Human interleukin (IL)-17 cytokine binding peptides

Abstract

The present disclosure provides peptide compounds that inhibit human IL-17 cytokines. The present disclosure also provide pharmaceutical compositions that include the peptide compounds. In addition, the present disclosure also provides methods of use of the peptide compounds, such as methods of treating or preventing diseases, conditions or disorders mediated or associated with IL-17.

Description

Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters[EN ]HUMAN INTERLEUKIN (IL)-17 CYTOKINE BINDING PEPTIDESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit if priority to U.S. Provisional Application Nos.63 / 614,421, filed December 22, 2023; 63 / 634,353, filed April 15, 2024; 63 / 664,097, filed June 25, 2024; 63 / 679,506, filed August 5, 2024; 63 / 684,260, filed August 16, 2024; 63 / 713,993, filed October 30, 2024; and 63 / 722,927, filed November 20, 2024, the disclosures of each of which are incorporated herein by reference in their entireties.INCORPORATION-BY-REFERENCE OF MATERIAL ELECTRONICALLY SUBMITTED

[0002] A Sequence Listing is provided herewith as a Sequence Listing XML, “PTGX-008WO_SEQ_LIST_12_24” created on December 17, 2024, and having a size of 2,770,896 bytes. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety.FIELD OF THE INVENTION

[0003] The present disclosure relates to peptide compounds which are human IL- 17 cytokine inhibitors or antagonists. The peptide compounds bind to a human IL- 17 cytokine in order to prevent or reduce the ability of the IL- 17 cytokine to bind to its cognate IL- 17 receptor(s). In this sense, the peptide compounds of the invention can also be considered to be neutralizing agents of human IL- 17 or (upstream) antagonists of human IL- 17 receptor activation. The present disclosure also relates to pharmaceutical compositions comprising the inhibitors, and methods of treating or preventing diseases, conditions or disorders mediated or associated with IL- 17.BACKGROUND

[0004] The interleukin- 17 (IL- 17) cytokine family consists of 6 members or isoforms, IL-17 A-F. These isoforms have the ability to form active cytokine dimers through disulfide bridges. (Aggarwal, S. et al., J. Leukoc. Biol. 2002, 71 (1), 1-8; Pappu, R. et al., Immunology 2011, 134 (1), 8-16). Among the IL-17 family, IL-17A is the most extensively studied member in terms of its biological activity. IL-17A and IL-17F are closely related isoforms and often co-expressed in cells. Besides for homodimers, they can also form a heterodimeric cytokine called IL-17A / F (IL-17AF). (Goepfert, A. et al., Sci. Rep. 2017, 7 (1), 8906). Inthis regard, IL-17AA (homodimer) can be used to refer to IL-17A, and IL-17FF (homodimer) can be used for IL-17F.

[0005] IL-17s are secreted by hematopoietic cells, including Thl7 (CD4+ T cells), Tcl7 (cytotoxic CD8+ T cells), other T cells such as y8T cells, NK cells, ILC3 (group 3 innate lymphoid cells), and “natural” Thl7 cells (CD4+ RORyT+ thymocytes). (Brembilla, N. C. el al., Immunol. 2018, 9, 1682), and myeloid cells. These IL-17s play a role in host defense and various immune functional responses. (Jin, W. et al., Emerg. Microbes Infect. 2013, 2 (9), 1-5). They induce the production of pro-inflammatory cytokines such as IL-1 , IL-6, and IL-21, as well as chemokines such as CXCL1. This leads to the recruitment of innate immune cells to the site of infection and facilitates the elimination of the pathogen. (Valeri, M. et al., Pathog. Dis. 2016, 74, ftwll 1).

[0006] While IL-17A is crucial for host defense, its deregulation can result in overproduction of pro-inflammatory cytokines, leading to tissue damage and chronic inflammation. Studies have demonstrated that IL-17AA is implicated in autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and nonradiographic axial spondyloarthritis. (Majumder, S. et al., Anna. Rev. Immunol.2021, 39, 537-556). IL-17A levels are elevated in various inflammatory conditions, including sepsis, pneumonia, systemic lupus erythematosus, rheumatoid arthritis, allograft rejection, and cancer.

[0007] IL- 17 cytokines mediate their biological functions by binding to specific surface receptors on target cells. The first identified IL-17 receptor (IL-17R) was IL-17RA, which was later followed by the discovery of four additional members of the IL-17R family (IL-17R B-E). IL-17 receptors are expressed in a variety of cell populations, including keratinocytes, fibroblasts, mesothelial cells, epithelial cells, and leukocytes. These receptors are mostly heterodimeric, composed of 2 subunits: IL-17RA through IL-17RE with IL-17RA serving as a common subunit. (Kirkham, B. W. et al. Immunology 2014, 141, 133-142).

[0008] IL-17RA is expressed in all cell types, especially on epithelial cells, fibroblasts, and innate immune cells like macrophages and neutrophils. (Ho, A. W. et al., Immunopathol.2010, 32, 33-42). Each subunit of the IL- 17 receptor has distinct regions, including an extracellular cytokine binding region, a transmembrane domain, and an intracellular signaling domain. Heterodimeric IL-17RA / IL-17RC complex serves as the primary receptor for IL-17AA, IL-17FF, and IL-17AF. Binding of these cytokines to the receptor leads to receptor dimerization. IL-17AA can also signal through the IL-17RA / IL-17RD heterodimer, while IL-17FF may bind to a homodimer of IL-17RC. The receptor dimer interacts viaSEFIR domains and mediates signaling via an Act 1 -dependent pathway, promoting the activation of pro-inflammatory factors such as NF-KB. (Velichko, S. et al., PLoS One 2016, 11).

[0009] Injectable monoclonal antibodies (mAb), such as the anti-IL-17A mAb secukinumab and ixekizumab, the dual anti-IL-17A and anti-IL-17F mAb bimekizumab and the anti-IL-17RA mAb brodalumab, are recognized as effective treatments with acceptable safety profiles for moderate to severe psoriasis and other inflammatory diseases such as psoriatic arthritis and axial spondyloarthritis. (Hawkes, J. E. et al., Immunol. 2018, 201 (6), 1605-1613). Secukinumab and izekizumab specifically target IL-17A, while bimekizumab binds to both IL-17A and IL-17F, thereby, blocking the activation of IL-17 receptors (composed of IL-17RA / IL-17RC), reducing the inflammatory drive to alleviate inflammation. Brodalumab, on the other hand, binds to the receptor, IL-17RA, which inhibits the activation of all receptors using IL-17RA as a subunit, including IL-17AA, AF, and FF, as well as IL-17C and IL-17E. (Tollenaere, M. A. X. et al., Br. J. Dermatol. 2021, 185 (3), 585-594).

[0010] However, monoclonal antibodies have disadvantages. They are typically expensive, administered non-orally, and have limited tissue penetration (Arkin, M. R. et al., Chem. Biol.2014, 21, 1102-1114). The challenge of modulating a large protein-protein interaction (PPI) using small molecules is well known, primarily due to their smaller size and low specificity. In contrast, peptide drugs have unique properties such as sufficient size combined with structural-backbone flexibility, enabling them to act as potent and specific inhibitors of PPIs (Wang L. et al., Signal Transduction and Targeted Therapy (2022) 7:48). Therefore, there is a need to develop novel peptide compounds that target IL- 17 cytokines for the treatment of various diseases. The present invention meets this and other needs.BRIEF SUMMARY OF THE INVENTION

[0011] As used herein, the “X” notation for residue positions is equivalent to the three-letter “Xaa” notation, and both “X” and “Xaa” mean that any amino acid, natural or unnatural, can be at that position, unless specified otherwise.

[0012] In one aspect, the invention provides a peptide comprising or consisting of a sequence of Formula (I): R’-XOO-XO-Xl^-XS^-XS-Xb^-XS-X -XlO-Xll-X -XlS-XM-XlS-X16-R2, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, !Pip_AceticAcid, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid,Mor_propanoic_acid, PVA (pivalic acid), 1PEG2_1PEG2_ISOG1U_C 12, 1 PEG2_1 PEG2_IsoGlu_C 12_Diacid, 1 PEG2_1 PEG2_IsoGlu_C 18_diacid,1 PEG2_ 1 PEG2_IsoGlu_Palm, 1 PEG2_ 1 PEG2_Ahx_C 18_Diacid, lPEG2_PEG2_Ahx_Palm, or absent;R2 is NH2 or OH or absent;X00 is Cha, dH, dK, Ogl, Tie or absent;XO is 2Pal, 3Pal, Aib, Asn, d2Pal, d3Pal, dA, dE, dF, dH, dK, dL, dQ, dS, Gin, Glu, Glu_OMe, His, He, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_Me3, NMe_His, Orn, Pro, Sar, Thr, Tie, or absent;XI is INal, Bip, Cha, Chg, Cyclopropyl_Ala, Dgl, DIP, di, hCha, hF, hhF, He, Lys,Ly s_ 1 PEG2_ 1 PEG2_IsoGlu_C 18_diacid, Ly s_ 1 PEG2_1 PEG2_IsoGlu_C 12, Lys_lPEG2_lPEG2_IsoGlu_Palm, Ogl, Phe_4Me, Tba, Tie, Vai, or absent;X2 is 2Pal, 3Pal, aMe_Arg, Agb, Agp, bhF, Cit, Dab, Dab_Ac, Dab_2HyAc, Dab_Ms, Dab_Ts, dDab2HyAc, dH, dT, Glu, Gin, His, hR, Hse, Lys, Lys_lPEG2_Ac, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_lsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, Lys_lPEG2Ac, Lys_2HyAc, LysMPA, Lys_Ms, Lys_Ns, Lys_Ts, NMe_Thr, Orn, Om_Ac, Om_Ms, OrnPVA, Om_Ts, Phe_2Ad, Phe_3Ad, Phe_4Ad, Phe_4_2ae, Phe_4ad, Phe_4_COOH, Phe_4_Cl, Phe_4guan, Phe_4OMe, Phe_4_Morph, Phe_pentaF, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Q_MecPro, Tetl, Thr, or Thi;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, bhV, Cha, Chg, Cprg, Cpg, cyclopentyl_Ala, cyclopropyl_Ala, Cys, Dgl, DiethylGly, dL, dV, H_Cha, Hey, hL, Hph, Igl, Nle, NMe_Leu, nVF3, O4S, O5S, Ogl, Phe_4tBu, Phe_4Cl, Phe_4_OMe, Phe_4_Me, Phe_3_4_C12 [Phe_34diCl], Phe_4_CF3, Peptoid_CH2_V, Pra, Tba, Tie, or Vai;X4 is Asn, dT, Dab, Gin, Glu, Glu_OMe, hE, His, hR, Lys_Me3, Orn, Phe4_COOH, Phe_4_Morph, Tetl, Thr, or Thr_Me;X5 is Abu, aMe_Lys_Ac, Cha, Cys, Chg, Dab_Acetyl, di, dLys_Ac, Glu, Hey, hE, Hhc, HhPen, He, Lys, Lys_Ac, LysN3, LysPhAc, NMe_Lys_Ac, O2S, O3S, O3S_Reduced, O4S_Reduced, O5S, O5S_Reduced, Om_Acetyl, or Pen;X6 is 4R_BenzyloxyPro, 4RPhePro, 4S_Amp, 4S_Amp_Cyclhex, 4S_Amp_Hex, 4S_Amp_TVA, 4S_Amp_tBu, 4SCF3Pro, 4ScyclohexPro, 5RPhePro, Azetidinone, Dfp, dP, Hpr, Oic, or Pro;X7 is Acvc, Aib, Ala, aMe_Phe, Arg, Aze, Cys, Dab, dC, Gin, Glu, His, Hpr, hR, Ly s_ 1 PEG2_ 1 PEG2_Ahx_C 18_Diacid, Lys_l PEG2_ 1 PEG2_IsoGlu_C 12,Lys_lPEG2_lPEG2_IsoGlu_C18_ diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_Ac, O3S, 03S_Me, O4S, Pro, Ser, Tba, or Tic;X8 is aMe_Asp, aMe_Glu, Asp, dD, Gia, Gin, Glu, Phe_3COOH, Phe_4COOH, Tetl, or Tet2; X9 is Aoc, Cha, Cys, Dgl, hCha, Hey, Leu, Nle, O3S, O3S_Reduced, O6S, Ogl, Phe_34diF, Phe_4CF3, or Tba;X10 is INal, 2Nal, Aib, aMe_Phe, aMe_Trp, Aoc, Cys, DIP, dW, hCha, Gin, Hph, Lys_lPEG2_lPEG2_IsoGlu_C12, Phe, Phe_34diCl, Phe_3Ad, Phe_4ad, Phe4_COOH, Phe_4OMe, Phg, Tba, Tie, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, Trp_7Phe, or Trp;XI 1 is Aib, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Cys, Chg, dA, dS, Gin, Glu, Hey, Leu, Lys_lPEG2_lPEG2_lsoGlu_C12, Lys_Ac, Lys_Me3, O3S, O3S_Me, O4S, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie;X12 is INal, aMe_Trp, Hph_34diCl, Om_Bz, Trp, Trp_4Cl, Trp_5Br, Trp_5Cl, Trp_5Et, Trp_5Me, Trp_56diCl, Trp_56diMe, Trp_6Cl, Trp_6CF3, Trp_6Me, or Trp_7Cl;XI 3 is Abu, aMe_Cys, aMe_Lys_Ac, Cys, Cha, Dab_Acetyl, Glu, Hey, hE, Hhc, HhPen, He, Lys, Lys_Ac, LysN3, O2S, O3S, 03S_Me, O3S_Me_Reduced, O3S_Reduced, O4S_Reduced, Om_Acetyl, or Pen;X14 is Aib, Arg, Asn, Cys, dE, dF, dH, dK, dL, dN, dQ, dR, Gin, Glu, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Hexy, Lys_PEG12_NH, Lys_PEG4_lPEG2_NH2, Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, O3S, O3S_Me, Om_Acetyl, PEG12, Tba, or absent;XI 5 is dE, dK, dR, Glu, Lys, Lys_PEG4_PEG4_NH2, Lys_Dimethyl, Pro, or absent; and X16 is dE, dF, dH, dK, dL, dR, dQ, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_PEG4_PEG4_NH2, Lys_Ac, or absent;wherein:(i) the peptide optionally comprises a cyclic structure wherein at least two amino acid residues in the peptide (monomer) are either: (a) directly covalently linked, or (h) indirectly covalently linked through a cyclization linker;(ii) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other, or indirectly covalently linked to each other through a dimerization linker; and / or(iii) the peptide is optionally conjugated with a half-life extension moiety.Formula (I).

[0013] In other aspects, to the extent a peptide Formula, including any of the SEQ ID NO formulas herein, does not include residue(s) at an X0 and / or an X00 position, the peptide may further comprise a residue(s) at X0 and / or X00 between R1 and XI , wherein the residue options for X0 and X00 are specified above in Formula (I).

[0014] In one aspect, a peptide of the invention comprises a cyclic structure characterized by an intramolecular cross-link between residues X5 and X13 (X5-X13), X7 and XI 1 (X7-X11), X9 and X13 (X9-X13), or X10 and X14 (X10-X14). The intramolecular cross-link can comprise a covalent bond directly or indirectly between the cross-linked residues, wherein the covalent bond comprises an amide bond (lactam bond), a disulfide bond, a thioether bond, a carbon-carbon single bond, or a carbon-carbon double bond (an olefin).

[0015] Furthermore, in other aspects, any Formula of the invention can be modified such that the residue options for one position of a cross-link can be swapped with the residue options for the other position of a cross-link. For example, if a Formula specifies certain residues at position X5 and other residues at position XI 3, the invention contemplates that the residue options at position X13 can instead be for X5, and the residue options at position X5 can instead be those for X13. This also applies for X7-X11, X9-X13, and X10-X14, whether the crosslinks are direct or indirect (via a cyclization linker) between the side chains of the residues.

[0016] In one aspect, a peptide of the invention comprises an intramolecular cross-link that is a direct covalent bond between the cross-linked residues. The two cross-linked amino acid residues can be, for example, at X5 and XI 3 or X9 and XI 3, and the two amino acids are directly covalently linked through a disulfide bond. The two amino acid residues cross-linked through a disulfide bond can be, for example, both, or individually, Hhc, Hey, Pen, hhPen, or Cys, their respective D-amino acid configuration, and their a-methyl variant.

[0017] In another aspect, a peptide of the invention comprises direct thioether cross-links between two amino acid side-chains, between a side-chain and an N-terminal (Rl) moiety, or between a side-chain and a C-terminal (R2) moiety. The two amino acid residues (or an amino acid and an R group) directly cross-linked through a thioether bond can be, for example, a residue with a free thiol in its side chain such as Cys, Hhc, Hey, Pen, or HhPen, with a residue with a free alkyl in its side chain such as aMe_Lys_Ac, Dab_Acetyl, Dap_Ac, dLys_Ac, NMe_Lys_Ac, Lys_Ac, Lys_PEG12_Ac, LysPhAc, and Om_Acetyl. In some aspects, their D-form or a-methyl variant can be used. With respect to N-terminal or C-terminal to side-chain cyclization, the N- or C-terminal can be a moiety with a free alkyl group such as an acetyl moiety, and the side chain can be a residue with a free thiol; vice-versa. Generally, for direct or indirect thioether cyclization, one residue or moiety has a free thiol group and the other residue or moiety has a free alkyl group such that cross-linking of these free groups results in a thioether bond.

[0018] In one aspect, a peptide of the invention comprises two directly cross-linked amino acid residues at X5 and X13, X7 and Xll, X9 and X13, or X10 and X14, and wherein these two amino acids are directly covalently linked through a thioether bond. The two amino acid residues directly cross-linked through a thioether bond can be, for example: aMe_Cys, Cys, dC, Hhc, Hey, or Pen (z.<?., an amino acid with a free thiol group in its side-chain), for one residue of the pair; and aMe_Lys_Ac, Dab_Acetyl dLys_Ac, Lys_Ac, LysPhAc, NMe_Lys_Ac, Om_Acetyl, O2S_Reduced, O3S_Reduced, O4S_Reduced, or O5S_Reduced for the other residue of the pair (i.e., an amino acid with a free acetyl group in its side-chain), in either order.

[0019] In another aspect, a peptide of the invention comprises two directly cross-linked amino acid residues are at X5 and X 13 , or X9 and X 13 , and the two amino acids are directly covalently linked through a carbon-carbon double bond. The two amino acid residues cross-linked through a carbon-carbon double bond can be, for example, both, or individually, O2S, O3S, O4S, O5S, O6S, or O3S_Me.

[0020] In another aspect, a peptide of the invention comprises two directly cross-linked amino acid residues are at X5 and XI 3, or at X9 and X13, and the two amino acids are directly covalently linked through a carbon-carbon single bond. The two amino acid residues crosslinked through a carbon-carbon single bond can be, for example, both, or individually, reduced version of the amino acids suitable for carbon-carbon double bond cross-links, i.e., reducedforms of O2S, O3S, O4S, O5S, O6S, or 03S_Me. In one aspect, the two amino acid residues cross-linked through a carhon-carhon single bond are individually or both O S_Me_Reduced, O3S_Reduced, or O4S_Reduced.

[0021] In another aspect, a peptide of the invention comprises two directly cross-linked amino acid residues at X5 and XI 3, and the two amino acids are directly covalently linked through an amide bond (lactam). The two amino acid residues are suitable for cyclic amide bond crosslinking if one has a side chain with a free amine and the other with a free carboxylic acid, such as Lys paired with Glu, hE, or Asp. Hence, in one aspect, one of X5 and XI 3 is Lys and the other is Glu, hE, or Asp.

[0022] In another aspect, a peptide of the invention comprises two directly cross-linked amino acid residues at X5LysN3 and X13Abu, or X5Abu and XI 3 LysN3. The side chains of these two amino acids are directly covalently linked. Specifically, a hydrogen from the azole ring of LysN3 reacts with a free hydroxyl from Abu to form the cross-link as shown in paragraph

[00324] ,

[0023] In one aspect, a peptide of the invention comprises an intramolecular cross-link that is an indirect covalent bond between the cross-linked residues, wherein each of the cross-linked residues form a direct covalent bond with a cyclization linker. The cyclization linker can be, for example, a linear or cyclic alkane or an alkene with two free alkyl groups, a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, an mXylene_Linker, a pXylene_Linker, or an oXylene_Linker.

[0024] In another aspect, for residues that include a free thiol group in their side chains (which includes, but are not limited to, Cys, Hey, Hhc, Pen, HHpen, their respective D-amino acid configuration, and their a-methyl variants), a Cyclization linker may be used to mediate a thioether (or a “bis-thioether”) intramolecular cross-link between each the two side chains. The free thiol group at each side chain forms a thioether bond with a free alkyl moiety of a Cyclization linker, and the Cyclization linker needs to have two free alkyl moieties. Representative Cyclization linkers include, but are not limited to, a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, a Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker a Pentane_Linker, a Propane_Linker, a Trimethylbenzene_Linker, an mXylene_Linker, a pXylene_Linker, or an oXylene_Linker. SeeTable 1 for abbreviations and corresponding structures for Cyclization linkers and unnatural amino acids. Herein, intramolecular cross-links formed with a Cyclization linker can be referred to as an “indirect” cross-link, and cross-linked formed without a Cyclization linker can be referred to as a “direct” cross-link.

