865); ALNG-(SEQ ID NO: 144)-PLSA (referred to herein as BCY25866); ALNG-(SEQ ID NO: 144)-PLSA-[K(PYA)] (referred to herein as BCY28840); A-(Sequence ID 145)-A (referred to herein as BCY24442); A-(Sequence ID 146)-A (referred to herein as BCY24443); A-(Sequence ID 147)-A (referred to herein as BCY24444); A-(Sequence ID 148)-A (referred to herein as BCY24445); A-(Sequence ID 149)-A (referred to herein as BCY24456); A-(Sequence ID 150)-A (referred to herein as BCY24457); A-(Sequence ID 151)-A (referred to herein as BCY24458); A-(Sequence ID 152)-A (referred to herein as BCY24459); A-(Sequence ID 153)-A (referred to herein as BCY24462); A-(Sequence ID 154)-A (referred to herein as BCY24466); A-(Sequence ID 155)-A (referred to herein as BCY24467); A-(Sequence ID 156)-A (referred to herein as BCY24468); A-(Sequence ID 157)-A (referred to herein as BCY24469); A-(Sequence ID 158)-A (referred to herein as BCY24471); A-(Sequence ID 159)-A (referred to herein as BCY24472); A-(Sequence ID 160)-A (referred to herein as BCY24473); A-(Sequence ID 161)-A (referred to herein as BCY24474); A-(Sequence ID 162)-A (referred to herein as BCY24475); A-(Sequence ID 163)-A (referred to herein as BCY24477); A-(Sequence ID 164)-A (referred to herein as BCY24478); A-(Sequence ID 165)-A (referred to herein as BCY24479); A-(Sequence ID 166)-A (referred to herein as BCY24480); A-(Sequence ID 167)-A (referred to herein as BCY24481); A-(Sequence ID 168)-A (referred to herein as BCY24482); A-(Sequence ID 169)-A (referred to herein as BCY24483); A-(Sequence ID 170)-A (referred to herein as BCY24484); A-(Sequence ID 171)-A (referred to herein as BCY24485); A-(Sequence ID 172)-A (referred to herein as BCY24486); A-(Sequence ID 173)-A (referred to herein as BCY24487); A-(Sequence ID 174)-A (referred to herein as BCY24488); A-(Sequence ID 175)-A (referred to herein as BCY24489); A-(Sequence ID 176)-A (referred to herein as BCY24490); A-(Sequence ID 177)-A (referred to herein as BCY24491); A-(Sequence ID 178)-A (referred to herein as BCY24492); A-(Sequence ID 179)-A (referred to herein as BCY24493); A-(Sequence ID 180)-A (referred to herein as BCY24495); A-(Sequence ID 181)-A (referred to herein as BCY24496); A-(Sequence ID 182)-A (referred to herein as BCY24497); A-(Sequence ID 183)-A (referred to herein as BCY24498); A-(Sequence ID 184)-A (referred to herein as BCY24499); A-(Sequence ID 185)-A (referred to herein as BCY24500); A-(Sequence ID 186)-A (referred to herein as BCY24501); A-(Sequence ID 187)-A (referred to herein as BCY24503); A-(Sequence ID 188)-A (referred to herein as BCY24504); A-(Sequence ID 189)-A (referred to herein as BCY24505); A-(Sequence ID 190)-A (referred to herein as BCY24506); A-(Sequence ID 191)-A (referred to herein as BCY24509); ALNG-(Sequence ID 192)-PLSA (referred to herein as BCY28838); ALNG-(SEQ ID NO: 192)-PLSA-[K(PYA)] (referred to herein as BCY28841); ALNG-(SEQ ID NO: 193)-PLSA (referred to herein as BCY28839); ALNG-(SEQ ID NO: 193)-PLSA-[K(PYA)] (referred to herein as BCY28842); ALEQN-(Sequence ID 194)-A (referred to herein as BCY25861); ALEQN-(SEQ ID NO: 194)-A-[K(PYA)] (referred to herein as BCY28843); ALEQN-(Sequence ID 195)-A (referred to herein as BCY28844); ALEQN-(SEQ ID NO: 195)-A-[K(PYA)] (referred to herein as BCY28845); and AHAGT-(SEQ ID NO: 196)-A (referred to herein as BCY25859) The bicyclic peptide ligand according to claim 3, comprising a more selected amino acid sequence, a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