[0025] In one aspect, a peptide of the invention comprises an intramolecular cross-link that is an indirect covalent bond between the cross-linked residues, the cyclization linker comprises one of the Xylene_Linkers, and the two amino acid residues cross-linked through a thioether bond with the cyclization linker are at X5 and X13, X7 and XI 1 , X9 and X13, or X10 and X14, wherein the residues are, for example, both, or individually, Cys or dC.

[0026] In one aspect, a peptide of the invention comprises an intramolecular cross-link that is an indirect covalent bond between the cross-linked residues, the cyclization linker comprises a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, or a Propane_Linker, and the two amino acid residues cross-linked through a (bis- or di-)thioether bond with the cyclization linker can be, for example, both, or individually, Cys, dC, Hey, Hhc, HhPen, or Pen (or a residue with a free thiol group), at for example, X5-X13, X9-X13, X10-X14, or X7-X11. These linkers are representative, and other alkane or alkene linkers are suitable if they have terminal ends or two suitable free chemical groups that can each react with a free thiol at each cyclization position to form thioether bonds (relative to the cyclization linker - a bis- or di-thioether bond) ((e.g., free alkyl groups of the cyclization linker can be modified to alkyl halides for reaction with deprotonated thiols to form thioether bonds).

[0027] In some aspects, a peptide of the invention can be a monomer (i.e., a monomeric subunit) of a homodimer or heterodimer peptide molecule. Each monomer of the dimer can have a direct covalent attachment to a dimerization linker, regardless of whether the monomer comprises a cyclic structure or a linear structure. Often, especially for cyclic monomers, each monomer of a dimer compound comprises Lys or dK at X14, X15, or XI 6 that is directly covalently linked to a PEG linker.

[0028] In one aspect, a PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25.

[0029] In one aspect for the dimers of the invention, each monomer is directly covalently linked to a PEG linker through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEGlinker. The PEG linker can be, for example, a molecule with repeating PEG units with an acidic moiety at the terminal ends of the molecule, such as PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[0030] In another aspect for the dimers of the invention, each monomer can comprise a residue with a free amine in its side chain such that the free amine can react with a free hydroxyl of a dimerization linker to form an amide bond. For example, XI 4 can be Lys_PEG4_PEG4_NH2, which has a free amine in its side chain, and the free amine can react with a free hydroxyl at one of the terminal ends of the DIG_Linker. If each monomer has X14Lys_PEG4_PEG4_NH2, then each monomer will form an amide bond with the DIG_Linker, thereby forming a dimer. The ordinary artisan understands that other amino acids are suitable, including other variants of lysine with PEG side chains having a free amine, including but not limited to, Lys_PEG8_NH2 and Lys_PEG4_lPEG2_NH2.

[0031] In some aspects, a dimer of the instant invention with a PEG dimerization linker (e.g., PEG21DA) attached to a lysine can be modified such that the lysine is substituted with Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, or Lys_PEG4_lPEG2_NH2, and the PEG linker is substituted with a DlG_Linker.

[0032] In another aspect for the dimers of the invention, each monomer is directly covalently linked to a pBiphenyl_Linker, as a dimerization linker, through a thioether bond. For example, a free thiol group in a side chain of an amino acid residue (e.g., Cys, Hey, Hhc, Pen, etc.) can be directly covalently linked to a pBiphenyl_Linker to form a (bis- or di-)thioether bond.

[0033] In one aspect, a peptide of the invention, whether linear or cyclic, and whether in monomeric or dimer form, exhibits an IC50 value of less than about 20 nM in a human IL- 17 HEK Blue assay. All of the exemplary peptide compounds of Figure 1 have an IC50 less than 20 nM in a human IL- 17 HEK Blue assay.

[0034] In related aspects, the peptide exhibits an IC50 value of less than about 10 nM, 5 nM, or 1 nM, in a human IL-17 HEK Blue assay. The human IL-17 HEK Blue assay can be, for example, a human IL-17AA HEK Blue assay, a human IL-17AF HEK Blue assay, or a human IL-17FF HEK Blue assay.

[0035] In one aspect, a peptide of the invention exhibits an IC50 value of less than about 1 nM in a human TL-17AA HEK Blue assay, less than about 1 nM in a human IL-17AF HEK Blue assay, and less than about 1, 5, 10, or 20 nM in a human IL-17FF HEK Blue assay.

[0036] In another aspect, a peptide of the invention exhibits an IC50 value of less than about 1 nM in a human IL-17AA HEK Blue assay and less than about 1, 5, or 10 nM in a human IL-17FF HEK Blue assay.

[0037] In another aspect, a peptide of the invention exhibits an IC50 value of less than about 1 nM in a human IL-17AA HEK Blue assay, less than 1 about InM in a human IL-17AF HEK Blue assay, and less than about 1, 5, or 10 nM in a human IL-17FF HEK Blue assay.

[0038] In one aspect, a peptide of the invention, whether linear or cyclic, and whether in monomeric or dimer form, exhibits a half-life greater than about 0.5 hours in an SGF and / or SIF stability assay. In related aspects, the peptide exhibits a half-life greater than about 1.0 hours, 1.5 hours, or 2.0 hours in an SGF and / or SIF stability assay.

[0039] In other aspects, a peptide of the invention exhibits an IC50 less than about 1 nM in a human IL-17AA HEK Blue assay and less than about 5 nM in a human IL-17FF HEK Blue assay, a half-life greater than about 0.5, 1.0, 1.5, or 2.0 hours in an SGF assay, and a half-life greater than about 2.0 hours in an SIF assay. In a related aspect, a peptide of the invention exhibits an IC50 less than about 1 nM in both a human IL-17AA HEK Blue assay and a human IL-17AF HEK Blue assay, less than about 5 nM in a human IL-17FF HEK Blue assay, a halflife greater than about 0.5, 1.0, 1.5, or 2.0 hours in an SGF assay, and a half-life greater than about 2.0 hours in an SIF assay. In a related aspect, when a peptide of the invention exhibits a half-life greater than 2.0 hours in an SGF assay and in an SIF assay, the peptide is suitable for formulation in solid or liquid form for oral administration, and without excipients or coating(s) to protect the peptide from the acidic conditions of the gastric environment. In another related aspect, when a peptide of the invention exhibits a half-life that does not exceed 0.5, 1.0, or 1.5 hours in an SGF assay, the peptide can be formulated in a solid form with an enteric coating.

[0040] In another aspect, a peptide of the invention that exhibits an IC50 less than about 20 nM, 10 nM, 5 nM, or 1 nM in a human IL- 17 AA, AF, or FF HEK Blue assay can be administered to a subject subcutaneously, irrespective of the peptide’s half-life in an SGF or SIF assay.

[0041] In another aspect, a homodimer peptide compound of the invention exhibits at least a 2-fold improvement in its IC50 value in a human IL-17 HEK Blue assay as compared to its monomeric form. In related aspects, said peptide compound exhibits at least a 5-fold, 10-fold, 20-fold, 25-fold, 50-fold, or 100-fold fold improvement (i.e., lower IC50) in its IC50 value in a human IL- 17 HEK Blue assay as compared to its monomeric form.

[0042] In another aspect, a homodimer peptide compound of the invention exhibits at least a 2-fold improvement in its half-life in an SGF and / or an SIF stability assay as compared to its monomeric form. In related aspects, said peptide compound exhibits at least a 3-fold, 4-fold, 5-fold, or 10-fold improvement (i.e., longer time) in its half-life in an SGF and / or an SIF stability assay.

[0043] In one aspect, for any one of the peptides comprising a monomer sequence of SEQ ID NO: 1-720, any of the amino acids, natural or unnatural, can be substituted with its corresponding D-amino acid, or vice versa. In related aspects, up to all, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid(s) can be substituted with its corresponding D-amino acid, or vice versa.

[0044] In another aspect, for any one of the peptides comprising a monomer sequence of SEQ ID NO: 1-720, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid(s) can be replaced with a conservative substitution and / or a corresponding analog (e.g., if the peptide has a lysine analog at a particular position, then other lysine analogs can provide the corresponding analog substitution, see Table 1). In one aspect, a peptide comprising a lysine analog can be substituted with a different lysine analog with a side-chain comprising one or more of: a palmitoyl moiety (Palm), a PEG moiety, an isoglutamine moiety (IsoGlu), an aminocaproic acid moiety (Ahx), a C 1-20 alkyl moiety, and a Cl -30 alkyl-C(O)- moiety.

[0045] In another aspect, if a peptide has a lysine analog at a particular position, the lysine analog can be substituted with another lysine analog that comprises a side-chain with one of the different combinations of linkers and half-life extension moieties listed in Table 4.

[0046] In another aspect, for any one of the peptides comprising a monomer sequence of SEQ ID NO:1-720, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 unnatural amino acid(s) can be replaced with its corresponding natural amino acid (e.g., if the peptide has a lysine analog at a particular position, then it can be substituted with lysine, see Table 1 for analog information).

[0047] For any of the Formulas herein, R1 and R2 can be the moieties specified for Formula(I) above. Herein, a “Formula” includes not only Formula (1) et al., but also SEQ ID NO formulas.

[0048] In one aspect, for a peptide according to any of the Formulas herein, R1 is, or can be changed to, acetyl, glutaric acid, or isovaleric acid, and R2 is amine.

[0049] In one aspect, for a peptide according to any of the Formulas herein, R1 is, or can be changed to, isovaleric acid, and R2 is amine.

[0050] In one aspect, for a peptide according to any of the Formulas herein, X0 is, or can be changed to, dE, E, His, dH, or absent. In one aspect, X0 can be changed to dE or E.

[0051] In another aspect, for a peptide according to any of the Formulas herein, X00 is, or can be changed to, dH.

[0052] In one aspect, for a peptide according to any of the Formulas herein, R1 is (or can be changed to) isovaleric acid, X0 is (or can be changed to) dH, and R2 is amine.

[0053] In one aspect, for a peptide according to any of the Formulas herein, XI is, or can be changed to, He or Vai.

[0054] In one aspect, for a peptide according to any of the Formulas herein, X2 is, or can be changed to, Lys_Me3.

[0055] In one aspect, for a peptide according to any of the Formulas herein, X3 is, or can be changed to, Tie or Vai.

[0056] In one aspect, for a peptide according to any of the Formulas herein, X4 is, or can be changed to, Glu.

[0057] In one aspect, for a peptide according to any of the Formulas herein X6 is, or can be changed to, Oic or an Oic analog.

[0058] In one aspect, for a peptide according to any of the Formulas herein, X7 is, or can be changed to, Ala.

[0059] In one aspect, for a peptide according to any of the Formulas herein, X8 is, or can be changed to, Asp.

[0060] In one aspect, for a peptide according to any of the Formulas herein, X9 is, or can be changed to, Ogl or an Ogl analog.

[0061] In one aspect, for a peptide according to any of the Formulas herein, X10 is, or can be changed to, Trp, INal, or a Trp analog.

[0062] In one aspect, for a peptide according to any of the Formulas herein, XI 1 is, or can be changed to, Asp or Glu.

[0063] In one aspect, for a peptide according to any of the Formulas herein, X12 is, or can be changed to, Trp or a Trp analog.

[0064] In one aspect for a peptide according to any of the Formulas herein, X14 is, or can be changed to, Lys, Lys_PEG8_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG4_PEG4_NH2.

[0065] In one aspect for a peptide according to any of the Formulas herein, XI 5 is, or can be changed to, dR.

[0066] In one aspect, for a peptide that is a monomer comprising X14Lys in a homodimer compound according to any of the Formulas herein, the dimerization linker is PEG21DA.

[0067] In one aspect, for a peptide that is a monomer in a homodimer compound according to any of the Formulas herein, a dimerization linker comprises a linear structure, a COOH group at both terminal ends, and between 15-25 PEG units.

[0068] In another aspect, for a peptide that is a monomer in a homodimer compound according to any of the Formulas herein, an X14 lysine residue can be modified such that the lysine side chain comprises between 4-25 PEG units, between 6-20 PEG units, or between 8-15 PEG units, and a free amine. In this aspect, the dimerization linker can comprise two free hydroxyls, such that each free hydroxyl can form an amide bond with the free amine present in the side chain of the modified lysine residue comprising said PEG units. As stated, the DIG linker can serve as a dimerization linker in this aspect, as the DIG linker has two carboxylic acid moieties (each comprising a free hydroxyl).

[0069] In one aspect, any one of the peptides of the invention may be in the form of a pharmaceutically acceptable salt.

[0070] In one aspect, the invention provides a homodimer peptide compound that exhibits an ICso equal to or less than 10 nM in a HEK Blue human IL- 17 assay, wherein the compound has two monomer cyclic peptides both comprising or consisting of the same amino acid sequence from Formula (II):R'-X00-X0-X I-X2-X3-X4-X5-X6-X7-X8-X9-X I0-X I I -X I 2-X I 3-X I4-X I 5-X I6-R2,wherein:R1 is acetyl (Ac), 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, !PEG2_lPEG2_IsoGlu_Palm, lPEG2_lPEG2_IsoGlu_C18_Diacid, 1PEG2_1PEG2_ISOG1U_C 12, or absent;R2 is NH2, OH, or absent;X00 is dH or absent;XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Cha, Chg, Cyclopropyl_Ala, DIP, He, Lys_lPEG2_lPEG2_IsoGlu_C12, Ogl, Tba, or Vai;X2 is 2Pal, 3Pal, Agb, Agp, Cit, Dab_Ac, Dab2HyAc, DabMs, DabTs, dDab2HyAc, Gin, Glu, His, hR, Hse, Lys, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, LysNs, LysTs, OrnAc, Orn2HyAc, OmMs, OrnPVA, OmTs, Phe_2Ad, Phe_3Ad, Phe_4_Morph, Phe_4Ad, Phe_4COOH, Phe_4Guan, Phe_4OMe, Phe_pentaF, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl, Thi, or Thr;X3 is AlaCF3, AlaCHF2, Ala_cycBu, Aoc, Cha, Chg, Cpg, cyclopentyl_Ala, cyclopropyl_Ala, Cys, dV, H_Cha, Hey, Hph, Igl, nVF3, Ogl, Phe_34diCl, Phe_4CF3, Phe_4Cl, Phe_4Me, Phe_4OMe, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, His, hE, hR, Lys_Me3, Phe4_COOH, Thr, or Thr_Me;X5 is Abu, Cys, Cha, Chg, Dab_Acetyl, Glu, Hey, hE, Hhc, He, Lys, Lys_Ac, LysN3, LysPhAc, O2S, O3S, O3S_Reduced, O4S, O4S_Reduced, Om_Acetyl, or Pen;X6 is 4RBenzyloxyPro, 4RPhePro, 4S_Amp_Cyclohex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4SCyclohexPro, 5RPhePro, Azetidinone, Hpr, Oic, or Pro;X7 is Ala, Acvc, Aib, aMe_Phe, Arg, Cys, Gin, Glu, His, hR,Lys_ 1 PEG2_ 1 PEG2_Ahx_C 18_diacid, Lys_ 1 PEG2_ 1 PEG2_IsoGlu_C 12,Lys_lPEG2_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_Ac, O3S_Me, Oic, Pro, Ser, or TbaX8 is aMe_Glu, Asp, dD, Gia, Glu, Phe_3COOH, Phe_4COOH, Tetl, or Tet2;X9 is Aoc, Dgl, Hey, Leu, O3S, O3S_Reduced, or Ogl;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Cys, Hph, Lys_lPEG2_lPEG2_IsoGlu_C12, Phe_4COOH, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, Trp_7Phe, or Trp;XI 1 is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Cys, Chg, Gin, Glu, Leu, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Me3, O3S_Me, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie;X12 is INal, aMe_Trp, Om_Bz, Trp, Trp_56diCl, Trp_56diMe, Trp_5Br, Trp_5Cl, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, or Trp6Me;X13 is Abu, aMe_Cys, aMe_Lys_Ac, Cys, Cha, Dab_Acetyl, Glu, Hey, hE, Hhc, He, Lys, Lys_Ac, LysN3, O2S, O3S, O3S_Me, O3S_Me_Reduced, O3S_Reduced, O4S, O4S_Reduced, Orn_Acetyl, or Pen;X14 is Asn, dK, dR, Lys, Lys_Ac, Lys_PEG4_lPEG2_NH2, Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, Orn_ Acetyl, or PEG12;X15 is dR, dK, Lys, Lys_PEG4_PEG4_NH2, or Lys_Dimethyl, or absent;X16 is dK, Lys, Lys_Ac, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_lsoGlu_Palm, Lys_PEG4_PEG4_NH2, or absent;wherein:(i) the monomer comprises a cyclic structure wherein two amino acid residues in the peptide monomer are directly covalently linked or indirectly covalently linked through a through an amide bond, a disulfide bond, a thioether bond, a carbon-carbon single bond, or a carboncarbon double bond, wherein the two amino acid residues are at X5 and XI 3, X7 and XI 1 , X9 and X13, or X10 and X14; and(ii.a) each monomer is directly covalently linked to a polyethylene glycol (PEG) linker at X14, X15, or X16 through an amide bond, wherein the PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25, and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or (ii.b) each monomer is directly covalently linked to a DIG_linker (diglycolic acid linker) at X14, X15, orX16 through an amide bond, where X14, X15, or X16 is Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2.(Formula (II).)

[0071] In another aspect, the invention provides a Formula (II) monomer that is not part of a homodimer compound. In this aspect, because X14Lys (or X15Lys or X16Lys) is often a residue that mediates dimerization, it can be substituted with another amino acid, for example, any of the residues listed at X14 in Formula (I). In some aspects, for a Formula (II) monomer that is not part of a homodimer compound, X14 is Asn or Lys_Ac.

[0072] In others aspects of Formula (II), the HEK Blue human IL- 17 assay is a human IL-17AA, human IL-17AF, or human IL-17FF assay.

[0073] For the following Formula (II) sub-formulas, i.e., Formula (ILA) et al., R1 and R2 are the moieties specified for Formula (II) above.

[0074] In another aspect, for a Formula (II) homodimer, the cyclic structure of each monomer comprises two amino acid residues directly covalently linked through a disulfide bond at: (a) X5 and X13, wherein X5 is Hhc and X13 is Hhc; or (b) X9 and X13, wherein X9 is Hey and X13 is Hhc.

[0075] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (ILA):R 1 -X00-X0-X 1 -X2-X3 -X4-X5 -X6-X7-X8-X9-X 10-X11 -X 12-X13-X14-X 15-X16-R2, wherein:R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH or absent,X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Chg, He, Lys_lPEG2_lPEG2_IsoGlu_C12, Ogl, or Vai;X2 is 2Pal, 3Pal, Agb, Agp, Dab_Acetyl, Dab_2HyAc, Dab_Ms, Dab_Ts, dDab_2HyAc, Gin, Glu, His, hR, Hse, Lys, Lys_lPEG2_lPEG2_C18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, LyslPEG2Ac, Lys2HyAc, LysMs, LysTs, OrnAc, OrnMs, OmTs, Phe_2Ad, Phe_3Ad, Phe_4Ad, Phe_4Guan, Q_NHMe, Q_NMe2, Q_Pyro, Tetl, or Thr;;X3 is Ala_cycBu, Aoc, Cha, Chg, Cpg, cyclopropyl_Ala, dV, H_Cha, Hph, Igl, Ogl, Phe_34diCl, Phe_4CF3, Phe_4Cl, Phe_4Me, Phe_4OMe, Phe_4tBu, Tba, Tie, or Vai;X4 is Glu, hR, or Thr;X5 is Hhc;X6 is Oic or Pro;X7 is Ala, Acvc, aMe_Phe, Gin, Glu, His, hR, Lys_Ac, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, dD, Gia, Glu, Tetl, or Tet2;X9 is Leu or Ogl;X10 is INal, aMe_Trp, Trp_7Phe, or Trp;XI 1 is aMe_Phe, Asp, or Glu;X12 is aMe_Trp, Trp_5Br, Trp_5Cl, Trp_5Me, Trp_6Cl, Trp_6Me, or Trp;X13 is Hhc;X14 is Asn, dR, dK, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Ly s_PEG4_PEG4_NH2 ;X15 is dR, Lys, or absent;XI 6 is absent;wherein: (a) X5 and XI 3 are directly covalently linked through a disulfide bond; wherein each monomer is directly covalently linked to a PEG linker at X14 or X15 through an amide bond, and (b) X14 or XI 5 is dK or Lys, and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or X2 is dK or Lys and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or X14 is Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, or Lys_PEG4_lPEG2_NH2, and wherein one monomer is linked to one terminal end of a DIG_Linker and the other monomer is linked to the other terminal end of the DIG_Linker. (Formula (II. A)).

[0076] In related aspects of Formula (ILA), Hhc at X5 and / or X13 can be substituted with another amino acid having a free thiol in its side-chain, such as Cys, Hey, Pen, HhPen, their D-forms, and their a-methyl variants.