7. CQPTX 30 -X 31 -CX 32 -X 33 -X 34 -X 35 -X 36 -X 37 -C (SEQ ID NO: 4) peptide ligand is as follows: CQPTPRCPFSTWPC (referred to herein as Sequence ID No. 197); CQPTPQCPYSTWPC (referred to as Sequence ID No. 198 in this specification, with the following structure: 【Chemistry 11】 (It has the formula, where * indicates a binding site of three cysteine ​​residues, and when complexed with a derivative of TATB, it is called BCY20723); CQPT[HyP]QCPYSTWPC (referred to herein as Sequence ID No. 199); CQPT[Cis-HyP]QCPYSTWPC (referred to herein as Sequence ID No. 200); CQPT[Pip]QCPYSTWPC (referred to herein as Sequence ID No. 201); CQPTPECPYSTWPC (referred to herein as Sequence ID No. 202); CQPTPQC[HyP]YSTWPC (referred to herein as Sequence ID No. 203); CQPTPQC[Cis-HyP]YSTWPC (referred to herein as Sequence ID No. 204); CQPTPQC[Aze]YSTWPC (referred to herein as Sequence ID No. 205); CQPTPQCP[2Nal]STWPC (referred to herein as Sequence ID No. 206); CQPTPQCP[4tBuPhe]STWPC (referred to herein as Sequence ID No. 207); CQPTPQCP[4FPhe]STWPC (referred to herein as Sequence ID No. 208); CQPTPQCP[3FTyr]STWPC (referred to herein as Sequence ID No. 209); CQPTPQCP[2FTyr]STWPC (referred to herein as Sequence ID No. 210); CQPTPQCPY[Dap]TWPC (referred to herein as Sequence ID No. 211); CQPTPQCPYS[Dap]WPC (referred to herein as Sequence ID No. 212); CQPTPQCPYST[2Nal]PC (referred to herein as Sequence ID No. 213); CQPTPQCPYST[1Nal]PC (referred to herein as Sequence ID No. 214); CQPTPQCPYST[6FTrp]PC (referred to herein as Sequence ID No. 215); CQPTPQCPYST[5FTrp]PC (referred to herein as Sequence ID No. 216); CQPTPQCPYST[6ClTrp]PC (referred to herein as Sequence ID No. 217); CQPTPQCPYST[4MeoTrp]PC (referred to herein as Sequence ID No. 218); CQPTPQCPYST[5MeoTrp]PC (referred to herein as Sequence ID No. 219); CQPTPQCPYST[Trp(S)]PC (referred to herein as Sequence ID No. 220); CQPTPQCPYST[AzaTrp]PC (referred to herein as Sequence ID No. 221); CQPTPQCPYSTW[HyP]C (referred to herein as Sequence ID No. 222); CQPTPQCPYSTW[Cis-HyP]C (referred to herein as Sequence ID No. 223); CQPTPQCPYSTW[Aze]C (referred to herein as Sequence ID No. 224); CQPTPQCPYSTW[Pip]C (referred to herein as Sequence ID No. 225); and CQPTPECPYNTWPC (referred to herein as Sequence ID No. 226) Includes more selective amino acid sequences, for example The molecular scaffold has the following structure: 【Chemistry 12】 It is a derivative of TATB, having the formula where * indicates a binding site 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 includes N and / or C-terminal additions, and as follows: A-(Sequence ID 197)-A (referred to herein as BCY16999); A-(Sequence ID 197)-A-[K(PYA)] (referred to herein as BCY17693); A-(Sequence No. 197)-A-[Sar 6 ]-[K(Ac)] (referred to herein as BCY19387); A-(Sequence ID 198)-A (referred to herein as BCY18126); Ac-A-(Sequence ID 198)-A (referred to herein as BCY20725); A-(Sequence ID 198)-NLNLK (referred to herein as BCY21770); VNENI-(Sequence ID 198)-A (referred to herein as BCY21771); A-(Sequence ID 198)-RNPHD (referred to herein as BCY21772); A-(Sequence ID 198)-IHNNG (referred to herein as BCY21774); TNEGI-(Sequence ID 198)-A (referred to herein as BCY21778); VNENI-(Sequence ID 198)-A-[K(PYA)] (referred to herein as BCY23767); A-(Sequence ID 199)-A (referred to herein as BCY20731); A-(Sequence ID 200)-A (referred to herein as BCY20732); A-(Sequence ID 201)-A (referred to herein as BCY20734); A-(Sequence ID 202)-A (referred to herein as BCY20735); A-(Sequence ID 203)-A (referred to herein as BCY20736); A-(Sequence ID 204)-A (referred to herein as BCY20737); A-(Sequence ID 205)-A (referred to herein as BCY20738); A-(Sequence ID 206)-A (referred to herein as BCY20741); A-(Sequence ID 207)-A (referred to herein as BCY20742); A-(Sequence ID 208)-A (referred to herein as BCY20743); A-(Sequence ID 209)-A (referred to herein as BCY20746); A-(Sequence ID 210)-A (referred to herein as BCY20747); A-(Sequence ID 211)-A (referred to herein as BCY20748); A-(Sequence ID 212)-A (referred to herein as BCY20749); A-(Sequence ID 213)-A (referred to herein as BCY20751); A-(Sequence ID 214)-A (referred to herein as BCY20752); A-(Sequence ID 215)-A (referred to herein as BCY20756); A-(Sequence ID 216)-A (referred to herein as BCY20757); A-(Sequence ID 217)-A (referred to herein as BCY20758); A-(Sequence ID 218)-A (referred to herein as BCY20759); A-(Sequence ID 219)-A (referred to herein as BCY20760); A-(Sequence ID 220)-A (referred to herein as BCY20761); A-(Sequence ID 221)-A (referred to herein as BCY20762); A-(Sequence ID 222)-A (referred to herein as BCY20763); A-(Sequence ID 223)-A (referred to herein as BCY20764); A-(Sequence ID 224)-A (referred to herein as BCY20765); A-(Sequence ID 225)-A (referred to herein as BCY20766); A-(Sequence ID 226)-A (referred to herein as BCY18127); and A-(Sequence ID 226)-A-[K(PYA)] (referred to herein as BCY19742) The bicyclic peptide ligand according to claim 3, comprising a more selected amino acid sequence, a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

8. CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5) peptide ligands are as follows: CYYPDYYACLDC (referred to herein as Sequence ID No. 227); CYYENYYACLDC (referred to herein as Sequence ID No. 228); and CYYPDWYACLDC (referred to herein as Sequence ID No. 229) Includes more selective amino acid sequences, for example The molecular scaffold has the following structure: 【Chemistry 13】 It is a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein the formula * indicates a binding site of three cysteine ​​residues, and CYYX 38 -X 39 -X 40 -YACLDC (SEQ ID NO: 5) peptide ligands further include N and / or C-terminal additions, and as follows: A-(Sequence ID 227)-A (referred to herein as BCY17007); A-(Sequence ID 228)-A (referred to herein as BCY18135); A-(Sequence ID 229)-A (referred to herein as BCY18136); and A-(Sequence ID 229)-A-[K(PYA)] (referred to herein as BCY19747) The bicyclic peptide ligand according to claim 3, comprising a more selected amino acid sequence, a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

9. 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) is as follows: CNNPVMTYWCTKGIC (referred to herein as Sequence ID No. 230); CNNPVMTYWCEKGIC (referred to herein as Sequence ID No. 231); CDNEVITYWCTKGIC (referred to herein as Sequence ID No. 232); CDNEV[tBuAla]TYWCTKGIC (referred to herein as Sequence ID No. 233); CDNEVFTYWCTKGIC (referred to herein as Sequence ID No. 234); CDNEV[Cba]TYWCTKGIC (referred to herein as Sequence ID No. 235); CDNEVITY[2Nal]CTKGIC (referred to herein as Sequence ID No. 236); CDNEVITY[1Nal]CTKGIC (referred to herein as Sequence ID No. 237); CDNEVITYWCT[Orn]GIC (referred to herein as Sequence ID No. 238); CDNEVITYWCT[HArg]GIC (referred to herein as Sequence ID No. 239); CDNEVITYWCTK[dA]IC (referred to herein as Sequence ID No. 240); CDNEVITYWCTKG[tBuGly]C (referred to herein as Sequence ID No. 241); CDNEVIT[DOPA]WCTKGIC (referred to herein as Sequence ID No. 242); CDNPVFTYWCTKGIC (referred to herein as Sequence ID No. 243); CNNPVMAYWCTKGIC (referred to herein as Sequence ID No. 244); CPNPVITYWCTKGIC (referred to herein as Sequence ID No. 245); CDNEVITYWCQMGVC (referred to herein as Sequence ID No. 246); CDNEVITYWCQRGVC (referred to herein as Sequence ID No. 247); CDNEVITYWCMRGIC (referred to herein as Sequence ID No. 248); CDNEVITYWCQRGIC (referred to herein as Sequence ID No. 249); CDNEVITY[6FTrp]CQRGIC (referred to herein as Sequence ID No. 250); CDNEVITY[5FTrp]CQRGIC (referred to herein as Sequence ID No. 251); CDNEVITY[5MeoTrp]CQRGIC (referred to herein as Sequence ID No. 252); CDNEVITY[Trp(S)]CQRGIC (referred to herein as Sequence ID No. 253); CDNEVITY[AzaTrp]CQRGIC (referred to herein as Sequence ID No. 254); CDNEVITYWCQ[HArg]GIC (referred to herein as Sequence ID No. 255); CDNEVITYWCQ[Cit]GIC (referred to herein as Sequence ID No. 256); CDNEVFEYWCTKGIC (referred to herein as Sequence ID No. 257); CDNEVITYWCERGIC (referred to herein as Sequence ID No. 258); CDNEVITYWCEMGIC (referred to herein as Sequence ID No. 259); CSNPVFAYWCSRQMC (referred to herein as Sequence ID No. 260); CSNPVFAYWCERGIC (referred to herein as Sequence ID No. 261, and also having the following structure: 【Chemistry 14】 (When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21615); CSNPVFAYWCER[K(PYA)]IC (referred to herein as Sequence ID No. 262); CSNPVFAYWCER[dK(PYA)]IC (referred to herein as Sequence ID No. 263); CSNPVFAYWCER[S-aMeLys(PYA)]IC (referred to herein as Sequence ID No. 264); CSNPVFAYWCER[R-aMeLys(PYA)]IC (referred to herein as Sequence ID No. 265); C[K(PYA)]NPVFAYWCERGIC (referred