[0077] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.B):R1 -X00-X0-X 1 -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X 11 -XI 2-X 13-X 14-X15-X 16-R2, wherein: R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; XOO is dH or absent, XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is His or Lys_Me3; X3 is Tba or Vai; X4 is Thr; X5 is Chg, lie, or Tie; X6 is Azetidinone, Oic, or Pro; X7 is Ala; X8 is Asp or Gla; X9 is Hey; X10 is Trp; XI 1 is Asp or Glu; X12 is Trp; X13 is Hhc; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; XI 5 is dR; XI 6 is absent; wherein: (i) the cyclic structure of each monomer comprises X9 and XI 3 that are directly covalently linked through a disulfide bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.B)).

[0078] In related aspects of Formula (II.B), Hey at X9 and / or Hhc at X13 can be substituted with another amino acid having a free thiol in its side-chain, such as Cys, Hey, Pen, HhPen, their D-forms, and their a-methyl variants.

[0079] In another aspect, for a Formula (II) homodimer, the cyclic structure of each monomer comprises two amino acid residues directly covalently linked through a thioether bond at: (a) X5 and X13, wherein X5 is Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, LysPhAc, Om_Acetyl, or Pen, and X13 is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, Om_Acetyl, or Pen; (b) X7 and XI 1, wherein X7 is Cys or Lys_Ac and XI 1 is Cys or Lys_Ac; or (c) X10 and X14, wherein X10 is Cys and X14 is Lys_Ac or Orn_Acetyl; and wherein aMe_Cys, Cys, Hey, Hhc, or Pen is paired with aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Om_Acetyl, and vice versa.

[0080] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.C):R1-X00-X0-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-X12-X13-X14-X15-X16-R2, wherein:R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Chg, He, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, Ogl, or Vai; X2 is 2Pal, 3Pal, Agb, Agp, aMe_Arg, Cit, Dab_Ac, Dab2HyAc, DabMs, DabTs, dDab2HyAc, Gin, Glu, His, hR, Hse, Lys, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, Lys_Ac, Lys_Dimethyl, Lys_Me3, LyslPEG2Ac, Phe_4_Morph, Phe_4COOH, Phe_4OMe, Phe_pentaF, Thr, or Thi; or Thr;X3 is Cha, H_Cha, Ogl, Phe_4tBu, Tba, or Tie, or Vai;X4 is Asn, Gin, Glu, His, Phe_4COOH, Thr, or Thr_Me;X5 is Cys, Dab_Acetyl, Hey, Lys_Ac, LysPhAc, Om_Acetyl, or Pen;X6 is Oic, or Pro;X7 is Aib, Ala, Arg, His, Lys_lPEG2_lPEG2_Ahx_C18_Diacid, Lys_lPEG2_lPEG2_lsoGlu_C18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Ogl;X10 is INal, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe;XI I is aMe_Asp, Asp, Gin, or Glu;X12 is Trp, Trp_56diCl, Trp_56diMe, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, or Trp_6Me;X13 is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, Om_Acetyl, or Pen; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2;X15 is dR;XI 6 is absent;wherein: (i) the cyclic structure of each monomer comprises X5 and X13 that are directly covalently linked through a thioether bond; wherein aMe_Cys, Cys, Hey, Hhc, or Pen is paired with aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Orn_Acetyl, and vice versa;and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker or each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG8_NH2, or X14Lys_PEG4_lPEG2_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II.C)).

[0081] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.D):R’-XOO-XO-X I -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein: R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, lie, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is His, Lys_Me3, or Thr; X3 is Tba, Tie, or Vai; X4 is Thr or Glu; X5 is He; X6 is Oic or Pro; X7 is Cys or Lys_Ac; X8 is Asp; X9 is Leu or Ogl; XI 0 is Trp or INal; XI 1 is Cys or Lys_Ac; X12 is aMe_Trp or Trp; X13 is He; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; X16 is absent; wherein X7 and XI 1 are not both Cys or Lys_Ac; and wherein: (i) the cyclic structure of each monomer comprises X7 and XI 1 that are directly covalently linked through a thioether bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker or each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, X14Lys_PEG8_NH2, throughan amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II.D).)

[0082] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.E):R'-XOO-XO-X I -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein: RI is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is Thr or Lys_Me3; X3 is Tba or Tie; X4 is Thr or Glu; X5 is Chg or He; X6 is Oic or Pro; X7 is Ala; X8 is Asp; X9 is Ogl; X10 is Cys; XI 1 is Asp or Glu; X12 is Trp; X13 is He; X14 is Lys or Om_Ac; X15 is dR; X16 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; wherein: (i) the cyclic structure of each monomer comprises XI 0 and XI 4 that are directly covalently linked through a thioether bond; and (ii) each monomer is directly covalently linked to a PEG linker at X16Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X16Lys_PEG4_PEG4_NH2, X16Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.E)).

[0083] In other aspects, the cyclic structure of a monomer of Formula (II) comprises the two amino acid residues directly covalently linked through: (a) a carbon-carbon single bond (-C-C-) at X5 and X13, X9-X13, X7-X11, or X10-X14, wherein the residues of these pairs are individually or both O3S_Reduced, O3S_Methyl_Reduced, or O4S_Reduced; or (b) a carbon-carbon double bond (-C=C-) at X5 and X13, X9-X13, X7-X11, or X10-X14, wherein the residues of these pairs are individually or both O2S, O3S, O4S, O3S_methyl, or O4S_Methyl.

[0084] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.F):R'-XOO-XO-X I-X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He, Vai, or Tba; X2 is Gin, His, Hse, Lys_Me3, or Thr; X3 is cyclopropyl_Ala, Tba, Tie, or Vai; X4 is Glu or Thr; X5 is O3S_Reduced or O4S_Reduced; X6 is Pro or Oic; X7 is Ala; X8 is Asp or Gia; X9 is Ogl; X10 is INal or Trp; XI 1 is Asp or Glu; X12 is Trp or Trp5Me; X13 is O3S_Reduced, O3S_Methyl_Reduced, O4S_Reduced; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; XI 5 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and XI 3 that are directly covalently linked through a carbon-carbon single bond (-C-C-); and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (ILF)).

[0085] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.G):R’-XOO-XO-X I -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 1 -X 14-X 15-X 16-R2, wherein R1 is acetyl, 3 -hydroxy propionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is Chg, Vai, or He; X2 is His, Lys_Me3, or Thr; X3 is Ogl, Vai, Tba, or Tie; X4 is Thr or Glu; X5 is lie or Chg; X6 is Oic or Pro; X7 is O3S_Me; X8 is Asp or Gia; X9 is Ogl; X10 is INal or Trp; XI 1 is O3S_Me; X12 is Trp; X13 is He; X14 is Asn; X15 is dR; and X16 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; wherein: (i) the cyclic structure of each monomer comprises X7 and XI 1 that are directly covalently linked through a carbon-carbon double bond (-C=C-); and (ii) each monomer is directly covalently linked to a PEG linker at X16Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X16Lys_PEG4_PEG4_NH2, X16Lys_PEG4_lPEG2_NH2, X16Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II. G)).

[0086] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.H):R '-X00-X0-X I -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein R1 is acetyl, 3 -hydroxy propionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is Chg, Vai, or He; X2 is His, Lys_Me3, or Thr; X3 is Ogl, Tba, Tie, or Vai; X4 is Thr or Glu; X5 is Chg or lie; X6 is Oic or Pro; X7 is Ala or Cys; X8 is Asp or Gia; X9 is O3S; X10 is Trp or INal; XI 1 is Asp, Glu, or Lys_Ac; X12 is Trp; X13 is O3S; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2; X15 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X9 and XI 3 that are directly covalently linked through a carbon-carbon double bond (-C=C-); and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II.H)).

[0087] In another aspect of Formula (II), each monomer of the dimer has a cyclic structure comprising two amino acid residues with a side-chain comprising a free thiol that are indirectly covalently linked through: a thioether bond with a Butane_Linker, a Carbonyl_Linker, aDimethylcyclopropane_Linker, an Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, an mXylene_Linker, a pXylene_Linker, or an oXylene_Linker. at: (a) X5 and XI 3, wherein the residues are individually or both, Cys, Hey, Hhc, or Pen, and with any of the linkers listed above or with any alkane or alkene linker with suitable ends or two suitable free chemical groups that can each react with a free thiol to form a thioether bond (or relative to the linker - a bis- or dithioether bond); (b) X7 and XU, wherein both X7 and XI 1 are Cys, and with the a Xylene linker, or (c) X7 and XI 1, wherein X7 and XI 1 are individually or both Cys or Hey and with the Propane_Linker.

[0088] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.I):R1-X00-X0-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-X12-X13-X14-X15-X16-R2, wherein:wherein: R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, lie, Lys_Me3, Sar, Tie, or absent; XI is Cha, Cyclopropyl_Ala, DIP, He, Tba, or Vai; X2 is Gin, His, Hse, Lys_Me3, Lys_Dimethyl, Lys_PEG2_Me3, Lys2HyAc, LysMPA, LysNs, Orn_Ac, Orn2HyAc, OmPVA, Phe_2Ad, Phe_3Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, or Tetl ; X3 is AlaCF3, AlaCHF2, cyclopentyl_Ala, cyclopropyl_Ala, nVF3, Tba, Tie, or Vai; X4 is Asn, Glu, Glu_OMe, hE, Lys_Me3, Phe_4COOH, or Thr; X5 is Cys, Hey, or Pen; X6 is 4RBenzyloxyPro, 4RPhePro, 4S_Amp_Cyclohex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4SCyclohexPro, 5RPhePro, Oic, or Pro; X7 is Ala, Gin, His, Lys_lPEG2_lPEG2_IsoGlu_C18_diacid, Lys_Ac, Oic, or Pro; X8 is Asp, Gia, Glu, Phe 3COOH, or Phe 4COOH; X9 is Aoc, Dgl, or Ogl; X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Hph, Phe_4COOH, or Trp; XI 1 is Aib, Ala, Asn, Asp, aMe_Leu, aMe_Phe, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie; X12 is INal, aMe_Trp, Om_Bz, Trp_6Cl, or Trp; X13 is Cys, Hey, or Pen; X14 is dK, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; XI 5 is dR; and XI 6 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and XI 3 that are indirectly covalently linked through a thioether bond with a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene linker, a Hexane_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane linker, an oXylene linker, an mXylene linker, or a pXylene_ linker; and (ii) each monomer is directly covalently linked to a PEG linker at XI 4 through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.I)).

[0089] In one aspect, for a Formula (II) homodimer, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II. J):R'-X00-X0-X l-X2-X3-X4-X5-X6-X7-X8-X9-X I0-X I I -X I 2-X 13-X I4-X I 5-X I6-R2, wherein R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is lie or Vai; X2 is His, Lys_Me3, or Thr; X3 is Tie or Vai; X4 is Glu or Thr; X5 is He; X6 is Pro or Oic; X7 is Cys; X8 is Asp or Gia; X9 is Leu or Ogl; X10 is INal or Trp; XI 1 is Cys or Hey; X12 is Trp; X13 is He; X14 is Asn, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; and X16 is Lys, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or absent; wherein: (i) the cyclic structure of each monomer comprises X7 and XI 1 that are indirectly covalently linked through a bis-thioether bond with the a Xylene linker (m-, o-, or p-) or a Propane_Linker; and(ii) each monomer is directly covalently linked to a PEG linker at X 14 or X 16 through an amide bond when X14 or X16 is Lys, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at XI 4 or XI 6, through an amide bond, wherein X14 or X16 is Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II. J)).

[0090] In some aspects, a homodimer compound of the invention lacks an amino acid at X00 and X0 positions.

[0091] In some aspects, a homodimer compound of the invention lacks an amino acid at X00. In another aspect, a homodimer compound of the invention can have, or can be modified to have, isovaleric acid at Rl, dH at X00 and dE at X0.

[0092] In other aspects, a homodimer compound of the invention has a dimerization linker that is a PEG linker, which can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, PEG25DA, or a PEG linker comprising greater than 25 PEG units.

[0093] In other aspects, a homodimer compound of the invention exhibits an ICso value of less than about 20 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, in a human IL- 17 HEK Blue assay.

[0094] In other aspects a homodimer compound of the invention exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours in an SGF and / or SIF stability assay.

[0095] In other aspects, for any of the homodimers of Formula (II), which includes Formula (II. A et al.), R1 and R2 are the same as for Formula (I).

[0096] In one aspect, the invention provides a peptide compound that has an IC50 less than 10 nM for each of hIL- 17 AA, hIL- 17 AF, and hIL- 17FF, or at least for each of hIL- 17 AA and hlL-17FF, in a human IL- 17 AA, AF, and / or FF HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (III): R1- X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2, wherein:R1 is lPip_AceticAcid, acetyl, 3 -hydroxy propionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, Mor_propanoic_acid, or absent; R2 is NH2 or OH or absent;X00 is Cha, dH, Tie, or absent;X0 is 2Pal, Asn, d2Pal, dE, dH, dQ, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, NMe_His, Om, Sar, Tie, or absent;XI is INal, Cha, Cyclopropyl_Ala, Dgl, DIP, hCha, hF, hhF, He, Ogl, Phe_4Me, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, Gin, Glu, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, Om_Ac, Orn2HyAc, OrnAc, OrnMs, OrnPVA, Phe_2Ad, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl, or Thr;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, hE, His, LysMe3, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, Lys_Ac, LysN3, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen;X6 is 4SCF3Pro, 4SCyclohexPro, Oic, or Pro;X7 is Acvc, Ala, Dab, Gin, Glu, His, Hpr, hR, Lys_Ac, Oic, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Aoc, Dgl, or Ogl;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, hCha, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe;XI 1 is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, O3S, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie;X12 is aMe_Trp, Trp, Trp_56diCl, Trp_5Cl, Trp_5Me, or Trp_6Cl;X13 is Abu, Cys, Dab_Acetyl, Hey, Hhc, O2S, O3S, O3S_Reduced, 03S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen;X14 is Aib, Asn, Cys, dK, dL, dN, dQ, dR, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, Tba, or absent; XI 5 is dR, dE, or absent;X16 is dE, dQ, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (III)).

[0097] In one aspect of Formula (III), both X5 and XI 3 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[0098] In another aspect of Formula (III), X5 is Lys_Ac and XI 3 is Cys, or X5 is Hhc and X13 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[0099] In another aspect of Formula (III), X5 is Lys_Ac and X13 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00100] In another aspect of Formula (III), X5 is Lys and X13 is hE (or vice versa), and these two residues are directly covalently linked through an amide bond (lactam).

[00101] In another aspect of Formula (III), X5 is LysN3 and X13 is Abu (or vice versa), and these two residue are directly covalently linked as shown in paragraph

[00324] .

[00102] In another aspect of Formula (III), X5 and X13 are individually or both O2S, O3S, O3S_Methyl, or O4S, and these two residues are directly covalently linked through a carboncarbon double bond.

[00103] In another aspect of Formula (III), X5 and X13 are individually or both O3S_Reduced, O3S_Me_Reduced, O4S_Reduced, or O5S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00104] In another aspect of Formula (III), X5 and X13 are both, or individually, Hey, Cys, Hhc, or Pen, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, or a Propane_Linker.

[00105] In another aspect of Formula (III), X5 and X13 are both, or individually, Hey, Cys, Hhc, or Pen, wherein X5 and X13 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a Xylene_Linker.

[00106] In other aspects of Formula (III), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at XI 4 through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, and wherein X14 is Lys or dK. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA. In another aspect, the PEG linker can comprise a linear structure with a COOH group at each terminal end and between 15-25 PEG units.

[00107] In other aspects of Formula (III), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14 through an amide bond, wherein one monomer is linked to one terminal end of the DIG_linker and the other monomer is linked to the other terminal end, and wherein XI 4 is Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2.

[00108] In one aspect of Formula (III), the compound exhibits an ICso value of less than about 5 nM, or 1 nM, in a human IL- 17 HEK Blue assay.

[00109] In other aspects of Formula (III), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or S1F stability assay.

[00110] In another aspect of Formula (III), R1 is acetyl, glutaric acid, or isovaleric acid, and R2 is an amine.

[00111] In one aspect, the invention provides a peptide compound that has an IC50 for hlL-17AA that is less than about InM and for ML-17FF that is less than about 10 nM in a human IL- 17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprises or consists of the sequence of Formula (IV):R'-X00-X0-X I-X2-X3-X4-X5-X6-X7-X8-X9-X I0-X I I -X I 2-X I 3-X I4-X I 5-X I6-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH, Tie, or absent;X0 is 2Pal, d2Pal, Asn, dE, dH, dQ, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, NMe_His, Om, Sar, Thr, Tie, or absent;XI is INal, Cha, Cyclopropyl_Ala, Dgl, DIP, hCha, hF, hhF, He, Ogl, Phe_4Me, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, E, Gin, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, OmAc, 0m2HyAc, OrnMs, OmPVA, Phe_2Ad, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl, or Thr;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, hE, His, LysMe3, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, Lys_Ac, LysN3, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen;X6 is 4SCF3Pro, 4SCyclohexPro, Oic, or Pro;X7 is Acvc, Ala, Dab, Gin, Glu, His, hR, Lys_Ac, Oic, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Aoc, Dgl, or Ogl;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, hCha, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4COOH, Trp_4Me, Trp_5CONH2, Trp_6CONH2, Trp_6Me, Trp_7Me, or Trp_7Phe;XI I is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Ser, Tba, or Tie;X12 is aMe_Trp, Trp, Trp_56diCl, Trp_5Cl, Trp_5Me, or Trp_6Cl;X13 is Abu, Cys, Dab_Acetyl, Hey, Hhc, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S, or Pen;X14 is Aib, Asn, Cys, dK, dN, dQ, dR, Gin, Lys, Lys_Ac, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, Tba, or absent;X15 is dE, dR, or absent; andXI 6 is dE, dQ, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (IV)).

[00112] In one aspect of Formula (IV), both X5 and XI 3 are both Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00113] In another aspect of Formula (IV), X5 is Lys_Ac and X13 is Cys, and these two residues are directly covalently linked through a thioether bond.

[00114] In another aspect of Formula (IV), X5 is Hhc and XI 3 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[00115] In another aspect of Formula (IV), X5 is O5S_Reduced and XI 3 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[00116] In another aspect of Formula (IV), X5 is O5S_Reduced and X13 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00117] In another aspect of Formula (IV), X5 is Lys and XI 3 is hE, or vice versa, and these two residues are directly covalently linked through an amide bond (lactam).

[00118] In another aspect of Formula (IV), X5 is LysN3 or Lys and X13 is Abu or hE, and these two residues are directly covalently linked as shown in paragraph

[00324] .

[00119] In another aspect of Formula (IV), both X5 and XI 3 are individually, or both, O3S_Reduced, O3S_Methyl_Reduced, or O4S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00120] In another aspect of Formula (IV), X5 and X13 are individually, or both, O2S, O3S, O3S_Me, or O4S, and these two residues are directly covalently linked through a carboncarbon double bond.

[00121] In another aspect of Formula (IV), X5 and X13 are individually, or both, Cys, Hey, Hhc, or Pen, wherein X5 and X13 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, or a pXylene_Linker.

[00122] In other aspects of Formula (IV), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00123] In another aspect of Formula (IV), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00124] In other aspects of Formula (IV), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00125] In one aspect, the invention provides a peptide compound that has an IC50 for hlL-17AA that is less than about InM and for hIL-17FF that is less than about 5 nM in a human IL- 17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide that comprises or consists of the sequence of Formula (V):R'-XOO-XO-X I-X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH, Tie or absent;X0 is dE, dH, dQ, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, Orn, Sar, Thr, Tie, or absent;XI is Cha, Cyclopropyl_Ala, Dgl, DIP, hhF, He, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, Gin, Glu, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, OmAc, Orn2HyAc, OmMs, OmPVA, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl, or Thr;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, hE, His, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, Lys_Ac, LysN3, 02S, 03S, 03S_Reduced, 03S_Me, 03S_Me_Reduced, 04S, 04S_Reduced, 05S_Reduced, or Pen;X6 is 4SCF3Pro or Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Oic, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Aoc, Dgl, or Ogl;X10 is INal, 2Nal, Aoc, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4COOH, Trp_6CONH2, Trp_6Me, Trp_7Me, or Trp_7Phe;XI 1 is Aib, Ala, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Ser, Tba, or Tie;X12 is aMe_Trp, Trp, Trp_56diCl, or Trp_6Cl;X13 is Abu, Cys, Dab_Acetyl, Hey, Hhc, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, or Pen;X14 Asn, dK, Gin, Lys, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or absent;X15 is dE, dR, or absent; andXI 6 is dE or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (V)).

[00126] In one aspect of Formula (V), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00127] In another aspect of Formula (V), X5 is Lys_Ac and XI 3 is Cys, and these two residues are directly covalently linked through a thioether bond.

[00128] In another aspect of Formula (V), X5 is Hhc and X13 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[00129] In another aspect of Formula (V), X5 is O5S_Reduced and X13 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00130] In another aspect of Formula (V), X5 is LysN3 andX13 is Abu, and these two residues are directly covalently linked as shown in paragraph

[00324] .

[00131] In another aspect of Formula (V), X5 is O2S, O3S, or O4S, and X13 is O2S, O3S, O4S, or O3S_Me, and these two residues are directly covalently linked through a carboncarbon double bond.