to herein as Sequence ID No. 266); CSNPVFAY[5FTrp]CERGIC (referred to herein as Sequence ID No. 267); CSNPVFAYWCERGI[Cysam] (referred to herein as Sequence ID No. 268, and also having the following structure: 【Chemistry 15】 (When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY21623); C[K(PYA)]NPVFAYWCERGI[Cysam] (referred to herein as Sequence ID No. 269); CSNPVFAYWC[Dap]RGIC (referred to herein as Sequence ID No. 270); CKNPVFAYWC[PG]RGIC (referred to herein as Sequence ID No. 271); CENPVFAYWCERGIC (referred to herein as Sequence ID No. 272); C[dA]NPVFAYWCERGIC (referred to herein as Sequence ID No. 273); CGNPVFAYWCERGIC (referred to herein as Sequence ID No. 274); C[Aib]NPVFAYWCERGIC (referred to herein as Sequence ID No. 275); CSN[trans-4FlPro]VFAYWCERGIC (referred to herein as Sequence ID No. 276); CSN[4FlPro]VFAYWCERGIC (referred to herein as Sequence ID No. 277); CSN[HyP]VFAYWCERGIC (referred to herein as Sequence ID No. 278); CSN[Cis-HyP]VFAYWCERGIC (referred to herein as Sequence ID No. 279); CSNP[HSer]FAYWCERGIC (referred to herein as Sequence ID No. 280); CSNPV[2FPhe]AYWCERGIC (referred to herein as Sequence ID No. 281); CSNPV[4CF3Phe]AYWCERGIC (referred to herein as Sequence ID No. 282); CSNPVFSYWCERGIC (referred to herein as Sequence ID No. 283); CSNPVF[Dap]YWCERGIC (referred to herein as Sequence ID No. 284); CSNPVF[CF3Ala]YWCERGIC (referred to herein as Sequence ID No. 285); CSNPVFA[2FTyr]WCERGIC (referred to herein as Sequence ID No. 286); CSNPVFA[3FTyr]WCERGIC (referred to herein as Sequence ID No. 287); CSNPVFAY[4FTrp]CERGIC (referred to herein as Sequence ID No. 288); CSNPVFAYWCE[Cit]GIC (referred to herein as Sequence ID No. 289); CSNPVFAYWCER[dA]IC (referred to herein as Sequence ID No. 290); CSNPVFAYWCERG[Nva]C (referred to herein as Sequence ID No. 291); CSNPVFAYWCERG[Nle]C (referred to herein as Sequence ID No. 292); CSNPVFAYWCERG[EPA]C (referred to herein as Sequence ID No. 293); CSNPVFAYWCERG[tBuGly]C (referred to herein as Sequence ID No. 294); CSN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 295); C[Aib]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 296); C[dS]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 297); C[K(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 298); C[dK(PYA)]N[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 299); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA]C (referred to herein as Sequence ID No. 300); CSN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to herein as Sequence ID No. 301); [dC]SN[4FlPro]VFAY[5FTrp]CERG[EPA][dC] (referred to herein as Sequence ID No. 302); CSNPVFAYWCSRNLC (referred to herein as Sequence ID No. 303); CSNPVFAYWCSRGLC (referred to herein as Sequence ID No. 304); CTTDMMWKVCRTLDC (referred to herein as Sequence ID No. 305); CATDHMWKVCRTLDC (referred to herein as Sequence ID No. 306); CKTDAMWKVCRTLDC (referred to herein as Sequence ID No. 307); CSTDQMWKVCRTLDC (referred to herein as Sequence ID No. 308); CSTDYMWKVCRTLDC (referred to herein as Sequence ID No. 309, and also having the following structure: 【Chemistry 16】 (When complexed with a tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT, in which * indicates a binding site of three cysteine ​​residues, it is called BCY23141); CSTDY[Nle]WKVCRTLDC (referred to herein as Sequence ID No. 310); CATDYMWKVCRTLDC (referred to herein as Sequence ID No. 311); CSTDAMWKVCRTLDC (referred to herein as Sequence ID No. 312); CSTDYAWKVCRTLDC (referred to herein as Sequence ID No. 313); CSTDYMWKACRTLDC (referred to herein as Sequence ID No. 314); CSTDYMWKVCRALDC (referred to herein as Sequence ID No. 315); CSTDYMWKVCRTADC (referred to herein as Sequence ID No. 316); C[CF3Ala]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 317); C[HSer]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 318); CTTDYMWKVCRTLDC (referred to herein as Sequence ID No. 319); C[3HyV]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 320); CS[3HyV]DYMWKVCRTLDC (referred to herein as Sequence ID No. 321); C[Dap]TDYMWKVCRTLDC (referred