[00132] In another aspect of Formula (V), X5 is O3S_Reduced and XI 3 is O3S_Reduced or O3S_Me_Reduced, and these two residues are directly covalently linked through a carboncarbon single bond.

[00133] In another aspect of Formula (V), X5 is Cys or Hey, and XI 3 is Cys or Hey, wherein X5 and X13 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, an Oxetane_Linker, a Pentane_Linker, Propane_Linker, or a pXylene_Linker.

[00134] In other aspects of Formula (V), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00135] In another aspect of Formula (V), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at XI4Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00136] In other aspects of Formula (V), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00137] In one aspect, the invention provides a peptide compound that has an ICso for hlL-17AA that is less than about InM and for hIL-17FF that is less than about 1 nM in a human IL-17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (VI):R'-XOO-XO-X I-X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein:R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH or absent;XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Cyclopropyl_Ala, He, Tba, or Vai;X2 is Dab_Ac, Gin, Glu, His, Hse, Lys_Ac, Lys_Me3, LyslPEG2Ac, Lys2HyAc, LysMs, 0m2HyAc, OmAc, Q_NHMe, Q_NMe2, Q_EtOMe, or Thr;X3 is Cyclopropyl_Ala, Ogl, Tba, Tie, or Vai;X4 is Asn, Glu, Glu_OMe, hE, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, O2S, O3S, O3S_Reduced, or O4S;X6 is Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba;X8 is Asp or Gia;X9 is Dgl, or Ogl;X10 is INal, 2Nal, or Trp;XI I is Aib, Asp, or Glu;X12 is aMe_Trp or Trp;X13 is Cys, Hey, Hhc, O2S, O3S, O3S_Me, O3S_Me_Reduced, O3S_Reduced, or O4S;X14 Asn, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2;X15 is dR; andX16 is dE or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (VI)).

[00138] In one aspect of Formula (VI), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00139] In another aspect of Formula (VI), X5 is O2S, O3S, or O4S, and X13 is O2S, O3S, O4S, or O3S_Me, and these two residues are directly covalently linked through a carboncarbon double bond.

[00140] In another aspect of Formula (VI), X5 is O3S_Reduced and X13 is O3S_Reduced or O3S_Me_Reduced, and these two residues are directly covalently linked through a carboncarbon single bond.

[00141] In another aspect of Formula (VI), X5 is Cys or Hey, and X13 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, an Oxetane_Linker, a Pentane_Linker, or a Propane_Linker.

[00142] In other aspects of Formula (VI), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00143] In another aspect of Formula (VI), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG\8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00144] In other aspects of Formula (VI), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00145] In one aspect, the invention provides a peptide compound that has an IC50 for hlL-17AA that is less than about InM, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (VII):R1-X00-X0-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-X12-X13-X14-X15-X16-X17-X18- X 19-X20-X21 -X22-X23-X24-R2,wherein:R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glycolic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2 or OH or absent; X00 is bA, dH, dK, Tie or absent;X0 is 2Pal, Aib, Asn, d2Pal, d3Pal, dA, dE, dH, dL, dQ, dS, Gia, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, NMe_His, Orn, Pro, Sar, Thr, Tie, or absent;XI is INal, Aph, Dgl, hCha, hF, hhF, He, Lys_lPEG2_lPEG2_IsoGluC12, Ogl, Phe_4Me, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Gin, His, Hse, Lys_lPEG2_lPEG2_IsoGluC12, Lys_Me3, Orn, Phe_3Ad, Phe_4_2ae, or Phe_4ad;X3 is Cpg, Cyclopropyl_Ala, Dgl, Ogl, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Glu, or Thr;X5 is Cys, Hey, Hhc, He, Lys_Ac, O3S, O3S_Reduced, or O5S_Reduced;X6 is Oic or Pro;X7 is Ala, Aze, Dab, His, Lys_Ac, O3S_Me, or Tic;X8 is Asp or Gia;X9 is Dgl, Ogl, or O3S;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, Gin, hCha, Hph, O3S, Phe_4Ad, Phe_4COOH, Tba, Tie, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5Me, Trp_6Cl, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe;XI I is Asp, dA, Glu, or O3S_Me;X12 is aMe_Trp, Trp, Trp_5Cl, Trp_5Me, or Trp_6Cl;X13 is Cys, Hey, Hhc, He, O3S, O3S_Me, O3S_Reduced, or O4S;X14 Aib, Arg, Asn, Asp, Cys, dE, dK, dN, dQ, dR, Glu, Gin, Gly, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, O3S_Me, Tba, or absent;X15 is Ala, Asn, dE, dR, dQ, Gin, Gly, Leu, Pro, Ser, or absent;XI 6 is Aad, dE, dH, dQ, PEG4, PEG6, PEG8, Ser, Thr, Vai, or absent;X17 is Asp, Gly, Glu, His, He, Pro, or absent;XI 8 is His, He, Ser, Tie, Vai, or absent;X19 is His, lie, Vai, or absent;X20 is His, Thr, Vai, or absent;X21 is He, Thr, Vai, or absent;X22 is He, Thr, or absent;X23 is He or absent;X24 is Oic, Pro, or absent;wherein the peptide comprises a cyclic structure wherein X5 and X13, X9 and X13, or X7 and XI 1, are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker.(Formula (VII)).

[00146] In one aspect of Formula (VII), the peptide compound consists of a monomer (i.e., not a multimer).

[00147] In one aspect of Formula (VII), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00148] In one aspect of Formula (VII), X5 is Lys_Ac and XI 3 is Cys, and these two residues are directly covalently linked through a thioether bond.

[00149] In one aspect of Formula (VII), X5 is O5S_Reduced and XI 3 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00150] In another aspect of Formula (VII), both X5 and X13 are O3S, or X5 and X13 are individually or both O3S, O4S, or O3S_Methyl, and these two residues are directly covalently linked through a carbon-carbon double bond.

[00151] In another aspect of Formula (VII), both X5 and XI 3 are O3S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00152] In another aspect of Formula (VII), X5 is Cys or Hey, and X13 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, Dimethylcyclopropane_Linker, an EButene_Linker, a Hexane_Linker, a Methyl ene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, or a Xylene_Linker.

[00153] In another aspect of Formula (VII), X9 and X13 are both O3S, which are directly covalently linked through a carbon-carbon single bond.

[00154] In another aspect of Formula (VII), X7 and XI 1 are both O3S_Me, which are directly covalently linked through a carbon-carbon double bond.

[00155] In other aspects, a peptide of Formula (VII) can be a monomer in a homodimer compound. As described herein, the monomer can be dimerized in multiple ways, such as having a lysine at a residue at X14-X16, which can be covalently attached to a PEG linker through an amide bond, or having a lysine with a modified side-chain that comprises PEG units and a free amine, such that the amine can form an amide bond with a linker having free COOH groups, such as the DIG_Linker.

[00156] In other aspects of Formula (VII), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00157] In another aspect of Formula (VII), the compound has an IC50 for hlL-17AA that is less than about InM and an IC50 for hIL-17FF that is less than about 10 nM, wherein the peptide comprises the following:R1 is acetyl, glutaric acid, glycolic acid, or isovaleric acid; R2 is NH2;X00 is bA or absent;X0 is 2Pal, d2Pal, dE, dH, Gia, Glu, His, NMe_His, Tie, or absent;XI is INal, Aph, Dgl, hF, hhF, He, Tie, or Vai;X2 is 2Pal, 3Pal, or His;X3 is Tba or Tie;X4 is Thr;X5 is Cys, Hey, Hhc, or O3S;X6 is Oic;X7 is Ala or Lys_Ac;X8 is Asp;X9 is Dgl or Ogl;X10 is Cys, Trp, Trp_7Me, or Trp_7Phe;XI 1 is Asp or Glu;X12 is aMe_Trp or Trp;X13 is Hey, Hhc, O3S, O3S_Me, or O4S;X14 Aib, Asn, Asp, Cys, Gin, Gly, Lys_lPEG2_lPEG2_IsoGlu_C12, or Lys_Ac;X15 is Ala, Asn, dQ, dR, Gin, Gly, Leu, Ser, or absent;X16 is Aad, dE, Ser, Thr, Vai, or absent;X17 is Asp, His, or absent; andXI 8 is Ser, Vai, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker.

[00158] In another aspect of Formula (VII), the compound has an IC50 for hIL-17AA that is less than about InM and an IC50 for hIL- 17FF that is less than about 10 nM, and the compound exhibits a half-life in both an SGF and an SIF assay greater than about 2 hours, wherein the peptide comprises the following:R1 is acetyl, glutaric acid, glycolic acid, or isovaleric acid; R2 is NH2;X00 is bA or absent;X0 is 2Pal, d2Pal, dE, dH, Glu, His, NMe_His, Tie, or absent;XI is INal, Aph, Dgl, hF, hhF, He, Tie, or Vai;X2 is 2Pal, 3Pal, or His;X3 is Tba or Tie;X4 is Thr;X5 is Cys, Hey, Hhc, or O3S;X6 is Oic;X7 is Ala or Lys_Ac;X8 is Asp;X9 is Dgl or Ogl;X10 is Cys, Trp, Trp_7Me, or Trp_7Phe;XI I is Asp or Glu;X12 is aMe_Trp or Trp;XI 3 is Hey, Hhc, O3S, 03S_Me, or O4S;X14 Aib, Asn, Cys, Gin, Lys_lPEG2_lPEG2_IsoGlu_C12, or Lys_Ac;X15 is Ala, dQ, dR, Gin, or absent;X16 is Aad, dE, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker.

[00159] In one embodiment of Formula (VII), X17-X24 are absent.

[00160] In one embodiment of Formula (VII), X19-X24 are absent.

[00161] In one aspect, the invention provides a peptide compound that has an IC50 for hlL-17AA and FF that is less than about InM, wherein the peptide compound exhibits a half-life in an SIF assay greater than about 2 hours, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (VIII):R1 -X00-X0-X 1 -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X 11 -XI 2-X 13-X 14-X15-X 16-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH or absent;X0 is dE, dH, Gin, Glu, His, He, Lys_Me3, Sar, Tie, or absent;XI is Cyclopropyl_Ala, He, Tba, or Vai;X2 is Dab_Ac, Gin, His, Lys_Ac, Lys_Me3, LyslPEG2Ac, Lys2HyAc, Orn2HyAc, OrnAc, or Thr;X3 is Cyclopropyl_Ala, Ogl, Tba, Tie, or Vai;X4 is Asn, Glu, Glu_OMe, hE, or Thr;X5 is Cys, Hey, Hhc, O2S, O3S, O3S Reduced, or O4S;X6 is Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba;X8 is Asp or Gia;X9 is Dgl, or Ogl;XIO is INal, 2Nal, or Trp;XI 1 is Aib, Asp, or Glu;XI 2 is aMe_Trp or Trp;X13 is Cys, Hey, Hhc, O2S, O3S, 03S_Me, O3S_Reduced, or O4S;X14 is Asn, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2;X15 is dR; andXI 6 is absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein the peptide is optionally a monomer in a homodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker.(Formula (VIII)).

[00162] In one aspect of Formula (VIII), both X5 and XI 3 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00163] In another aspect of Formula (VIII), X5 and X13 are individually, or both, O2S, O3S, O3S_Me, or O4S, and these two residues are directly covalently linked through a carboncarbon double bond.

[00164] In another aspect of Formula (VIII), X5 is O3S_Reduced and X13 is O3S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00165] In another aspect of Formula (VIII), X5 is Cys or Hey, and XI 3 is Cys or Hey, wherein X5 and X13 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Dimethylcyclopropane_Einker, an Oxetane_Einker, a Pentane_Einker, or a Propane_Einker.

[00166] In other aspects of Formula (VIII), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00167] In another aspect of Formula (VIII), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker atX14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00168] In other aspects of Formula (VIII), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF stability assay.

[00169] In one aspect, the invention provides a peptide compound that has an IC50 for hlL-I7AA that is less than about 1 nM and for IL-17FF that is less than about 5nM, wherein the peptide compound exhibits a half-life in both an SGF and an SIF assay greater than about 2 hours, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (IX):R '-X00-X0-X I -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2 or OH or absent;X00 is dH or absent;X0 is dE, dH, Glu, His, lie, Lys_Me3, Sar, Tie, or absent;XI is He or Vai;X2 is His, Lys_Me3, or Gin;X3 is Tba, Tie, or Vai;X4 is Asn, Glu, Glu_OMe, hE, or Thr;X5 is Cys, Hey, Hhc, O3S, or O3S_Reduced;X6 is Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba;X8 is Asp or Gia;X9 is Dgl or Ogl;X10 is INal, 2Nal, or Trp;XI I is Aib, Asp, or Glu;X12 is aMe_Trp or Trp;X13 is Cys, Hey, Hhc, O3S, O3S_Me, or O3S_Reduced;X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_ NH2;X15 is dR; andXI 6 is absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is a monomer in a homodimer complex, wherein each monomer is covalently linked to a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (IX)).

[00170] In one aspect of Formula (IX), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00171] In another aspect of Formula (IX), X5 is O3S, and X13 is O3S or O3S_Me, and these two residues are directly covalently linked through a carbon-carbon double bond.

[00172] In another aspect of Formula (IX), X5 is O3S_Reduced and X13 is O3S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00173] In another aspect of Formula (IX), X5 is O5S_Reduced and X13 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00174] In another aspect of Formula (IX), X5 is Cys or Hey, and X13 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Dimethylcyclopropane_Linker, a Pentane_Linker, or a Propane_Linker.

[00175] In other aspects of Formula (IX), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys or X14dK through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00176] In another aspect of Formula (IX), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2 (or its D-form, i.e., dK_PEG4_PEG4_NH2 et al.) through an amide bond, wherein one monomer islinked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00177] In another aspect of Formula (IX), the peptide has an IC50 less than 1 nM in a HEK Blue human IL-17FF assay.

[00178] In other aspects of the invention, a peptide can be a monomer in a homotrimer compound, and wherein the monomer has a modified lysine with a side-chain comprising at least one PEG unit and a free amine, such as Lys_PEG4_PEG4_NH2, Lys_PEG4_lNH2, Lys_PEG8_NH2, Lys_PEG10_NH2, or Lys_PEG12_NH, at X14, X15, or X16. The modified lysine residue in each monomer is covalently linked to the same multimerization linker (e.g., TAEP linker) with at least three free COOH groups, such that the COOH groups and the free amine in the modified lysine side-chains can form an amide bond. The PEG 12 portion can be modified to increase or decrease the number of PEG units.

[00179] In other aspects of the invention, a peptide can be a monomer in a homotetramer compound with Lys_Hexy at X14, X15, or X16, and wherein the methyl at the terminal end of the side chain of Lys_Hexy residue in each monomer is covalently linked to the same multimerization linker, TetN3, through a carbon-carbon single bond.

[00180] In other aspects, the invention provides a peptide compound comprising a sequence of any one of SEQ ID NO: 1-720 and / or having the two-dimensional chemical structure as encoded by a SMILES formula as listed in Figure 1.

[00181] In one aspect, the invention provides a pharmaceutical composition comprising a peptide of any one of the Formulas herein (including SEQ ID NO formulas), any of the peptide compounds of Figure 1 (i.e., compounds 1-897) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[00182] In another aspect, the invention provides a method of inhibiting the binding of a human IL- 17 cytokine to a human IL- 17 receptor, the method comprising contacting the human IL- 17 cytokine with a peptide of any one of the Formulas herein (including SEQ ID NO formulas), or any one of the compounds of Figure 1 (i.e., compounds 1-897), or a pharmaceutically acceptable salt or solvate thereof.

[00183] In one aspect, the invention provides a method for treating an IL- 17 related inflammatory disease or an autoimmune disease in a subject, the method comprising: administrating to the subject an effective amount of a peptide of any one of the Formulas herein (including SEQ ID NO formulas). The inflammatory disease or autoimmune disease can be, for example, psoriasis, plaque psoriasis, generalized pustular psoriasis, psoriatic erythroderma, psoriatic arthritis (including moderate to severe psoriatic arthritis) , rheumatoid arthritis, ulcerative colitis, hidradentis suppurativa, spondyloarthritis (SpA), SpA types including ankylosing spondylitis, axial spondyloarthritis, enteropathic spondyloarthritis, peripheral spondyloarthritis, psoriatic arthritis, reactive arthritis, , or nonradiographic axial spondyloarthritis.

[00184] In one aspect, the present disclosure provides a peptide comprising the sequence set forth in one of the SEQ ID NO sequence formulas listed in Figure 1.

[00185] In another aspect, the present disclosure provides a peptide compound as described by its SMILES formula as listed in Figure 1.

[00186] In another aspect, the present disclosure provides a peptide compound having the two-dimensional chemical structure encoded by its SMILES formula as listed in Figure 1.

[00187] In another aspect, the present disclosure provides a peptide compound having the two-dimensional chemical structure as shown in Figure 6.

[00188] In one aspect, the present disclosure provides a method for treating a human IL- 17 related disease or disorder in a subject by administering a peptide compound comprising the two-dimensional chemical structure as shown in Figure 6.

[00189] In one aspect, the present disclosure provides a method for treating a human IL- 17 related disease or disorder in a subject by administering a peptide compound comprising a sequence set for in one of the SEQ ID NO sequence formulas listed in Figure 1 or as described by its SMILES formula as listed in Figure 1.BRIEF DESCRIPTION OF THE FIGURES

[00190] Figure 1. Figure 1.1-1.245 provides a summary table for over 800 different peptide based compounds of the invention. These are representative compounds that exhibit potency in inhibiting human IL- 17 cytokine biological activity. All of the peptide compounds described in Figure 1 have an IC50 less than or equal to 20 nM in a human IL- 17 HEK Blue Assay.

[00191] Figure 1 provides three rows of information for each peptide compound. Each peptide compound is given a Compound number (C#). The first row provides information per the columns of the Tables. The second row provides the peptide string sequence of the peptide compound, which string sequence includes terminal chemical moieties (i.e., R1 at the N-terminus and R2 at the C-terminus of the peptide string sequence). The third row provides the SMILES string sequence of the peptide compound. SMILES stands for Simplified Molecular Input Line Entry System, which is an ASCII string line notation that represents a chemical structure. The SMILES strings for the compounds disclosed herein can be translated to a two-dimensional chemical structure through numerous publicly available sites, including the Smi2Depict tool from the ChemDB Portal: https: / / re.edugen.wiley.com / cgibin / Smi2DepictWeb.py

[00192] The first column provides information as to whether the compound is a Monomer (M) or a Dimer (D) and its molecular weight (MW) in Daltons. If a compound is a dimer, the default is that the compound is a homodimer. It will be explicitly stated if a dimer compound is a heterodimer. In the broadest sense, the invention contemplates that any monomer disclosed herein can be used to form homodimers, heterodimers (i.e., different monomer peptides dimerized together), homotrimers, homo tetramers, or other multimers, and Figure 1 includes many non- limiting examples between monomers and their respective homodimer complexes.

[00193] First row information also includes three columns relating to cyclization. If a peptide compound comprises a monomer that is cyclized, the “Cyclization Positions” column will indicate a pair of residues that are cross-linked. For example, the notation “X7C-X11C” indicates that a cysteine at position 7 and a cysteine at position 11 are cross-linked. The table includes some bicyclic compounds where two pairs of residues are cross-linked, e.g., “X7C-Xl lLys_Ac” and “X9O3S and X13O3S.” The next column, “Cyclization Chemical Bond,” indicates the type of covalent bond that is formed between the pair or pairs of cross-linked residues. The third column relating to cyclization is “Cyclization Linker.” If a Cyclization Linker is present, this indicates that the residues at the Cyclization Positions are indirectly linked, as each Cyclization Position residue makes a direct linkage with the Cyclization Linker. Furthermore, for homodimers, by definition, both monomers are identical, and both will include the Cyclization Linker. If a Cyclization Linker is not present, but Cyclization Positions are indicated, this means that the residues at the Cyclization Positions make a direct linkage with each other. The resultant chemical bonds formed between the Cyclization Position residues and the Cyclization Linker or between the Cyclization Position residues directly is indicated under the Cyclization Chemical Bond column. The Cyclization Positions in this Table are not necessarily meant to be limiting, and some compounds might comprise an additional cyclic structure besides those formed at position pairs X5-X13, X7-X11, X9-X13, and X10-XI 4. The chemical structure encoded by the SMILES strings will indicate whether the compounds have a monomer with one cyclic structure or multiple cyclic structures. Further, the Cyclization Positions can inform whether the first amino acid residue in a string sequence starts at XI, XO, X-l, etc., with respect to the Formulas herein. For example, Compound 601 has a peptide monomer sequence of ac-I-Lys_Me3-V-E-Hcy-Oic-A-D-Ogl-W-E-W-Hcy-K-dR-am (SEQ ID NO:438). The first moiety “ac” (acetyl) is Rl, as acetyl is not an amino acid.The first amino acid, “I” or isoleucine is at position XO as Figure 1 states that the Cyclization Positions for SEQ ID NO:438 are X5Hcy and X13Hcy.