to herein as Sequence ID No. 322); CSTD[4FPhe]MWKVCRTLDC (referred to herein as Sequence ID No. 323); CSTD[1Nal]MWKVCRTLDC (referred to herein as Sequence ID No. 324); CSTD[2Nal]MWKVCRTLDC (referred to herein as Sequence ID No. 325); CSTD[26DiMeTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 326); CSTD[3FTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 327); CSTD[2FTyr]MWKVCRTLDC (referred to herein as Sequence ID No. 328); CSTD[DOPA]MWKVCRTLDC (referred to herein as Sequence ID No. 329); CSTDY[Nva]WKVCRTLDC (referred to herein as Sequence ID No. 330); CSTDY[TfNle]WKVCRTLDC (referred to herein as Sequence ID No. 331); CSTDYEWKVCRTLDC (referred to herein as Sequence ID No. 332); CSTDY[CF3Nva]WKVCRTLDC (referred to herein as Sequence ID No. 333); CSTDYM[1Nal]KVCRTLDC (referred to herein as Sequence ID No. 334); CSTDYM[4FTrp]KVCRTLDC (referred to herein as Sequence ID No. 335); CSTDYM[5FTrp]KVCRTLDC (referred to herein as Sequence ID No. 336); CSTDYM[6FTrp]KVCRTLDC (referred to herein as Sequence ID No. 337); CSTDYM[7FTrp]KVCRTLDC (referred to herein as Sequence ID No. 338); CSTDYM[2MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 339); CSTDYM[4MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 340); CSTDYM[5MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 341); CSTDYM[6MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 342); CSTDYM[7MeTrp]KVCRTLDC (referred to herein as Sequence ID No. 343); CSTDYM[AzaTrp]KVCRTLDC (referred to herein as Sequence ID No. 344); CSTDYMW[HArg]VCRTLDC (referred to herein as Sequence ID No. 345); CSTDYMW[Orn]VCRTLDC (referred to herein as Sequence ID No. 346); CSTDYMW[Agb]VCRTLDC (referred to herein as Sequence ID No. 347); CSTDYMWK[tBuGly]CRTLDC (referred to herein as Sequence ID No. 348); CSTDYMWK[Cbg]CRTLDC (referred to herein as Sequence ID No. 349); CSTDYMWK[C5g]CRTLDC (referred to herein as Sequence ID No. 350); CSTDYMWK[3HyV]CRTLDC (referred to herein as Sequence ID No. 351); CSTDYMWKVC[HArg]TLDC (referred to herein as Sequence ID No. 352); CSTDYMWKVC[Arg(Me)]TLDC (referred to herein as Sequence ID No. 353); CSTDYMWKVCR[3HyV]LDC (referred to herein as Sequence ID No. 354); CSTDYMWKVCRT[tBuAla]DC (referred to herein as Sequence ID No. 355); CSTDYMWKVCRT[Cba]DC (referred to herein as Sequence ID No. 356); CSTDYMWKVCRT[Nva]DC (referred to herein as Sequence ID No. 357); CSTDYMWKVCRT[Nle]DC (referred to herein as Sequence ID No. 358); CTTDMAWRDCRTLDC (referred to herein as Sequence ID No. 359); CTTDMAWRLCRTLDC (referred to herein as Sequence ID No. 360); CTTDMVWKVCRTLDC (referred to herein as Sequence ID No. 361); CVTDYMWKVCRTLDC (referred to herein as Sequence ID No. 362); CYTDSMWKVCRTLDC (referred to herein as Sequence ID No. 363); CTTDMMWKVCREPDC (referred to herein as Sequence ID No. 364); CTTDMMWKVCRSMDC (referred to herein as Sequence ID No. 365); and CTTDMMWKVCRTLDC (referred to herein as Sequence ID No. 366) Includes more selective amino acid sequences, for example The molecular scaffold has the following structure: 【Chemistry 17】 A derivative of TATA having, where * indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 230)-A (referred to herein as BCY15211); A-(Sequence ID 230)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15199); A-(Sequence ID 231)-A (referred to herein as BCY15737); A-(Sequence ID 232)-A (referred to herein as BCY15739); A-(Sequence No. 232)-A-[Sar 6 ]-[KFl] (referred to herein as BCY15738); A-(Sequence No. 232)-A-[Sar 6 ]-[K(Ac)] (referred to herein as BCY19386); A-(Sequence ID 232)-AGAAAE (referred to herein as BCY19581); A-(Sequence ID 233)-A (referred to herein as BCY17047); A-(Sequence ID 234)-A (referred to herein as BCY17049); A-(Sequence ID 235)-A (referred to herein as BCY17051); A-(Sequence ID 236)-A (referred to herein as BCY17055); A-(Sequence ID 237)-A (referred to herein as BCY17056); A-(Sequence ID 238)-A (referred to herein as BCY17057); A-(Sequence ID 239)-A (referred to herein as BCY17058); A-(Sequence ID 240)-A (referred to herein as BCY17059); A-(Sequence ID 241)-A (referred to herein as BCY17061); A-(Sequence ID 242)-A (referred to herein as BCY17656); A-(Sequence ID 243)-A (referred to herein as BCY15741); A-(Sequence ID 244)-A (referred to herein as BCY15743); A-(Sequence ID 245)-A (referred to herein as BCY15745); A-(Sequence ID 246)-A (referred to herein as BCY16668); A-(Sequence ID 247)-A (referred to herein as BCY16669); A-(Sequence ID 248)-A (referred to herein as BCY16670); A-(Sequence ID 249)-A (referred to herein as BCY16671); A-(Sequence No. 249)-A-[Sar 6 ]-[KFl] (referred to herein as BCY16647); Ac-A-(Sequence ID 249)-A (referred to herein as BCY19586); A-(Sequence ID 250)-A (referred to herein as BCY18510); A-(Sequence ID 251)-A (referred to herein as BCY18511); A-(Sequence ID 251)-A-[K(PYA)] (referred to herein as BCY25826); A-(Sequence ID 252)-A (referred to herein as BCY18514); A-(Sequence ID 253)-A (referred to herein as BCY18515); A-(Sequence ID 254)-A (referred to herein as BCY18518); A-(Sequence ID 255)-A (referred to herein as BCY18519); A-(Sequence ID 256)-A (referred to herein as BCY18520); A-(Sequence ID 257)-A (referred to herein as BCY16672); A-(Sequence ID 258)-A (referred to herein as BCY16673); A-(Sequence No. 258)-A-[Sar 6 ]-[KFl] (referred to herein as BCY16649); A-(Sequence ID 258)-A-[K(PYA)] (referred to herein as BCY17237); Ac-A-(SEQ ID NO: 258)-A (referred to herein as BCY19585); and A-(Sequence ID 259)-A (referred to herein as BCY16674) A more selected amino acid sequence, or a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof, or The molecular scaffold has the following structure: [Chemistry 18] A tri-substituted 2,4,6-tris(bromomethyl)-s-triazine derivative of TBMT or TCTZ, wherein the formula * indicates a binding site 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 N and / or C-terminal additions, and as follows: A-(Sequence ID 260)-A (referred to herein as BCY17002); A-(Sequence ID 260)-A-[K(PYA)] (referred to herein as BCY19745); A-(Sequence ID 261)-A (referred to herein as BCY18130); A-(Sequence ID 261)-A-[K(PYA)] (referred to herein as BCY20847); [PYA]-A-(Sequence ID 261)-A (referred to herein as BCY20852); Ac-(Sequence ID 261) (referred to herein as BCY21616); A-(Sequence ID 261) (referred to herein as BCY21617); Ac-A-(Sequence ID 261) (referred to herein as BCY21618); [PYA]-(Sequence ID 261) (referred to herein as BCY21619); [GuanAc]-(SEQ ID NO: 261)-A (referred to herein as BCY23043); A-(Sequence ID 261)-[CF3Ala] (referred to herein as BCY23080); A-(Sequence ID 261)-S (referred to herein as BCY23081); A-(Sequence ID 262)-A (referred to herein as BCY20848); A-(Sequence ID 263)-A (referred to herein as BCY20849); A-(Sequence ID 264)-A (referred to herein as BCY20850); A-(Sequence ID 265)-A (referred to herein as BCY20851); A-(Sequence ID 266)-A (referred to herein as BCY20853); A-(Sequence ID 266) (referred to herein as BCY21620); A-(Sequence ID 267)-A (referred to herein as BCY21622); A-(Sequence ID 267)-A-[K(PYA)] (referred to herein as BCY21607); Ac-(Sequence ID 268) (referred to herein as BCY21624); A-(Sequence ID 268) (referred to herein as BCY21625); [PYA]-(Sequence ID 268) (referred to herein as BCY21626); A-(Sequence ID 269) (referred to herein as BCY21627); Ac-(Sequence ID 270) (referred to herein as BCY22879); Ac-(Sequence ID 271) (referred to herein as BCY22880); A-(Sequence ID 272)-A (referred to herein as BCY23044); A-(Sequence ID 273)-A (referred to herein as BCY23045); A-(Sequence ID 274)-A (referred to herein as BCY23046); A-(Sequence ID 275)-A (referred to herein as BCY23047); A-(Sequence ID 276)-A (referred to herein as BCY23050); A-(Sequence ID 277)-A (referred to herein as BCY23051); A-(Sequence ID 278)-A (referred to herein as BCY23052); A-(Sequence ID 279)-A (referred to herein as BCY23053); A-(Sequence ID 280)-A (referred to herein as BCY23054); A-(Sequence ID 281)-A (referred to herein as BCY23058); A-(Sequence ID 282)-A (referred to herein as BCY23059); A-(Sequence ID 283)-A (referred to herein as BCY23062); A-(Sequence ID 284)-A (referred to herein