[00194] The column “Dimerization; Linker, Position, Chemical Bond” relates to compounds that are dimers. If a Dimerization Linker is present, this indicates that each monomer of the dimer makes an indirect linkage with each other as each monomer makes a direct linkage with the Dimerization Linker. If a Dimerization Linker is not present, but the compound is a dimer, this means that the residue at the Dimerization Position of each monomer makes a direct linkage with each other. The resultant chemical bonds formed between the Dimerization Position residues and the Dimerization Linker or directly between the Dimerization Position residues is indicated.

[00195] The next column is titled “Stability Assays (SGF; SIF).” As described in more detail herein (e.g., Example 7), SGF and SIF are assays that can be used to assess the stability of peptides in conditions that simulate gastric (SGF) and intestinal (SIF) conditions. For compounds that have been tested in one or both of these assays, time of stability data is presented, where : >2 hours of stability is indicated by ++++, 1.5-2 hours is +++, 1-1.5 (not including 1.5) is ++, and <1 hour is +.

[00196] The final column presents potency data, i.e., whether the compound exhibits inhibitory or neutralizing characteristics against human IL- 17 cytokine biological activity or function. The column provides human IL- 17 HEK Blue assay (e.g., Example 5) IC50 data, where each compound has at least been tested with respect to its potency against the human IL-17 “AA” isoform. If the compound has also been tested against the human IL-17AF or FF isoforms and showed sufficient potency, then the “AF” and / or the “FF” data has also been included. The legend for the IC50 data is: <1 nM is -H-++, from 1 nM to 5 nM (including 5 nM) is +++, > 5 nM to 10 nM (including 10 nM) is ++, and greater than 10 nM to 20 nM is +).

[00197] Figure 2 shows a schematic of the human IL- 17 HEK Blue assay (Invivogen). In the top panel, when either human IL-17AA, AF, or FF is contacted with HEK Blue cells, the binding of these cytokines with the shown IL- 17 receptor (IL-17RA-IL-17RC heterodimer receptor) leads to activation of downstream intracellular signaling such that the AP-1 and NF-kB transcription factors are activated to upregulate expression of the SEAP reporter gene (which allows for colorimetric analysis of SEAP reporter gene expression). The bottom panel shows the activity of the human IL-17AA and human IL-17FF in the assay, with the murine IL-17AA isoform being a negative control. The inhibitory (or neutralizing / antagonist) potency of the compounds of the invention can be tested by determining the amount of the compound needed to reduce the activity of the human cytokine by half, i.e., the IC50 of the compound.

[00198] Figure 3 presents an in vivo model and data for evaluating pharmacodynamic and pharmacokinetic properties of the peptide-based compounds of the invention. (See Example 6.) The in vivo model is a murine inflammation / psoriasis model with human IL- 17. Recombinant human IL-17A (rhIL-17A) is administered subcutaneously to the mice. The rhlL-17A upregulates the expression of CXCL1, which is a chemokine produced by keratinocytes. By monitoring CXCL1 levels in the ear and serum, one can assess the pharmacodynamic properties of the peptide-based compounds of the invention by determining the levels needed to reduce the rhIL-17A-triggered upregulation of CXCL1 levels. Furthermore, repeated administration of rhIL-17A triggers a psoriasis-like cutaneous phenotype characterized by erythema and ear thickness.

[00199] The top panel of Figure 3 shows the design of the initial experiments conducted with the in vivo model. (Example 6.) There are three treatment groups for each experiment, where mice were treated with either: (a) vehicle (no active ingredient - otherwise same formulation solution as with PO or SC), (b) Compound 82 through oral administration (“PO”), and (c) Compound 82 by subcutaneous injection (“SC” or “sc”). After 0.5 hours, mice in each treatment group were given 0.2 pg / animal of rhIL- 17A subcutaneously. At least two hours after rhIL-17A, ear and serum samples are collected and analyzed for CXCL1 levels (ear and / or serum) and for Compound levels (ear and / or serum). The data in the bottom left panel shows that there is a significant reduction of rhIL-17 induced CXCL-1 secretion after a single PO dose of Compound 82.

[00200] Figure 4 and Figure 5 show data from in vivo model experiments conducted with Compound 285 and Compound 288, respectively. See Example 6. These experiments show that the in vitro potency and stability profiles of the peptide compounds can be consistent with in vivo potency and stability.

[00201] Figure 6 provides two-dimensional chemical structures for several peptide compounds of the invention. Figure 6A provides the structure for C599, which is an example of alkane or alkene linker-mediated cyclization with residues having a free thiol group in their side chains, and shows (di)thioether cyclization of X5Hcy and X13Hcy via a Propane_linker. Figure 6B provides the structure for C600, which is another example of (di)thioether cyclization. Figure 6C provides the structure for C601, which is another example of (di)thioether cyclization.Figure 6D provides the structure for C581, which is another example of (di)thioether cyclization. Figure 6E provides the structure for C587, which is an example of a hydrocarbon cyclization from the direct covalent linkage of O3S side-chains. Figure 6F provides the structure for C314, which is an example of disulfide cyclization between the free thiol groups of X5Hhc and X13Hhc. Figure 6G provides the structure for C533, which is an example of a hydrocarbon cyclization from the direct covalent linkage of O3S_Reduced side-chains. Figure 6H provides the structure for C517, which is another example of (di)thioether cyclization.Figure 61 provides the structure for C537, which is yet another example of alkane or alkene linker-mediated cyclization with residues having a free thiol group in their side chains, and shows (di)thioether cyclization of X5Cys and X13Cys via a Pentane_linker. Figure 6J provides the structure for C535, which is another example of O3S-O3S cyclization. Figure 6K provides the structure for C764, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6L provides the structure for C792, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6M provides the structure for C609, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker.Figure 6N provides the structure for C677, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 60 provides the structure for C796, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6P provides the structure for C8O8, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6Q provides the structure for C665, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6R top image provides the structure for C815; the bottom image provides the structure for a DKP-type prodrug form of C815, wherein instead of dK at position XO, the tripeptide dK-Sar-isoDLys_lPEG2_lPEG2_isoGlu_C18_Diacid is present. Figure 6S provides the structure for C813, which shows carbon-carbon single bond cyclization of X5O3S_Reduced and X13O3S_Reduced. Figure 6T provides the structure for C824, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6U provides the structure for C825, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker.Figure 6V provides the structure for C829, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6W provides the structure for C833, which shows thioether cyclization of X5Hcy and X13 Hey via a Propane_Linker. Figure 6X provides the structure for C834, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker. Figure 6Y provides the structure for C836, which shows carbon-carbon single bond cyclization of X5O3S_Reduced and X13O3S_Me_Reduced. Figure 6Z provides the structure for C847, which shows thioether cyclization of X5Hcy and XI 3 Hey via a Propane_Linker.

[00202] Figures 7A-7C provide the serum and skin CXCL- 1 levels after oral administration with Compounds 829, 834 (serum only), and 836 and rhIL-17, respectively. (See Example 6; modified Figure 3 model.). These orally administrated compounds reduced serum and skin CXCL-1 levels as compared to levels with rhIL-17 administration alone.

[00203] Figure 8 presents data with Compounds 829, 834, and 836 in a rat 5-day IL-23-induced skin inflammation efficacy model. In this model, ear inflammation is induced by repeated intradermal injections of IL-23, and ear thickness is measured over time. (See Examples.) Repeated injections with IL-23 resulted in an increase in ear thickness by day 5. IL-23-induced ear thickness was significantly lower by day 5 in rats receiving oral Compound 829 and 836.DETAILED DESCRIPTION OF THE INVENTION

[00204] In general, the present disclosure relates to synthetic or recombinant peptides exhibiting IL- 17 inhibitory activities and methods of using the same. In some embodiments, the peptides exhibit inhibitory activity against a human IL- 17 cytokine by preventing or reducing the ability of a human IL- 17 cytokine to bind to its cognate receptor, thereby preventing or reducing IL- 17 receptor activation and downstream signal transduction. In some embodiments, the peptides disclosed herein have a cyclic structure, which herein, is also referred to as an intramolecular cross-link between two amino acids (i.e., a direct covalent bond between the side-chains of the two amino acids or an indirect covalent bond between the sidechains of the two amino acids mediated by a cyclization linker), between two terminal chemical groups (e.g., R1 and R2 for a head-to-tail cyclization), or between an amino acid side chain and an R 1 or R2 group.

[00205] As stated, side-chain to side-chain cyclic ring structures are formed either by direct covalent linkage between two peptide residues or by indirect covalent linkage between two peptide residues, wherein each residue makes a direct covalent linkage with a linker, often at the terminal ends of the linker. Four major cyclization structures are described for peptides: X5-X13, X9-X13, X7-X11, and X10-X14, where these X pairing indicate the positions of two residues that are covalently cross-linked together, whether directly or indirectly through a linker. It should be noted that these cyclization positions do not necessarily correspond to positional length, i.e., some peptides have amino acids at X00 and / or X0, which are located N-terminal to position XI . In yet other embodiments, the peptides disclosed herein have a dimeric structure, wherein two monomeric peptides or peptide fragments are covalently linked together either directly or through a linker or linking moiety. In other embodiments, the peptides disclosed herein have a non-cyclic or linear structure. Herein, when a linker is used to mediate cyclization, it is referred to as a cyclization linker; and when a linker is used to mediate dimerization, it is referred to as a dimerization linker.

[00206] The invention provides a large representative set of compounds that are potent inhibitors of human IL- 17 cytokines, which is exhibited by their nanomolar potency in IL- 17 functional assays. Further, the invention contemplates peptide compounds that are suitable for oral administration, which is reflected by compound stability in assays that simulate gastric and intestinal conditions. Indeed, the invention provides murine in vivo data showing the peptide compounds can inhibit human IL- 17 cytokine function, whether by subcutaneous injection or oral administration.1. Definitions and Nomenclature

[00207] Unless otherwise defined herein, scientific and technical terms used in this application shall have meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[00208] As used herein, the following terms have the meanings ascribed to them in the art unless specified otherwise.

[00209] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).

[00210] The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise.

[00211] The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[00212] The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats). The term “mammal” refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[00213] The term “peptide,” as used herein, refers broadly to a sequence of two or more amino acids joined together by peptide bonds, where such amino acids can be natural or unnatural amino acid residues. Further, it should be understood that this term does not connote a specific length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring.

[00214] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3.

[00215] The recitations “sequence identity”, “percent identity”, “percent homology”, or, for example, comprising a “sequence 50% identical to,” as used herein, refer to the extent that sequences are identical on a nucleotide-by-nucleotide basis or an amino acid-by-amino acid basis over a window of comparison. Thus, a “percentage of sequence identity” may be calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[00216] Calculations of sequence similarity or sequence identity between sequences (the terms are used interchangeably herein) can be performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In certain embodiments, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.

[00217] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[00218] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch, (1970, J. Mol. Biol. 48: 444-453) algorithm which has been incorporated into the GAP program in the GCG software package, using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using an NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[00219] The peptide sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al., (1990, J. Mol. Biol, 215: 403-10). BLAST nucleotide searches can be performed with the NBLAST program, score = 100, word length = 12 to obtain nucleotide sequences homologous to nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, word length = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[00220] The term "conservative substitution" as used herein denotes that one or more amino acids are replaced by another, biologically similar residue. Examples include substitution of amino acid residues with similar characteristics, e.g., small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino acids. See, for example, the table below. In some embodiments of the invention, one or more Met residues are substituted with norleucine (Nle) which is a bioisostere for Met, but which, as opposed to Met, is not readily oxidized. Another example of a conservative substitution with a residue normally not found in endogenous, mammalian peptides and proteins, is the conservativesubstitution of Arg or Lys with, for example, ornithine, canavanine, aminoethylcysteine or another basic amino acid. In some embodiments, one or more cysteines of a peptide analogue of the invention may be substituted with another residue, such as a serine. For further information concerning phenotypically silent substitutions in peptides and proteins, see, for example, Bowie et.al. Science 247, 1306-1310, 1990. In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. I: neutral, hydrophilic, II: acids and amides, III: basic, IV: hydrophobic, V: aromatic, bulky amino acids. 

[00221] In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. VI: neutral or hydrophobic, VII: acidic, VIII: basic, IX: polar, X: aromatic. 

[00222] The term “amino acid” or “any amino acid” as used here refers to any and all amino acids, including naturally occurring amino acids (e.g., a-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. It includes both D- and L-amino acids. Natural amino acids include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building-blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. The 20 “standard,” natural amino acids are listed in the above tables. The “nonstandard,” natural amino acids are pyrrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (present in many non eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts). “Unnatural” or “non-natural” amino acids are non-proteinogenic amino acids (i.e., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 unnatural amino acids are known and thousands of combinations are possible. Examples of “unnatural” amino acids include P-amino acids (P3 and P2), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring- substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, alpha-methyl amino acids and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. “Modified” amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety not naturally present on the amino acid. Numerous examples of unnatural amino acids are described in Table 1.

[00223] All amino acids have a central carbon atom surrounded by a hydrogen atom, a carboxyl group (COOH), an amino group (NH2) and an R-group (also referred to as the sidechain). Amino acids are often modified by attaching chemical moieties to the central carbon atom (also referred to as the a-carbon), side-chain, amino group, or the carboxyl group. For example, a-methyl variants of an amino acids have a methyl group attached to the central carbon, replacing the hydrogen that is normally attached. N-methyl variants have a methyl group attached to the nitrogen of the amino group, replacing a hydrogen. N-methylation (left) vs. alpha-methylation (right) is shown below. 

[00224] The names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of a-Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader.

[00225] Throughout the present specification, unless naturally occurring amino acids are referred to by their full name (e.g., alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise indicated, three-letter and single-letter abbreviations of amino acids refer to the L-isomeric form of the amino acid in question. The term “L-amino acid,” as used herein, refers to the “L” isomeric form of a peptide, and conversely the term “D-amino acid” refers to the “D” isomeric form of a peptide (e.g., (D)Asp or D-Asp or dAsp or dD; (D)Phe or D-Phe or dPhe or dF). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, whether natural or unnatural, as long as the desired function is retained by the peptide. D-amino acids may be indicated as customary in lower case prefix letter “d.” For example, L-arginine can be represented as “Arg” or “R,” while D-arginine can be represented as “dArg” or “dR.” Similarly, L-lysine can be represented as “Lys” or “K,” while D-lysine can be represented as “dLys” or “dK.” The D-amino acid nomenclature can also be used with unnatural amino acids, e.g., see Table 1.

[00226] The term “linker moiety” or “linker” or “linking moiety” as used herein, refers broadly to a doubly functionalized chemical structure that is capable of linking or joining together at least two chemical groups.

[00227] The term “disulfide bond” or “disulfide linkage” has its conventional meaning, e.g., a R1-S-S-R2 bond. The linkage is also called a disulfide bridge and is usually derived by the coupling of two thiol groups. Amino acids with free thiol groups include Cys, Hey, Hhc, Pen, HhPen, dCys, dPen, dHcy, dHhc, dHhPen, and the like.

[00228] The term “thioether bond” or “thioether linkage” has its conventional meaning, e.g., a R1-S-R2 bond. Thioethers are also called sulfides, and thioethers are typically prepared by alkylation of thiols.

[00229] The term “amide bond” or “amide linkage” has its conventional meaning, e.g., an -NH-C(O)- or a -C(O)-NH- bond. A common preparation is to couple a carboxylic acid with an amine.

[00230] The term “solvate” in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (e.g., an IL- 17 cytokine inhibitor or pharmaceutically acceptable salt thereof according to the invention) and a solvent. The solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.

[00231] The term “alkyl” includes a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl. n-hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, sec-butyl, isobutyl, rert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyls include, without limitation, cyclopentenyl, cyclohexenyl, and the like.

[00232] The term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include CM, CI-6, C1-20 and the like.

[00233] The term “alkyl” includes a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Hie term alkyl,” refers to an alkyl group having n io m carbon atoms. For example, “C1-6 alkyl” refers to a hydrocarbon radical straight or branched, containing from 1 to 6 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-bulyl, n-pentyl, n-hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, sec-butyl, isobutyl, terf-butyl, isopentyl, and the like.

[00234] The term “alkylene” refers to a divalent alkyl group, particularly having from 1 to 24 carbon atoms. The term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.

[00235] The term “alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[00236] The term “alkenyl” alone or in combination with other terms, means a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term "Cn-m alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 16, 2 to 14, or 2 to 8 carbon atoms. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl. isopropenyl, zi-butenyl, sec-butenyl, 5-pentenyl, 8-octenyl, and the like.

[00237] The term “alkenylene” means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon double bond. Representative alkenylene include -CH=CH-, -CH2 CH=CH-, -C(CH3)=CH-, -CH2 CH=CHCH2-, and the like

[00238] The term “cycloalkyl” or “carbocycle” by themselves or in combination with other terms means cyclic versions of "alkyl" in which all ring atoms are carbon. "Cycloalkyl" or "carbocycle" refers to a mono- or polycyclic group. When used in connection with cycloalkyl substituents, the term "polycyclic" refers herein to fused and non-fused alkyl cyclic structures. "Cycloalkyl" or "carbocycle" may form a bridged ring or a spiro ring. In some embodiments, the cycloalkyl group may have one or more double or triple bond(s) in the cycloalkyl ring. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[00239] The term “halo” or “halogen” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.

[00240] The term “haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl and the like.

[00241] The term “alkanoyl” means an alkyl-C(O)- group, wherein the alkyl group is as defined herein. Representative alkanoyl groups include methanoyl, ethanoyl, 3-methylbutanoyl, and the like.

[00242] “Benzyl” means a phenyl-CH2 - group. Representative benzyl include 4-bromobenzyl, 4-methoxybenzyl, 4-aminobenzyl, and the like.

[00243] “Carbamoyl” means a group of formula RxRyNCO- wherein Rx and Ry are independently hydrogen or alkyl. Representative carbamoyl groups include carbamoyl (H2NCO-), methylcarbamoyl (MeNHCO-), and the like.

[00244] “Thiol”, “mercapto” or “sulfanyl” means an -SH group.

[00245] The term “alkylthio” means an alkyl-S- group, wherein the alkyl group is defined herein. Representative alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, and the like.

[00246] As used herein, “functional group” on the side chain of an amino acid means -COOH, -NH2, -NH-, -SH, -SCH3, -OH, -C(O)NH2, guanidinyl, imidazoyl, pyrrolidinyl, phenyl, indolyl, and the like.

[00247] The term “NH2,” as used herein, refers to the free amino group that is often present at the amino terminus of a peptide. The term “OH,” as used herein, refers to a free carboxy group, often present at the carboxy terminus of a peptide. Further, the term “Ac,” as used herein, refers to acetyl group, wherein acetyl protection of a NH2 terminus of a peptide can be achieved through acylation.

[00248] The term “carboxy,” as used herein, refers to -CO2H.

[00249] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including, Sar or Sarc (sarcosine, i.e. N-methylglycine), Aib (a-aminoisobutyric acid), Daba (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), y-Glu (y-glutamic acid), pGlu (pyroglutamic acid), Gaba (y-aminobutanoic acid), P-Pro (pyrrolidine-3-carboxylic acid), 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (2-aminobutyric acid), bhPro (P-homo-proline), bhPhe (P-homo-L-phenylalanine), bhAsp ( -homo-aspartic acid]), Dpa (P,P diphenylalanine), Ida (Iminodiacetic acid), hCys (homocysteine), bhDpa (P-homo-P,p -diphenylalanine). Additional unnatural amino acids are listed in Table 1.

[00250] As is clear to the skilled artisan, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. In many embodiments, peptide sequences disclosed herein comprise an “Ac” (acetyl) moiety at the amino terminus (N-terminus) and an “Am” moiety (amine; see Table 1, “am” = H2N-R1) (which covers amide moieties when Ri of H2N-R1 comprises a carbonyl) as well at the carboxy terminus (C-terminus) of the sequence. In some cases, a “H” moiety at the N-terminus indicates a hydrogen atom, corresponding to the presence of a free primary or secondary amino group at the N-terminus, while an “-OH” or an “-NH2” moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, corresponding to the presence of an amido (CONH2) group at the C-terminus, respectively. In each sequence of the invention, a C-terminal “-OH” moiety may be substituted for a C-terminal “-NH2” moiety, and vice-versa. Peptide Formulas of the invention refer to N-terminal moieties as an “Rl” (or Ri) group and C-terminal moieties as an “R2” (or R2) group.

[00251] As used herein, the term "cycle” or “cyclic” and the like, refers to a molecule having a chemical structure that includes a ring or cycle formed by at least eight covalently bonded ring atoms. In some embodiments, a cyclic peptide means the peptide comprises a ring or cycle formed by at least 9 covalently bonded ring atoms. The term “cyclized” or “cyclization,” as used herein, refers to a reaction in which one part of a peptide molecule becomes linked to another part of the peptide molecule to form a closed ring, such as by forming a disulfide bridge or other similar bond. Herein, a “cyclic peptide,” is a peptide that has been cyclized or “cross-linked” (an intramolecular cross-link) by covalently bonding two amino acids together, whether directly or indirectly through a cyclization linker.

[00252] One of skill in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogen may be removed or replaced by the bond. As conventionally understood, each amino acid has a specific side chain, known as an R group, that is attached to the a carbon. Unnatural amino acids often differ from natural amino acids by side chain substitution. Amino acid side chains, natural or unnatural, can comprise “reactive” or “free” substituent chemical moieties that can form chemical bonds with other molecules. For example, the side-chain of cysteine comprises a free thiol (sulfhydryl) group that can react with another free thiol group to form a disulfide bond or with a free alkyl group to form a thioether bond.

[00253] “Pharmaceutically effective amount” refers to an amount of a compound of the invention in a composition or combination thereof that provides the desired therapeutic or pharmaceutical result.

[00254] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[00255] Provided are also pharmaceutically acceptable salts and tautomeric forms of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[00256] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the peptides or compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit / risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. A pharmaceutically acceptable salt may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type NX4+ (wherein X is Ci-Ce alkyl). Also included are base addition salts, such as sodium or potassium salts. Other examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), Tnforma Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also, for a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Other suitable base salts are formed from bases which form non-toxic salts. Representative examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases may also be formed, e.g., hemisulphate and hemicalcium s alts .

[00257] Compounds described herein may include isotopically labeled compounds, which are identical to those recited in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as 2H, 3H, '3C, 14C, 15N, 18O, 170, 35S, 18F, 36C1, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In particular embodiments, the compounds disclosed herein are isotopically substituted with deuterium. In more particular embodiments, one or more hydrogen atoms in the compounds disclosed herein can be replaced by a deuterium atom or D.

[00258] The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( / ?)- or C.S')- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the aspect encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the aspect is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1 : 1.

[00259] “Stereoisomer” and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[00260] “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[00261] “Therapeutically effective amount” or “effective amount” as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[00262] “Treatment” or “treat” or “treating” as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present invention, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom and / or preventing a worsening of a symptom associated with a disease or condition. In one aspect, “treatment” or “treating” includes one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); (c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival; and (d) preventing the disease, condition or disorder in a subject who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments, treating refers to inhibiting or ameliorating the disease. In some embodiments, treating is preventing the disease,

[00263] “Co-administration” as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some aspects, a unit dose of a compound of the invention is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other aspects, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some aspects, a unit dose of a compound of the invention is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other aspects, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.

[00264] With respect to the IL- 17 cytokine binding peptides of the invention, the terms "antagonizing” or “inhibiting” or “neutralizing” are used synonymously, and mean the peptides can reduce or prevent IL- 17 cytokine binding with its cognate IL- 17 receptor(s). The inhibitory activity of a peptide compound of the invention can be assessed, for example, by assaying the activity of the IL- 17 receptor signaling pathway. Because an inhibitor of an IL- 17 cytokine may prevent or inhibit or decrease the ability of an IL- 17 cytokine to bind to its cognate IL- 17 receptor(s), inhibition of IL- 17 cytokine binding to its receptor(s) should therefore decrease or prevent downstream signaling events of an activated IL- 17 receptor complex. For example, the inhibitory peptides can decrease the expression level of genes that are upregulated from IL- 17 receptor activation. Downstream signaling events of IL-17AA, AF, and FF can lead to overexpression of IL-6, TNFa, COX2, G-CSF, GM-CSF, CXCL10, CXCL1, CCL2, CXCL2, CCL7, CXCL5, CCL20, and / or CXCL8, which can contribute to autoimmunity and inflammatory diseases or disorders.

[00265] The term “Polyethylene glycol” or “PEG” is a polyether compound of general formula H-(O-CH2-CH2)n-OH. PEGS are also known as polyethylene oxides (PEOs) orpolyoxyethylenes (POEs), depending on their molecular weight PEO, PEE, or POG, as used herein, refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but PEG has tended to refer to oligomers and polymers with a molecular mass below 20,000 g / mol, PEO to polymers with a molecular mass above 20,000 g / mol, and POE to a polymer of any molecular mass. PEG and PEO are liquids or low-melting solids, depending on their molecular weights. Throughout this disclosure, the three names may be used indistinguishably. PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g / mol to 10,000,000 g / mol. While PEG and PEO with different molecular weights find use in different applications, and have different physical properties (e.g., viscosity) due to chain length effects, their chemical properties are nearly identical. The polymeric moiety is preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymeric moieties include polyethylene glycols (PEG), homo- or co-polymers of PEG, a monomethylsubstituted polymer of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68: 1 (1998); Bioconjugate Chem. 6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also encompassed are PEGs that are prepared for purpose of halflife extension, for example, mono-activated, alkoxy-terminated polyalkylene oxides (POA’s) such as mono-methoxy-terminated polyethyelene glycols (mPEG’s); bis activated polyethylene oxides (glycols) or other PEG derivatives are also contemplated. Suitable polymers will vary substantially by weights ranging from about 200 to about 40,000 are usually selected for the purposes of the present invention. In certain embodiments, PEGs having molecular weights from 200 to 2,000 daltons or from 200 to 500 daltons are used. Different forms of PEG may also be used, depending on the initiator used for the polymerization process, e.g., a common initiator is a monofunctional methyl ether PEG, or methoxypoly (ethylene glycol), abbreviated mPEG. Other suitable initiators are known in the art and are suitable for use in the present invention.

[00266] Lower-molecular-weight PEGs are also available as pure oligomers, referred to as monodisperse, uniform, or discrete. These are used in certain embodiments of the present invention.

[00267] PEGs are also available with different geometries: branched PEGs have three to ten PEG chains emanating from a central core group; star PEGs have 10 to 100 PEG chains emanating from a central core group; and comb PEGs have multiple PEG chains normally grafted onto a polymer backbone. PEGs can also be linear. The numbers that are often included in the names of PEGs indicate their average molecular weights (e.g. a PEG with n = 9 would have an average molecular weight of approximately 400 daltons, and would be labeled PEG 400.

[00268] As used herein, “PEGylation” is the act of coupling (e.g., covalently) a PEG structure to a desired molecule forming a PEGylated molecule. Herein, in some embodiments, a linker molecule comprising a PEG structure connects two peptides of the invention thereby forming a dimeric molecule e.g., a homodimer comprising two identical peptide monomers or a heterodimer comprising two different peptide monomers). Herein, PEG comprising linkers can be used as dimerization linkers and / or to improve the in vivo half-life of the peptide compounds of the invention.

[00269] The skilled worker will be well aware of suitable techniques which can be used to perform the coupling reaction. As discussed herein, PEG linkers can comprise one or more reactive groups (and for dimerization, at least two separate functional groups), including an amine, carboxylic acid, and acrylate groups. Further, a PEG moiety bearing a methoxy group can be coupled to a Cys thiol group by a maleimido linkage using reagents commercially available from Nektar Therapeutics AL.

[00270] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of a- Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader. Some abbreviations useful in describing the invention are defined below in the following Table 1. Table 1 does not usually include D-forms of amino acids (natural or unnatural) - the POSA understands that the stereogenic carbon alpha to the amino group simply has the D-configuration rather than the L-configuration.

[00271] Table 1. Abbreviations of Non-Natural Amino Acids and Chemical Moieties      Ill   

[00272] 2. Peptide-Based Compounds That Bind to Human IL-17 Cytokines

[00273] The peptide compounds of the invention are synthetic or recombinant peptide-based compounds that bind to one or more human IL- 17 cytokine isoforms. In most embodiments, the peptide compounds of the invention are potent inhibitors of human IL- 17 cytokines, which is reflected by nanomolar and sub-nanomolar IC50 values for the peptides in inhibiting / reducing IL- 17 dependent secreted embryonic alkaline phosphatase (SEAP) reporter gene expression in the human IL- 17 HEK-BlueTM assay. (InvivoGen IL- 17 Reporter HEK 293 Cells; see Figure 1 and Example 5.) In other embodiments, the peptide compounds exhibit stability in a simulated gastrointestinal degradation assays (SGF and SIF assays). In certain instances, the peptide compounds will have both nanomolar (or less) potency and stability. In some embodiments, the peptide compounds have a cyclic (an intramolecular cross-link between at least two positions of the peptide) or linear structure. In some embodiments, the peptide compounds are monomeric or dimeric compounds. As explained hereinbelow, the peptide compounds of the invention can be categorized into various groupings based on one or more structural or functional features.

[00274] In most embodiments, the main subunit of the peptide compounds of the invention is a string of natural and / or unnatural amino acids mostly having a length of 14-16 amino acids. This main subunit can be referred to as a monomer, monomer peptide, a monomeric unit or subunit, a monomeric peptide, and the like. Sometimes the monomer includes a chemical moiety, that is not a natural or unnatural amino acid, interspersed within the carbon backbone of the string of amino acids (natural and / or unnatural. In other words - a chemical moiety that is not an amino acid will only be given an X position within a sequence formula if is not at the terminal ends of the peptide string (as such non-amino acid moieties present at a terminal end of a peptide string are identified as R1 or R2 within a sequence formula). A monomer of the invention can have a linear structure or comprise a cyclic structure. See Section 2A below regarding cyclic structures. A monomer of the invention can also be part of a multimeric molecule, whether a homodimeric molecule, a heterodimeric molecule, or other multimers such as homotrimers and homotetramers. Multimeric molecules can be formed by joining monomer subunits by any conventional means. In some embodiments, dimeric molecules are formed by covalently linking monomers directly, or indirectly through a dimerization linker molecule. See Section 2B below regarding dimers. For trimers and tetramers, multimerization linkers with multiple equivalent reactive ends (see, e.g., TAEP (for trimerization) or TetN3 (for tetramerization) in Table 1) are used. It is desired that the peptide compounds of the invention demonstrate significant potency in inhibiting or neutralizing human IL- 17 function. See Section 2C. Additionally, the peptide compounds may exhibit potential for oral administration as reflected by time of stability in assays that simulate gastric and intestinal conditions. See Section 2C. However, peptide compounds that do not exhibit stability in such assays are still suitable for other modes of administration, e.g., subcutaneous injection or intravenous injection.

[00275] For all Formulas (including SEQ ID NOs) of the invention, the sequence can comprise natural and unnatural amino acids, as well as chemical moieties that are not natural or unnatural amino acids. Abbreviations for unnatural amino acids and chemical moieties are provided in Table 1. The sequences reflect a linear monomer peptide sequence and do not necessarily reflect the secondary structure of the peptide compound. Table 1 provides information for when the linear monomer peptide sequence underlies a cyclic peptide structure and / or a dimeric (or other multimeric) structure. When the peptide-based compounds comprise a cyclic structure, at least two positions in the linear peptide sequence will be connected or cross-linked, whether through a direct covalent linkage or through an indirect covalent linkage (where at least two positions in the peptide sequence each make an independent covalent linkage with a cyclization linker). Further, when the peptide monomers are part of a dimeric (or other multimeric) peptide complex, Table 1 provides the dimerization (or other multimerization) information. At least one position from each monomer will be covalently connected to each other directly, or more often, indirectly through a covalent linkage with a dimerization / multimerization linker. The peptide compositions of the invention can comprise linear peptide monomers, linear peptide dimers, cyclic peptide monomers, cyclic peptide dimers, and other linear or cyclic multimers.

[00276] For the Formulas, including the SEQ ID NO formulas, the R1 (or Rl) and R2 (or R2) positions represent non-amino acid (natural or unnatural) chemical moieties that are present on the terminal ends of the linear amino acid sequence. In most embodiments, Rl represents a chemical moiety present at the N-terminus (or left terminus) of a monomeric peptide string, wherein R1 is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl. A common R1 group is an acetyl (Ac) or isovaleric acid (IVA) group. Sometimes R1 is absent. In most embodiments, R2 represents a chemical moiety present at the C-terminus (or right terminus) of a monomeric peptide string, wherein R2 is NH2 or OH. Sometimes R2 is absent. In some embodiments, the Ri and R2 options presented in Formula (I) can be applied for any peptide of the invention.

[00277] A generic formula for the peptide monomers of the invention is a peptide sequence of Formula (I):R’-XOO-XO-X I -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, !Pip_AceticAcid, cyclohexanecarhoxylic acid, glutaric_Acid, isovaleric acid, Mor_propanoic_acid, 1 PEG2_ 1 PEG2_IsoGlu_C 12, 1 PEG2_ 1 PEG2_IsoGlu_C 12_Diacid, 1PEG2_1PEG2_ISOG1U_C18_diacid, lPEG2_lPEG2_IsoGlu_Palm, lPEG2_lPEG2_Ahx_C18_Diacid, lPEG2_PEG2_Ahx_Palm, or absent;R2 is NH2 or OH or absent;X00 is Cha, dK, Ogl, Tie or absent;XO is 2Pal, 3Pal, Aib, Asn, d2Pal, d3Pal, dA, dE, dF, dH, dK, dL, dQ, dS, Gin, Glu, Glu_OMe, His, He, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Pahn, Lys_Me3, NMe_His, Orn, Pro, Sar, Thr, Tie, or absent;XI is INal, Bip, Cha, Chg, Cyclopropyl_Ala, Dgl, DIP, di, hCha, hF, hhF, He, Lys,Ly s_ 1 PEG2_ 1 PEG2_IsoGlu_C 18_diacid, Ly s_ 1 PEG2_1 PEG2_IsoGlu_C 12, Lys_lPEG2_lPEG2_IsoGlu_Palm, Ogl, Phe_4Me, Tba, Tie, Vai, or absent;X2 is 2Pal, 3Pal, aMe_Arg, Agb, Agp, bhF, Cit, Dab, Dab_Ac, Dab_2HyAc, Dab_Ms, Dab_Ts, dDab2HyAc, dH, dT, Glu, Gin, His, hR, Hse, Lys, Lys_lPEG2_Ac, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_lsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, Lys_lPEG2Ac, Lys_2HyAc, LysMPA, Lys_Ms, Lys_Ns, Lys_Ts, NMe_Thr, Orn, Om_Ac, Orn_Ms, OmPVA, Orn_Ts, Phe_2Ad, Phe_3Ad, Phe_4Ad, Phe_4_2ae, Phe_4ad, Phe_4_COOH, Phe_4_Cl, Phe_4guan, Phe_4OMe, Phe_4_Morph, Phe_pentaF, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Q_MecPro, Tetl, Thr, or Thi;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, bhV, Cha, Chg, Cprg, Cpg, cyclopentyl_Ala, cyclopropyl_Ala, Cys, Dgl, DiethylGly, dL, dV, H_Cha, Hey, hL, Hph, Igl, Nle, NMe_Leu, nVF3, O4S, O5S, Ogl, Phe_4tBu, Phe_4Cl, Phe_4_OMe, Phe_4_Me, Phe_3_4_C12 [Phe_34diCl], Phe_4_CF3, Peptoid_CH2_V, Pra, Tba, Tie, or Vai;X4 is Asn, dT, Dab, Gin, Glu, Glu_OMe, hE, His, hR, Lys_Me3, Orn, Phe4 COOH, Phe_4_Morph, Tetl, Thr, or Thr_Me;X5 is Abu, aMe_Lys_Ac, Cha, Cys, Chg, Dab_Acetyl, di, dLys_Ac, Glu, Hey, hE, Hhc, HhPen, He, Lys, Lys_Ac, LysN3, LysPhAc, NMe_Lys_Ac, O2S, O3S, O3S_Reduced, O4S_Reduced, O5S, O5S_Reduced, Om_Acetyl, or Pen;X6 is 4R_BenzyloxyPro, 4RPhePro, 4S_Amp, 4S_Amp_Cyclhex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4ScyclohexPro, 5RPhePro, Azetidinone, Dfp, dP, Hpr, Oic, or Pro;X7 is Acvc, Aib, Ala, aMe_Phe, Arg, Aze, Cys, Dab, dC, Gin, Glu, His, Hpr, hR,Ly s_ 1 PEG2_ 1 PEG2_Ahx_C 18_Diacid, Ly s_ 1 PEG2_ 1 PEG2_Iso Glu_C 12 ,Lys_lPEG2_lPEG2_IsoGlu_C18_ diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_Ac, O3S, 03S_Me, O4S, Pro, Ser, Tba, or Tic;X8 is aMe_Asp, aMe_Glu, Asp, dD, Gia, Gin, Glu, Phe_3COOH, Phe_4COOH, Tetl, or Tet2; X9 is Aoc, Cha, Cys, Dgl, hCha, Hey, Leu, Nle, O3S, O3S_Reduced, O6S, Ogl, Phe_34diF, Phe_4CF3, or Tba;X10 is INal, 2Nal, Aib, aMe_Phe, aMe_Trp, Aoc, Cys, DIP, dW, hCha, Gin, Hph, Lys_lPEG2_lPEG2_IsoGlu_C12, Phe, Phe_34diCl, Phe_3Ad, Phe_4ad, Phe4_COOH, Phe_4OMe, Phg, Tba, Tie, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, Trp_7Phe, or Trp;XI 1 is Aib, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Cys, Chg, dA, dS, Gin, Glu, Hey, Leu, Lys_lPEG2_lPEG2_lsoGlu_C12, Lys_Ac, Lys_Me3, O3S, O3S_Me, O4S, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie;X12 is INal, aMe_Trp, Hph_34diCl, Om_Bz, Trp, Trp_4Cl, Trp_5Br, Trp_5Cl, Trp_5Et, Trp_5Me, Trp_56diCl, Trp_56diMe, Trp_6Cl, Trp_6CF3, Trp_6Me, or Trp_7Cl;XI 3 is Abu, aMe_Cys, aMe_Lys_Ac, Cys, Cha, Dab_Acetyl, Glu, Hey, hE,,Hhc, HhPen, He, Lys, Lys_Ac, LysN3, O2S, O3S, 03S_Me, O3S_Me_Reduced, O3S_Reduced, O4S_Reduced, Om_Acetyl, or Pen;X14 is Aib, Arg, Asn, Cys, dE, dF, dH, dK, dL, dN, dQ, dR, Gin, Glu, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Hexy, Lys_PEG12_NH, Lys_PEG4_PEG4_NH2, O3S, 03S_Me, Om_ Acetyl, PEG12, Tba, or absent;X15 is dE, dK, dR, Glu, Lys, Lys_PEG4_PEG4_NH2, Lys_Dimethyl, Pro, or absent; and X16 is dE, dF, dH, dK, dL, dR, dQ, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_PEG4_PEG4_NH2, Lys_Ac, or absent;wherein:(i) the peptide optionally comprises a cyclic structure wherein at least two amino acid residues in the peptide (monomer) are either: (a) directly covalently linked, or (b) indirectly covalently linked through a cyclization linker;(ii) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other, or indirectly covalently linked to each other through a dimerization linker; and / or(iii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (I).)

[00278] To the extent that a Formula is described differently between different parts of the application, the Formulas should be reconciled by over-inclusion. For example, if a Formula in one part of the application states that a particular X position can have a residue not described for the same Formula in another part of the application, then the Formula should include the residue.

[00279] To provide a representative scope of the invention, Figure 1 (i.e., Figure 1.1 et al.) presents biochemical and functional information for over 800 different peptide-based compounds that are all potent (at least nanomolar) inhibitors of human IL- 17 cytokines. These compounds include monomeric linear peptide compounds, dimeric linear peptide compounds, monomeric cyclic peptide compounds, dimeric cyclic peptide compounds, trimeric cyclic peptide compounds, and tetrameric cyclic peptide compounds, all of which have an IC50 of 20 nM or less in at least the human IL-17AA HEK Blue Assay. Accordingly, all of the peptide compounds described in Figure 1 are potent inhibitors of human IL- 17 and have therapeutic potential as injectable compounds. A large subset of these potent compounds also show potential for oral administration and oral formulation given their stability as measured by halflife time (Tl / 2) in SGF and / or SIF assays.

[00280] In some embodiments, the invention also provides specific selections (or substitutions) that can be applied to the Formulas herein and to the peptides described in Figure 1 :

[00281] In some embodiments, R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, or methanesulfonyl acetic acid.

[00282] In some embodiments, R1 is substituted for Hexafluoro_Isovaleric acid.

[00283] In some embodiments, X00 is dH.

[00284] In some embodiments, X0 is dE, dH, Glu, His, Tie, Tie, or Sar.

[00285] In some embodiments, XI is He or Vai.

[00286] In some embodiments, XI is Tie.

[00287] In some embodiments, X0 is His or dH, and XI is INal, hF, hhF, or Phe_4Me.

[00288] In some embodiments, X2 is Gin, His, or Lys_Me3.

[00289] In some embodiments, X3 is Tba, Tie, or Vai.

[00290] In some embodiments, X4 is Asn, hE, Glu, Glu_OMe, or Thr.

[00291] In some embodiments, X5 and X13 are directly or indirectly cross-linked. In some embodiments, the direct cross-link can be a disulfide bond between X5Hhc and X13Hhc, a carbon-carbon single bond between X5O3S_Reduced- and X13O3S_Reduced or X13O3S_Me_Reduced, or a carbon-carbon double-bond between X5O3S and X13O3S or X5O3S and X13O3S_Methyl. In some embodiments, the indirect cross-link can be mediated by a Dimethylcyclpropane_Linker, a Pentane_Linker, or a Propane_Linker with X5Hcy-X13Hcy or X5Cys-X13Cys.

[00292] In some embodiments, X6 is Oic.