as BCY23063); A-(Sequence ID 285)-A (referred to herein as BCY23064); A-(Sequence ID 286)-A (referred to herein as BCY23066); A-(Sequence ID 287)-A (referred to herein as BCY23067); A-(Sequence ID 288)-A (referred to herein as BCY23068); A-(Sequence ID 289)-A (referred to herein as BCY23071); A-(Sequence ID 290)-A (referred to herein as BCY23072); A-(Sequence ID 291)-A (referred to herein as BCY23073); A-(Sequence ID 292)-A (referred to herein as BCY23074); A-(Sequence ID 293)-A (referred to herein as BCY23075); A-(Sequence ID 294)-A (referred to herein as BCY23079); [GuanAc]-(SEQ ID NO: 295)-COOH (referred to herein as BCY27058); [GuanAc]-(SEQ ID NO: 295) (referred to herein as BCY27059); [CIA]-[K(PYA)]-(Sequence ID 295)-A (referred to herein as BCY27064); [CIA]-[dK(PYA)]-(Sequence ID 295)-A (referred to herein as BCY27065); [GuanAc]-(SEQ ID NO: 296) (referred to herein as BCY27060); [GuanAc]-(SEQ ID NO: 297) (referred to herein as BCY27061); [GuanAc]-(Sequence ID 298) (referred to herein as BCY27062); [GuanAc]-(Sequence ID 299) (referred to herein as BCY27063); [GuanAc]-(SEQ ID NO: 300) (referred to herein as BCY27066); [GuanAc]-(Sequence ID 301) (referred to herein as BCY27067); [GuanAc]-(Sequence ID 302) (referred to herein as BCY27068); A-(Sequence ID 303)-A (referred to herein as BCY18131); A-(Sequence ID 304)-A (referred to herein as BCY18132); A-(Sequence ID 305)-A-[K(PYA)] (referred to herein as BCY19588); A-(Sequence ID 306)-A (referred to herein as BCY19933); A-(Sequence ID 307)-A (referred to herein as BCY19934); A-(Sequence ID 308)-A (referred to herein as BCY19935); A-(Sequence ID 309)-A (referred to herein as BCY19936); A-(Sequence ID 309)-A-[K(PYA)] (referred to herein as BCY21606); Ac-(Sequence ID 309) (referred to herein as BCY23139); Ac-A-(Sequence ID 309)-A (referred to herein as BCY23140); [dA]-(Sequence ID 309)-A (referred to herein as BCY32061); A-(Sequence ID 309) (referred to herein as BCY32074); Ac-A-(Sequence ID 309) (referred to herein as BCY32075); (Sequence ID 309)-A (referred to herein as BCY32076); Ac-(Sequence ID 309)-A (referred to herein as BCY32077); A-(Sequence ID 309)-A-[dK(PYA)] (referred to herein as BCY32126); A-(Sequence ID 309)-[K(PYA)] (referred to herein as BCY32127); A-(Sequence ID 309)-[dK(PYA)] (referred to herein as BCY32128); A-(Sequence ID 310)-A (referred to herein as BCY23138); A-(Sequence ID 310)-A-[K(PYA)] (referred to herein as BCY24613); A-(Sequence ID 311)-A (referred to herein as BCY32062); A-(Sequence ID 312)-A (referred to herein as BCY32065); A-(Sequence ID 313)-A (referred to herein as BCY32066); A-(Sequence ID 314)-A (referred to herein as BCY32069); A-(Sequence ID 315)-A (referred to herein as BCY32071); A-(Sequence ID 316)-A (referred to herein as BCY32072); A-(Sequence ID 317)-A (referred to herein as BCY32078); A-(Sequence ID 318)-A (referred to herein as BCY32079); A-(Sequence ID 319)-A (referred to herein as BCY32080); A-(Sequence ID 320)-A (referred to herein as BCY32081); A-(Sequence ID 321)-A (referred to herein as BCY32082); A-(Sequence ID 322)-A (referred to herein as BCY32083); A-(Sequence ID 323)-A (referred to herein as BCY32084); A-(Sequence ID 324)-A (referred to herein as BCY32085); A-(Sequence ID 325)-A (referred to herein as BCY32086); A-(Sequence ID 326)-A (referred to herein as BCY32087); A-(Sequence ID 327)-A (referred to herein as BCY32088); A-(Sequence ID 328)-A (referred to herein as BCY32089); A-(Sequence ID 329)-A (referred to herein as BCY32090); A-(Sequence ID 330)-A (referred to herein as BCY32091); A-(Sequence ID 331)-A (referred to herein as BCY32092); A-(Sequence ID 332)-A (referred to herein as BCY32093); A-(Sequence ID 333)-A (referred to herein as BCY32095); A-(Sequence ID 334)-A (referred to herein as BCY32096); A-(Sequence ID 335)-A (referred to herein as BCY32098); A-(Sequence ID 336)-A (referred to herein as BCY32099); A-(Sequence ID 337)-A (referred to herein as BCY32100); A-(Sequence ID 338)-A (referred to herein as BCY32101); A-(Sequence ID 339)-A (referred to herein as