[00293] In some embodiments, X6 is an Oic analog residue having the structure: wherein either A or B or both are present, and wherein A and B are both attached to position 4 and / or 5. A and B can be identical or different, and comprises a small hydrophobic group. In one related embodiment, A and B result in a fused carbocyclic or heterocyclic ring system between positions 3 and 4, or 4 and 5.

[00294] In some embodiments, X6 is the Oic analog 45cHept_Pro, 45cOct_Pro, Oic_4CF3, Oic_5CF3, Oic_5Me, Oic_6Me, or Oic_6CF3.

[00295] In some embodiments, X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba.

[00296] In some embodiments, X8 is Asp or Gia.

[00297] In some embodiments, X9 is Dgl, Ogl, or an analog of Ogl with a hydrophobic sidechain comprising an alkane chain of 6-20 CH2 moieties, either straight-chain or branched.

[00298] In some embodiments, X9 is the Ogl analog Trifluoro_Ogl, Ddgl, or Phenyl_Hgl.

[00299] In some embodiments, X6 is Oic and X9 is Dgl or Ogl.

[00300] In some embodiments, X10 is INal, 2Nal, or Trp.

[00301] In some embodiments, X10 is Phe_4COOH, Phe_4ad, Trp_7Me, or Trp_7Phe.

[00302] In some embodiments, X10 Aoc.

[00303] In some embodiments, XI 1 is Aib, Asp, or Gin.

[00304] In some embodiments, XI 1 is Ser or Phe_4ad.

[00305] In some embodiments, X12 is aMe_Trp or Trp.

[00306] In some embodiments, X12 is Trp_5Cl.

[00307] In some embodiments, X14 is dK, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2.

[00308] In some embodiments, XI 5 is dR.

[00309] In some embodiments, XI 6 is dE.

[00310] In some embodiments, a peptide has two intramolecular cross-links at X5-X13 and X10-X14. In related embodiments, X5-X13 are both O3S and are directly covalently attached through a carbon-carbon double bond, and X10-X14 are both Cys and are indirectly crosslinked through a Xylene_Linker or a Propane_Linker. In related embodiments, X5-X13 are both Hey and are indirectly cross-linked through a Propane_Linker, and X10-X14 are directly covalently linked through a carbon-carbon double bond and are individually, or both, 03 S or O3S_Me.

[00311] In some embodiments, X14 and X15 are absent (and any other residues C-terminal to XI 4 or XI 5 are also absent if present in a peptide to be modified).

[00312] The invention contemplates that any monomer described in Figure 1 (e.g., by the SEQ ID NOs) or by any of the peptide Formulas herein, can be part of a homodimer or heterodimer or other multimeric composition. In other words, any peptide monomer of the invention may be part of homodimer or heterodimer or other multimeric complexes, including any combination of two or more different monomers from Figure 1. Likewise, any dimer or other multimeric compound of Figure 1 that has a monomer that is not already described as a separate monomeric compound, the invention encompasses such monomeric peptide compounds. The invention also extends to linear counterparts of the cyclic peptides of the invention. For example, the linear counterparts would not have side chains or other reactive substituents crosslinked between X5-X13, X9-X13, X7-X11 , and / or X10-14. Furthermore, the invention contemplates variants of the monomers described in Figure 1 (including if the monomer is part of a dimer or other multimeric compound), including variants with one conservative substitution at X00 through XI 6, two conservative substitutions at X00 through XI 6, or three or more conservative substitutions at X00 through X16. In some embodiments, the invention contemplates variants of the monomers described in Figure 1, where in some embodiments, conservative substitutions are not allowed at cyclization positions (if cross-linked residues are described for the peptide). In some embodiments, the invention includes variants of the monomers described in Figure 1, where 1, 2, 3, 4, 5, or more residues are substituted with an analog of the amino acid (e.g., if the residue is a Tyr, then it can be substituted with an analog of Tyr; if the residue is already an analog of Tyr, then it can be substituted with a different analog of Tyr). In some embodiments, the invention encompasses peptide compounds comprising a monomer peptide that has at least 90%, 91%, 92%, 93%, 94%, or 95% sequence identity, or the monomer peptide comprises at least 10, 11, 12, 13, or 14 identical amino acids when aligned to a primary monomer sequence of Figure 1 (i.e., alignment of linear sequences).

[00313] In some embodiments, as reflected by human IL- 17 HEK Blue IC50 values in the about 20 nM range or less, peptides comprising a cyclic structure can exhibit high potency against one or more human IL- 17 cytokine isoforms. In some instances, a peptide of the invention has a human IL- 17 HEK Blue ICso value less than about 10 nM, less than about 5 nM, or less than about 1 nM.

[00314] In some embodiments, a peptide of the invention has a half-life time greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2 hours in a SGF and / or SIF stability assay.

[00315] In some embodiments, a peptide of the invention has an IC50 value in a human IL- 17 HEK Blue assay of about 20 nM or less, of about 10 nM or less, of about 5 nM or less, or about 1 nM or less, and a half-life time greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2 hours in a SGF and / or SIF stability assay.

[00316] In some cases, peptides comprising a cyclic structure have greater potency as compared to a cyclic peptide’s linear form (see, e.g., Figure 1 of compounds sharing the same peptide sequence, i.e., SEQ ID NO, but where one of the compounds is linear and the other is cyclized).

[00317] In some embodiments, linear peptide compounds, whether in monomeric or dimeric form, are suitable for oral administration, as many exhibit half-lives greater than 0.5 hours, 1.0 hours, 1.5 hours, or 2 hours, in an SGF and / or SIF assay (see Figure 1).

[00318] In some embodiments, a peptide comprising a cyclic structure can be more suitable for oral administration as compared to the same peptide without intramolecular cross-links between two or more positions, when the cyclic compound exhibits more stability as compared to its linear form in a Simulated Gastric Fluid (SGF) and / or a Simulated Intestinal Fluid (SIF) assay (see e.g., Example 7 and Figure 1). A peptide compound exhibits stability in these assays if its half-life is greater than: 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours. SGF and SIF stability assays are commonly used to assess the degradation of drugs in simulated stomach and intestinal environments, respectively. Accordingly, peptides that exhibit increasing stability times in these assays have potential as a pharmaceutical drug for oral administration. See Section 2C below. In some embodiments, peptides comprising a cyclic structure can exhibit both high potency and stability. See Section 2C.

[00319] In some embodiments, homodimeric peptide compounds can exhibit greater potency and / or stability as compared to their corresponding monomer compounds, whether the monomer comprises a cyclic structure or is linear. In some embodiments, homodimeric cyclic peptide compounds can exhibit greater potency and / or stability as compared to their corresponding cyclic peptide monomer compounds. (See, e.g., compare potency and stability data between dimer and monomer compounds having the same monomer SEQ ID NO.)

[00320] Thus, the peptide compounds of the invention can be organized or classified by one or more structural and / or functional features. To the extent that the instant teachings do not already explicitly describe structural or functional features for a peptide sequence Formula herein, then the Formula may be sub-categorized into progeny Formula based on structural and / or functional requirements. Typically, sub-category formulas generated by the requirement of additional structural and / or functional features narrows the available residue options set forth by a peptide sequence Formula. See, for example, Formula (III) and its related sub-category formulas Formula (III. A) et al. Therefore, any peptide sequence Formula described herein maybe divided into related sub-formulas by requiring the peptide to have one or more of the following structural or functional features (to the extent said Formula does not already require the features(s)): (1) cyclic structure or linear structure (no intramolecular cross-linking between different residues of the monomer peptide sequence), (2) for cyclic peptides, the position of the cross-linked pairs of residues in the peptide sequence Formula, e.g., X5-X13, X7-X11, X9-X13, and X10-X14, (3) the type of chemical bond of the cross-link, e.g., amide, disulfide, thioether, carbon-carbon single bond, carbon-carbon double bond, (4) a direct covalent link between the cross-linked pairs of residues or an indirect covalent link between the cross-linked pairs of residues, (5) the type of cyclization linker mediating the indirect covalent link, (6) if the peptide sequence underlies a monomer of a dimer, (7) for dimers, the position of the residue on each monomer that is linked to a dimerization linker, (8) the type of dimerization linker, (9) the level of potency in a human IL- 17 HEK Blue assay, (10) the level of potency in a human IL-17 HEK Blue assay against one or more human IL-17 cytokine isoforms, and (11) the halflife time in an SGF and / or SIF assay.

[00321] 2A. Cyclic Structure

[00322] The instant peptides can have a “cyclic” structure that comprises a ring with greater than 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 atoms or more. The cyclic structure can comprise a single ring or multiple rings (e.g., a bicyclic structure). Figure 1 identifies numerous peptide compounds of the invention with cyclic structures, and the two-dimensional (2D) chemical structure for such peptide compounds can be visualized through standard translation of their SMILES code, which is also present in Figure 1. In addition, Figure 1 includes linear peptides, i.e., non-cyclic peptides, and in some embodiments, these can be cyclized according to whether their positional residue content corresponds to the X5-X13, X9-X13, X7-X11, and X10-X14 scaffold requirements described below.

[00323] In most embodiments, a peptide is cyclized by covalently linking, i.e., “cross-linking,” any two positions of a peptide monomer (i.e., Ri, X0 through X16, and R2, of a peptide of Formula I), directly or indirectly through a cyclization linker to form a cyclic peptide. This can be done in different ways depending on the type of chemical moieties or amino acids to be cross-linked: head-to-tail cyclization (N- to C-terminal), head-to-side chain cyclization, side-chain-to-tail cyclization, and side-chain-to-side-chain cyclization.

[00324] In some embodiments, a peptide is cyclized by (a) directly linking the side chains of two amino acid residues to form an amide bond, (e.g., -NHC(O)- or -C(O)NH-, i.e., when an intramolecular cross-link between the side chains of two amino acids creates an amide bond and a cyclic structure for a portion of the peptide, this is referred to as a bond - which occurs when there is a coupling between an amine and a carboxylic acid within the same peptide molecule - whether side-chain to side-chain, head to side-chain, tail to side-chain, or head to tail)), a disulfide bond (e.g., -S-S-), a thioether bond (e.g., -C-S-C-), a carbon-carbon single bond (e.g., -CH2-CH2-), or a carbon-carbon double bond (e.g., -CH=CH-); or (b) linking the side chains of two amino acids through a cyclization linker to form two thioether bonds, one between the side chain of one of the amino acids with a chemical group of the linker and one between the side chain of the other amino acid with a different chemical group of the linker. In other embodiments, a peptide has a cyclic structure comprising an intramolecular cross-link between two amino acid residues (or between two amino acid residues via a cyclization linker) that comprises a lactam, an olefin, a triazole (e.g., click chemistry), a selenoether, or a diselenide bond.

[00325] Whether the cyclization is direct or indirect, representative pairs of chemical moieties for cross-linking are: an amine group and a carboxylic acid group to form an amide bond (a lactam when the amide bond forms a cyclic structure, i.e., a cyclic amide; as opposed to amide bond based dimerization of peptide monomers, where the amide bond is not part of a linkage forming a cyclic structure); two thiols groups to form a disulfide bond; a thiol group and an alkyl group to form a thioether bond; two alkenyl groups to form a carbon-carbon double bond; and carbon-carbon double bond can be reduced to a carbon-carbon single bond.

[00326] In addition to Figure 1 , which indicates the type of cyclization chemistry (if cyclized) for each peptide, and the person of ordinary skill can determine the structure and therefore type of bond(s) of the intramolecular cross-link through the conversion of the provided SMILES code of the peptide compound into two-dimensional structure. Figure 6 provides two-dimensional depictions of several compounds of the invention, and these chemical structures show some of the main types of cyclization chemistry used herein. In addition, representative cross-links of cyclized peptides are shown below: 

[00327] In other embodiments, the peptide is cyclized by covalently linking two pairs of any two residues in the monomer, or any of three of the residues, directly or indirectly through a cyclization linker to form a bicyclic peptide.

[00328] In some embodiments, the peptide is cyclized at positions X5-X13 (herein, when describing cyclization, the notation X#-X# means that the residues at these two positions are cross-linked and it does not mean a range of positions), X7-X11, X9-X13, or X10-X14. These cyclization positions are sometimes referred to as “scaffolds” to describe different structural categories for cyclic peptides of the invention. Cyclization at these pairs of positions involve either direct side-chain to side-chain covalent linkages or “indirect” side-chain to linker covalent linkages. For example, the notation X5-X13 indicates that the residues at position X5 and position X13 are directly or indirectly covalently linked or “cross-linked”, thereby forming a cyclic structure. If a peptide is described as having both X5-X13 and X7-X1 1 or X5-X7-X 11 , then this indicates two separate cross-links that form a bicyclic structure.

[00329] 2A.1 Cyclic Structure - Directly Cross-Linked Scaffold Structures

[00330] In some embodiments of the compounds of Formula (I), a peptide comprises a cyclic structure comprising two cross-linked amino acids at residues at X5 and X13, X7 and XI 1, X9 and XI 3, or XI 0 and XI 4, which two amino acid residues are directly covalently linked through a disulfide bond, a thioether bond, a carbon-carbon double bond, or a carbon-carbon single bond.

[00331] In some cases, when the two cross-linked amino acid residues are at X5 and X13 or X9 and XI 3, the two amino acids are directly covalently linked through a disulfide bond. The two amino acid residues cross-linked through a disulfide bond can be, for example, both or individually, Hhc, Hey, Pen, hhPen, or Cys (or their D-amino acid or a-methyl variant form). Other residues with a free thiol group may also be suitable for disulfide bond cross-linking. In some cases, the disulfide bond cross-linked residues are: both Hhc at X5 and X13, both Hey at X5 and XI 3, Hey atX5 and Cys atX13, or Hey atX9 and Hhc atX13. Representative examples of cyclic peptide compounds with these types of cross-linked monomers are listed in Figure 1 (see cyclization information); SEQ ID NOs are for the monomer sequence.

[00332] In some embodiments, for any of the Compounds that have a disulfide cross-link, these Compounds can be modified to include a Cyclization Linker connecting the side chains of the two cyclization residues such that the cross-link is indirect between the two residues and such that the cross-link comprises a thioether bond between the Cyclization Linker and each side-chain.

[00333] In some cases, when the two directly cross-linked amino acid residues are at X5 and XI 3, X7 and XI 1, X9 and XI 3, or XI 0 and XI 4, the two amino acids are directly covalently linked through a thioether bond. The two amino acid residues directly cross-linked through a thioether bond can be, for example, a residue with a free thiol in its side chain such as aMe_Cys, Cys, Hhc, Hey, Pen, or HhPen, with a residue with a free alkyl in its side chain such as aMe_Lys_Ac, Dab_Acetyl, Dap_Ac, dLys_Ac, NMe_Lys_Ac, Lys_Ac, Lys_PEG12_Ac, LysPhAc, O2S_Reduced, O3S_Reduced, O4S_Reduced, or O5S_Reduced, or Orn_Acetyl. Insome cases, the D-form of the amino acid or its cc-methyl variant can be used. The invention contemplates other types of residue pairs, where one member of the pair has a free thiol group and the other member of the pair has a free alkyl group, including an acetyl comprising a free alkyl group, such that direct cross-linking of these side chains results in a thioether bond. Figure 1 provides numerous representative examples of peptide compounds with side-chains directly cross-linked through a thioether bond.

[00334] In some cases, when the two directly cross-linked amino acid residues are at X5 and XI 3, X7 and XI 1, X9 and XI 3, or XI 0 and XI 4, the two amino acids are directly covalently linked through a carbon-carbon double bond. The two amino acid residues cross-linked through a carbon-carbon double bond can be, for example, both or individually, O2S, O2S_Methyl, O3S, O3S_Methyl, O4S, O4S_Methyl, O5S, or O5S_Methyl. Other residues with a free alkenyl group may also be suitable for carbon-carbon double bond cross-linking. Representative examples of cyclic peptide compounds with these types of cross-linked monomers are provided in Figure 1.

[00335] In some cases, when the two directly cross-linked amino acid residues are at X5 and XI 3, X7 and XI 1, X9 and XI 3, or XI 0 and XI 4, the two amino acids are directly covalently linked through a carbon-carbon single bond. The two amino acid residues cross-linked through a carbon-carbon single bond can be, for example, both or individually, O2S_Reduced, O3S_Reduced, O3S_Me_Reduced, O4S_Reduced, or O5S_Reduced. Other residues with a free alkyl group may also be suitable for carbon-carbon single bond cross-linking - where double bonds are first formed and then reduced to a single bond. Representative examples of cyclic peptide compounds with these types of cross-linked monomers are provided in Figure 1.

[00336] In another embodiment, when the two directly cross-linked amino acid residues at X5 and X13 (or at X7-X11, X9-X13, or X10-X14), the two amino acids are directly covalently linked through an amide bond (cyclic amide or lactam). The two amino acid residues are suitable for amide bond cyclization if one has a side chain with a free amine and the other with a free carboxylic acid, such as Lys paired with Glu, hE, or Asp. Hence, in one embodiment, one of X5 and XI 3 is Lys and the other is Glu, hE, or Asp. Representative examples are provided in Figure 1.

[00337] In another embodiment, when the two directly cross-linked amino acid residues at X5 and XI 3 (or at X7-X11 , X9-X1 , or X10-X14), two directly cross-linked amino acid residues are X5LysN3 and X13Abu, or X5Abu and X13 LysN3. The side chains of these two amino acids are directly covalently linked. Specifically, a hydrogen from the azole ring of LysN3 reacts with a free hydroxyl from Abu to form the cross-link as shown in paragraph

[00324] . Representative examples are provided in Figure 1.

[00338] In one embodiment, the invention provides a peptide monomer comprising the sequence of Formula (I), but further comprises X17-X22, wherein: X16 is PEG4, PEG6, PEG8; X17 is He or Gly; X18 is His or He; X19 is His or Vai; X20 is Thr or Vai; X21 is lie or Thr; and X22 is He or absent. In this embodiment, R2 would follow X22.

[00339] 2A.2 Cyclic Structure - Indirectly Cross-Linked Scaffold Structures

[00340] In some embodiments of the compounds of Formula (I), a peptide comprises a cyclic structure comprising two indirectly cross-linked amino acids at residues at X5 and X13, X7 and XI 1, X9 and X13, or X10 and X14, which two amino acid residues are indirectly covalently linked through a thioether bond with a cyclization linker that comprises at least two free methyl (CH3) or alkyl groups that can form covalent bonds with a thiol group from the side chains of the two amino acid residues. Representative cyclization linkers suitable for (bis-or di-)thioether cross-linking include a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, a Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker a Pentane_Linker, a Propane_Linker, an mXylene_Linker, a pXylene_Linker, or an oXylene_Linker, as described in Table 1. Other cyclization linkers are contemplated, such as other alkane or alkene linkers with terminal -CH3 moieties, or linkers comprising a ring structure with at least two methyl groups on different carbon positions of a ring structure (or linkers with at least two free methyl groups that are situated at least two backbone carbons apart).

[00341] In some cases, when the two cross-linked amino acid residues are at X5 and XI 3, X7 and Xl l, X9 and XI 3, orXlO and X14, the two amino acids are indirectly cross-linked through a cyclization linker that is mXylene_Linker, pXylene_Linker, or oXylene_Linker, and where each residue of the pair makes a direct covalent bond with the cyclization linker forming a thioether bond. The two amino acid residues cross-linked through a thioether bond with thecyclization linker can be, for example, individually or both Cys dC, Hey, Hhc, HhPen, or Pen. Other amino acids with a thiol side chain may be suitable. Representative examples are provided in Figure 1.

[00342] In some embodiments, when the two cross-linked amino acid residues are at X5 and X13, X7 and XI 1, X9 and X13, or X10 and X14, the two amino acids are indirectly crosslinked through a cyclization linker that comprises an alkane or an alkene with at least two free methyl (CHr) or alkyl groups (at least one at each terminal end of the linker) that can form covalent bonds with a thiol group from the side chains of the two amino acid residues, such as a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker a Pentane_Linker, or a Propane_Linker, (see Table 1). The two amino acid residues cross-linked through a thioether bond with the cyclization linker can be, for example, individually or both Cys, dC, Hey, Hhc, Pen, or hhPen. Other linkers and other amino acids with thiol containing side chains may be suitable as taught herein. Representative examples of cyclic peptide compounds with these types of cross-linked monomers are provided in Figure 1.

[00343] 2B. Dimers

[00344] The main subunit of the instant peptide-based compositions is a monomeric peptide. Any monomeric peptide can be readily made into a homodimer or heterodimer or other multimeric compound. Two monomer units can be directly or indirectly linked together at any position, i.e., R1-X00...X16-R2. For example, head-to-tail dimerization would involve forming a covalent bond between R1 of one monomer and R2 of the other monomer, whether directly or through a dimerization linker. Side-chain to side chain dimerization would involve forming a covalent bond between an X position side-chain of one monomer and an X position side-chain of the other monomer, whether directly or through a dimerization linker. Head to side-chain and tail to side-chain dimerization is also contemplated. The peptide dimer can comprise linear or cyclic monomers.