BCY32103); A-(Sequence ID 340)-A (referred to herein as BCY32104); A-(Sequence ID 341)-A (referred to herein as BCY32105); A-(Sequence ID 342)-A (referred to herein as BCY32106); A-(Sequence ID 343)-A (referred to herein as BCY32107); A-(Sequence ID 344)-A (referred to herein as BCY32108); A-(Sequence ID 345)-A (referred to herein as BCY32109); A-(Sequence ID 346)-A (referred to herein as BCY32110); A-(Sequence ID 347)-A (referred to herein as BCY32112); A-(Sequence ID 348)-A (referred to herein as BCY32113); A-(Sequence ID 349)-A (referred to herein as BCY32114); A-(Sequence ID 350)-A (referred to herein as BCY32115); A-(Sequence ID 351)-A (referred to herein as BCY32116); A-(Sequence ID 352)-A (referred to herein as BCY32117); A-(Sequence ID 353)-A (referred to herein as BCY32120); A-(Sequence ID 354)-A (referred to herein as BCY32121); A-(Sequence ID 355)-A (referred to herein as BCY32122); A-(Sequence ID 356)-A (referred to herein as BCY32123); A-(Sequence ID 357)-A (referred to herein as BCY32124); A-(Sequence ID 358)-A (referred to herein as BCY32125); A-(Sequence ID 359)-A (referred to herein as BCY19937); A-(Sequence ID 360)-A (referred to herein as BCY19938); A-(Sequence ID 361)-A (referred to herein as BCY19939); A-(Sequence ID 362)-A (referred to herein as BCY19940); A-(Sequence ID 363)-A (referred to herein as BCY19941); A-(Sequence ID 364)-A (referred to herein as BCY19942); A-(Sequence ID 365)-A (referred to herein as BCY19943); and A-(Sequence ID 366)-A (referred to herein as BCY18253) The bicyclic peptide ligand according to claim 3, comprising a more selected amino acid sequence, a modified derivative thereof, and / or a pharmaceutically acceptable salt thereof.

10. A polymer-bound complex or a pharmaceutically acceptable salt thereof comprising at least two bicyclic peptide ligands as described in any one of claims 3 to 9, wherein the peptide ligands may be the same or different.

11. A polymer-binding complex according to claim 10, comprising one or more identical bicyclic peptides (i.e., homopolymers), or a pharmaceutically acceptable salt thereof.

12. A polymer-binding complex according to claim 10, comprising different bicyclic peptides (i.e., heteromultimers), or a pharmaceutically acceptable salt thereof.

13. It contains two bicyclic peptides that are either identical (i.e., homodimers) or different (i.e., heterodimers), for example: Table 1 A polymer-bound complex according to claim 10, comprising the same as a pharmaceutically acceptable salt thereof.

14. The multimer-binding complex contains three bicyclic peptides that are either identical (i.e., homotrimers) or different (i.e., heterotrimers), for example, a heterotrimer containing one bicyclic peptide in the first sequence and two bicyclic peptides in the second sequence, in particular: Table 2 A polymer-bound complex according to claim 10, comprising the same as a pharmaceutically acceptable salt thereof.

15. The multimer-binding complex contains four bicyclic peptides that are either identical (i.e., homotetramer) or different (i.e., heterotetramer), for example, the heterotetramer contains one bicyclic peptide in the first sequence and three bicyclic peptides in the second sequence, or the heterotetramer contains two bicyclic peptides in the first sequence and two bicyclic peptides in the second sequence, in particular: Table 3 A polymer-bound complex according to claim 10, comprising the same as a pharmaceutically acceptable salt thereof.

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 polymer-bound complex according to any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable additives.

17. A peptide ligand according to claim 1, or a bicyclic peptide ligand according to any one of claims 2 to 9, or a polymer-bound complex according to any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, for use in preventing, suppressing or treating a TLR3-mediated disease or disorder; or a pharmaceutical composition according to claim 16.

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