[00345] In another aspect, the present disclosure provides a dimeric peptide or a peptide dimer, which is formed by directly or indirectly covalently linking a peptide comprising or consisting of a sequence of Formula (I) with another peptide comprising or consisting of a sequence of Formula (I). The two monomer peptides can have the same amino acid sequence (homodimer) or different amino acid sequences (heterodimer).

[00346] . In some embodiments, dimerization linkers for cyclic or linear monomers comprise an unbranched and unsaturated carbon backbone length of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 carbons.

[00347] In some embodiments, for dimers with cyclic monomers cross-linked at X5-X13, X9-X13, X10-X14, or X7-X11, the monomer units each comprise an amino acid at XI 4, XI 5, or X16 that has a free amine group, such as Lys or dK or analogs of Lys (see, e.g., Table 1), that is covalently linked to a dimerization linker. The X14, X15, and X16 position are potentially suitable dimerization positions because they lie outside the cyclic structure formed by the crosslinks atX5-X13, X9-X13, X10-X14, orX7-Xl 1. Other potential dimerization positions include the terminal ends and the residues before and after the cyclization positions, e.g., for X5-X13 monomers, Rl, X00, X0, XI, X2, X3, X4, X14, XI 5, XI 6, R2. The same rationale would apply for X9-X13, X7-X11, and also X10-X14. However, dimerization can occur at any position of a cyclic or a linear monomer given the variety of side-chain structures of natural and unnatural amino acids, the variety of potential linkers, and the option to integrate non-amino acid chemical moieties into the residue string of the monomer.

[00348] In some embodiments, whether for linear or cyclic monomers, a dimerization linker comprises a string of multiple PEG subunits (-(OCH2CH2)n-) with functionalized terminal ends. The functionalized terminal ends are covalently attached to each monomer, e.g., through an amide, a thiol, via click chemistry, a lactam, or via any other suitable means known in the art. In some embodiments, a PEG linker is attached through an amide bond and, as such, certain PEG derivatives used will be appropriately functionalized. For example, common PEG linkers have a free amine and / or a free carboxylic acid at their terminal ends for covalent attachment to peptides.

[00349] Accordingly, in some embodiments, dimers comprise two cyclic monomers, each monomer comprising a cyclic structure characterized by cross-links at X5-X13, X9-X13, X10-X14, or X7-X11, and each monomer comprising a Lys or dK at X14 or X16, wherein X14 or XI 6 is covalently linked to a terminal end of a PEG DA (PEG diacid) linker. In some embodiments, the PEGDA linker comprises between 10-50 PEG subunits (e.g., PEG10DA-PEG50DA), 10-40 PEG subunits, 10-30 PEG subunits, or 15-25 PEG subunits. In some embodiments, XI 4 or XI 6 is Lys in each monomer, wherein XI 4 or XI 6 is covalently attached to a terminal end of a PEG21DA or a PEG25DA dimerization linker through an amide bond.

[00350] In some embodiments, two linear monomers are dimerized either directly or through a dimerization linker. For example, two linear monomers each comprising an amino acid residue comprising a free amine can (indirectly) dimerize through a dimerization linker with two free reactive groups (i.e., carboxylic acid groups) such that the amine and carboxylic acid groups can form an amide bond. In some embodiments, the residue is X14K or X14dK and the dimerization linker is a PEGDA linker. A large number of representative compounds have this type of dimerization structure (see Figure 1 for sequence and additional dimerization information).

[00351] In another embodiment, each monomer of a dimer can comprise a residue with a free amine in its side chain such that the free amine can react with a free hydroxyl of a dimerization linker to form an amide bond. For example, X14 can be Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2, which have a free amine in their side chains, and the free amine can react with a free hydroxyl at one of the terminal ends of the DIG Linker. If each monomer has X14Lys_PEG4_PEG4_NH2 et al., then each monomer will form an amide bond with the DIG_Linker, thereby forming a dimer. The ordinary artisan understands that other amino acids are suitable, including other variants of lysine with PEG side chains having a free amine. For example, the following lysine analogs have different combinations of PEG units in the side-chain (the NHFmoc protecting group and the Boc protecting group would be removed prior to dimerization such that NHFmoc becomes NH2 and the terminal group would be a free amine, e.g., Lys_PEG4_PEG4 below would be Lys_PEG4_PEG4_NH2):  Lys_1 PEG2_1 PEG2 PEG2

[00352] Accordingly, in some embodiments, a dimer compound of the invention comprises two monomer peptides each comprising one of the modified Lys residues above (Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_lPEG2_lPEG2_NH2, Lys_PEG8_NH2, Lys_lPEG2_lPEG2_lPEG2_NH2), wherein the modified Lys residue is attached through an amide bond with a DTG_Linker.

[00353] In some aspects, a dimer of the instant invention with a PEG linker attached to a lysine can be modified such that the lysine is substituted with Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2, and the PEG linker is substituted with a DIG_Linker.

[00354] In another example, two linear monomers each comprising a residue with a free thiol can be indirectly covalently attached to a dimerization linker with at least two free alkyl groups. For example, the free thiol group of a Cys from each monomer can be reacted with free alkyl groups of a dimerization linker such that each Cys is covalently attached to the dimerization linker through a thioether bond. Other amino acid residues with free thiol groups are suitable for this approach, for example, Hey and Hhc. Exemplary dimerization linkers with two free and separated alkyl groups include the pBiphenyl_Linker, the series of Xylene_Linkers, the Ebutene_Linker, . Representative compounds having this type of dimerization structure include Cl 6, C26, C28, C62, C77, C255, C277, C278, C279, and C280 (see Figure 1 for sequence and additional dimerization information).

[00355] In another examples, two linear monomers comprising a PEG molecule at an internal residue position (i.e., serving as a residue of the linear peptide string rather than as a dimerization linker or a half-life extension moiety) with a free carboxylic acid and an amino acid residue comprising a free amine group can directly dimerize. For example, the carboxylic acid and the free amine from residues on different monomers can form an amide bond. Representative compounds with this type of dimerization include C17 and C23.

[00356] In some embodiments, a homodimer peptide compound exhibits substantially more potency as compared to its corresponding monomeric peptide compound. For example, Table 2 shows a few representative hIL-17 HEK Blue IC50 comparisons between homodimer and monomeric compounds that comprise the same monomer peptide unit. Other comparisons can be made by examining the monomer and dimer peptide compounds in Figure 1 that have the same monomer SEQ ID NO. Potency ratios are with respect to hIL-17AA, unless otherwise noted. Furthermore, in some embodiments, a homodimer peptide compound exhibits more stability as compared to its corresponding monomeric peptide compound in an SGF and / or SIF assay - see Figure 1 and compare monomer and dimer compounds comprising the same SEQ ID O. Thus, in some embodiments, a peptide homodimer compound exhibits greater than 2-fold, 3 -fold, 5 -fold, 10-fold, 25 -fold, 50-fold, 100-fold, 200-fold, or 300-fold or more potency with respect to a lower IC50 value in a hIL-17 HEK Blue assay as compared to its monomeric form; and such homodimers may further require exhibiting an improved stability as compared to its monomeric form with respect to a greater half-life time in an SGF and / or SIF stability assay.Table 2 - Exemplary Homodimer v. Monomer Potency Ratios  

[00357] 2C. Functional Activity Against IL- 17 & Stability

[00358] The peptide compounds of the invention can exhibit nanomolar or sub-nanomolar potency against human IL- 17 cytokines, and in some instances, also exhibit stability in simulated gastrointestinal environments. The potency is shown by the nanomolar and sub-nanomolar IC50 values in the human IL- 17 HEK Blue Assay. Exemplary structures-function relationships are provided in the Formulas herein.

[00359] In some embodiments, a homodimer peptide compound exhibits an IC50 equal to or less than 10 nM in a HEK Blue human IL-17 assay, wherein the compound has two monomer cyclic peptides both comprising or consisting of the same amino acid sequence from Formula (II):R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-XI2-X13-X14-XI5-X16-R2, or a pharmaceutically acceptable salt or solvate thereof,wherein:R1 is acetyl (Ac), 3 -hydroxy propionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, lPEG2_lPEG2_IsoGlu_Palm, lPEG2_lPEG2_IsoGlu_C18_Diacid, 1PEG2_1PEG2_ISOG1U_C12, or absent;R2 is NH2, OH, or absent;X00 is dH or absent;X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Cha, Chg, Cyclopropyl_Ala, DIP, He, Lys_lPEG2_lPEG2_IsoGlu_C12, Ogl, Tba, or Vai;X2 is 2Pal, 3Pal, Agb, Agp, Cit, Dab_Ac, Dab2HyAc, DabMs, DabTs, dDab2HyAc, Gin, Glu, His, hR, Hse, Lys, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, LysNs, LysTs, OrnAc, Orn2HyAc, OmMs, OrnPVA, OmTs, Phe_2Ad, Phe_3Ad,Phe_4_Morph, Phe_4Ad, Phe_4C00H, Phe_4Guan, Phe_40Me, Phe_pentaF, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl , Thi, or Thr;X3 is AlaCF3, AlaCHF2, Ala_cycBu, Aoc, Cha, Chg, Cpg, cyclopentyl_Ala, cyclopropyl_Ala, Cys, dV, H_Cha, Hey, Hph, Igl, nVF3, Ogl, Phe_34diCl, Phe_4CF3, Phe_4Cl, Phe_4Me, Phe_4OMe, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, His, hE, hR, Lys_Me3, Phe4_COOH, Thr, or Thr_Me;X5 is Abu, Cys, Cha, Chg, Dab_Acetyl, Glu, Hey, hE, Hhc, He, Lys, Lys_Ac, LysN3, LysPhAc, O2S, O3S, O3S_Reduced, O4S, O4S_Reduced, Om_Acetyl, or Pen;X6 is 4RBenzyloxyPro, 4RPhePro, 4S_Amp_Cyclohex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4SCyclohexPro, 5RPhePro, Azetidinone, Hpr, Oic, or Pro;X7 is Ala, Acvc, Aib, aMe_Phe, Arg, Cys, Gin, Glu, His, hR,Ly s_ 1 PEG2_ 1 PEG2_Ahx_C 18_diacid, Lys_ 1 PEG2_1 PEG2_IsoGlu_C 12,Lys_lPEG2_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_Ac, 03S_Me, Oic, Pro, Ser, or TbaX8 is aMe_Glu, Asp, dD, Gia, Glu, Phe_3COOH, Phe_4COOH, Tetl, or Tet2;X9 is Aoc, Dgl, Hey, Leu, O3S, O3S_Reduced, or Ogl;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Cys, Hph, Lys_lPEG2_lPEG2_IsoGlu_C12, Phe_4COOH, Trp_4Cl, Trp_4Me, Tip_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, Trp_7Phe, or Trp;XI 1 is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Cys, Chg, Gin, Glu, Leu, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Me3, 03S_Me, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie;X12 is INal, aMe_Trp, Om_Bz, Trp, Trp_56diCl, Trp_56diMe, Trp_5Br, Trp_5Cl, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, or Trp6Me;X13 is Abu, aMe_Cys, aMe_Lys_Ac, Cys, Cha, Dab_Acetyl, Glu, Hey, hE, Hhc, He, Lys, Lys_Ac, LysN3, O2S, O3S, O3S_Me, O3S_Me_Reduced, O3S_Reduced, O4S, O4S_Reduced, Orn_Acetyl, or Pen;X14 is Asn, dK, dR, Lys, Lys_Ac, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, Orn_ Acetyl, or PEG12;X15 is dR, dK, Lys, Lys_PEG4_PEG4_NH2, or Lys_Dimethyl, or absent;X16 is dK, Lys, Lys_Ac, Lys_lPEG2_lPEG2_IsoGlu_C12,Lys_lPEG2_1PEG2_IsoGlu_Palm, Lys_PEG4_PEG4_NH2, or absent;wherein:(i) the monomer comprises a cyclic structure wherein two amino acid residues in the peptide monomer are directly covalently linked or indirectly covalently linked through a through an amide bond, a disulfide bond, a thioether bond, a carbon-carbon single bond, or a carboncarbon double bond, wherein the two amino acid residues are at X5 and XI 3, X7 and XI 1 , X9 and X13, or X10 and X14; and(ii.a) each monomer is directly covalently linked to a polyethylene glycol (PEG) linker at X14, XI 5, or XI 6 through an amide bond, wherein XI 4, XI 5, or XI 6 is Lys or dK and the PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25, and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or (ii.b) each monomer is directly covalently linked to a DIG_linker (diglycolic acid linker) at XI 4, XI 5, or XI 6 through an amide bond, where XI 4, X15, or X16 is Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2.(Formula (11). )

[00360] In other embodiments, a Formula (II) monomer may not be part of a homodimer compound. In this situation, because X14 (or X15 or XI 6) is often a residue that mediates dimerization, it can be substituted with another amino acid, for example, any of the residues listed at X14 in Formula (I). In some embodiments, for a Formula (II) monomer that is not part of a homodimer compound, X14 is Asn or Lys_Ac.

[00361] In others embodiments of Formula (II), the HEK Blue human IL- 17 assay is a human IL-17AA, human IL-17AF, or human IL-17FF assay.

[00362] For any of the Formulas herein, R1 and R2 can be expanded to include the moieties specified for Formula (I).

[00363] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II.A):Ri -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15-X 16-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH or absent;XO is dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Chg, He, Lys_lPEG2_lPEG2_IsoGlu_C12, Ogl, or Vai;X2 is 2Pal, 3Pal, Agb, Agp, Dab_Acetyl, Dab_2HyAc, Dab_Ms, Dab_Ts, dDab_2HyAc, Gin, Glu, His, hR, Hse, Lys, Lys_lPEG2_lPEG2_C18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, LyslPEG2Ac, Lys2HyAc, LysMs, LysTs, OrnAc, OrnMs, OmTs, Phe_2Ad, Phe_3Ad, Phe_4Ad, Phe_4Guan, Q_NHMe, Q_NMe2, Q_Pyro, Tetl , or Thr;;X3 is Ala_cycBu, Aoc, Cha, Chg, Cpg, cyclopropyl_Ala, dV, H_Cha, Hph, Igl, Ogl, Phe_34diCl, Phe_4CF3, Phe_4Cl, Phe_4Me, Phe_4OMe, Phe_4tBu, Tba, Tie, or Vai;X4 is Glu, hR, or Thr;X5 is Hhc;X6 is Oic or Pro;X7 is Ala, Acvc, aMe_Phe, Gin, Glu, His, hR, Lys_Ac, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, dD, Gia, Glu, Tetl, or Tet2;X9 is Leu or Ogl;X10 is INal, aMe_Trp, Trp_7Phe, or Trp;XI I is aMe_Phe, Asp, or Glu;X12 is aMe_Trp, Trp_5Br, Trp_5Cl, Trp_5Me, Trp_6Cl, Trp_6Me, or Trp;X13 is Hhc;X14 is Asn, dR, dK, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Ly s_PEG4_PEG4_NH2 ;X15 is dR, Lys, or absent;XI 6 is absent;wherein: (a) X5 and XI 3 are directly covalently linked through a disulfide bond; wherein each monomer is directly covalently linked to a PEG linker at X14 or X15 through an amide bond, and (b) XI 4 or XI 5 is dK or Lys, and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or X2 is dK or Lys and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or X14 is Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, or Lys_PEG4_lPEG2_NH2, and wherein one monomer is linked to one terminal end of a DIG_Linker and the other monomer is linked to the other terminal end of the DIG_Linker. (Formula (II. A)).

[00364] Representative compounds of Formula (ILA) include: C45, C80, C81, C82, C83, C87, C88, C89, C120, C121, C122, C138, C139, C147, C162, C180, C182, C184, C186, C188, C190, C192, C194, C196, C206, C207, C208, C209, C210, C213, C215, C217, C219, C221, C222, C224, C256, C262, C281, C294, C295, C296, C297, C298, C300, C302, C303, C304, C3O5, C307, C308, C309, C310, C311, C312, C313, C314, C315, C316, C317, C318, C319, C328, C329, C330, C331, C332, C333, C334, C335, C336, C340, C345, C347, C388, C390, C412, C413, C414, C428, C429, C430, C431, C433, C434, C435, C531, C542, C543, C544, C545, C546, C547, C548, C571, C572, C645, C689, C690, C728, C729, C730, C731, C732, and C733.

[00365] As Formula (ILA) is a sub-formula of Formula (II), all of these representative homodimer compounds have an IC50 equal to or less than 10 nM in a human HEK Blue IL-17 assay (see Fig. 1, AA, AF, or FF activity of ++, +++, or ++-H-) This dimer and potency cut-off also applies to the other Formula (II) sub-formulas herein.

[00366] Furthermore, in some embodiments, Formula (II) dimers (including Formula (II) subformulas) comprise Figure 1 monomers that do not have its homodimer form listed in Figure 1, where such monomers exhibit an IC50 value of equal to or less than 10 nM or less (++-1-1-, +++, ++). For example, at least the C288 and C290 compounds are monomers that would fall under Formula II (others, see Fig. 1 monomer compounds), but for the homodimer requirement. Thus, in some embodiments, monomers with X14N are changed to X14Lys to allow for routine dimerization via a PEGDA linker.

[00367] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II.B):Ri -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15 -X 16-R2, wherein: Rl is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent; XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is His or Lys_Me3; X3 is Tba or Vai; X4 is Thr; X5 is Chg, lie, or Tie; X6 is Azetidinone, Oic, or Pro; X7 is Ala; X8 is Asp or Gla; X9 is Hey; X10 is Trp; XI 1 is Asp or Glu; X12 is Trp; X13 is Hhc; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; XI 5 is dR; XI 6 is absent; wherein: (i) the cyclic structure of each monomer comprises X9 and XI 3 that are directly covalently linked through a disulfide bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.B)).

[00368] Representative compounds of Formula (II.B) include C46, C84, C85, C86, C140, and C145.

[00369] In other embodiments of a Formula (11) homodimer, the cyclic structure of each monomer comprises two amino acid residues directly covalently linked through a thioether bond at: (a) X5 and XI 3, wherein X5 is Cys, Dab_Acetyl, Hey, Hcy_sulfoxide, Hhc, Lys_Ac, LysPhAc, Om_Acetyl, or Pen, and XI 3 is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, Hey, Hey _sulf oxide, Hhc, Lys_Ac, Orn_Acetyl, or Pen; (b) X7 and XI 1, wherein X7 is Cys, Hey, or Lys_Ac and XI 1 is Cys or Lys_Ac; or (c) X10 and X14, wherein X10 is Cys and X14 is Lys_Ac or Om_Acetyl; and wherein aMe_Cys, Cys, Hey, Hcy_sulfoxide, Hhc, or Pen is paired with aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Orn_Acetyl, and vice versa.

[00370] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II.C):Ri -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15-X 16-R2, wherein: Rl is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is Chg, He, Lys_lPEG2_lPEG2_C18_diacid,Lys_ 1PEG2_1 PEG2_IsoGlu_Palm, Lys_l PEG2_1 PEG2_IsoGlu_C 12, Lys_lPEG2_1PEG2_IsoGlu_Cl 8_Diacid, Ogl, or Vai; X2 is 2Pal, 3Pal, Agb, Agp, aMe_Arg, Cit, Dab_Ac, Dab2HyAc, DabMs, DabTs, dDab2HyAc, Gin, Glu, His, hR, Hse, Lys, Lys_lPEG2_lPEG2_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, Lys_Ac, Lys_Dimethyl, Lys_Me3, LyslPEG2Ac, Phe_4_Morph, Phe_4COOH, Phe_40Me, Phe_pentaF, Thr, or Thi; or Thr; X3 is Cha, H_Cha, Ogl, Phe_4tBu, Tba, or Tie, or Vai; X4 is Asn, Gin, Glu, His, Phe_4COOH, Thr, or Thr_Me; X5 is Cys, Dab_Acetyl, Hey, Lys_Ac, LysPhAc, Om_Acetyl, or Pen; X6 is Oic, or Pro; X7 is Aib, Ala, Arg, His, Lys_lPEG2_lPEG2_Ahx_C18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm; X8 is aMe_Glu, Asp, or Gia, Glu, or Tetl; X9 is Ogl; X10 is INal, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe; XI 1 is aMe_Asp, Asp, Gin, or Glu; X12 is Trp, Trp_56diCl, Trp_56diMe, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, or Trp_6Me; X13 is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, Om_Acetyl, or Pen; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; XI 6 is absent;wherein: (i) the cyclic structure of each monomer comprises X5 and X13 that are directly covalently linked through a thioether bond; wherein aMe_Cys, Cys, Hey, Hhc, or Pen is paired with aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Orn_Acetyl, and vice versa;and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker or each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG8_NH2, or X14Lys_PEG4_lPEG2_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.Formula (II.C)

[00371] Representative compounds of Formula (II.C) include: C124, C161, C225, C226, C227, C228, C229, C230, C263, C264, C265, C266, C267, C289, C291 , C320, C321 , C322, C323, C324, C325, C326, C327, C339, C341, C385, C405, C415, C416, C417, C418, C419, C420, C423, C424, C425, C426, C465, C466, C485, C486, C487, C488, C501, C502, C503, C504, C5O5, C523, C524, C525, C526, C527, C554, C555, C556, C557, C558, C559, C560, C561, and C562.

[00372] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II. D):RI-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2, wherein: R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is His, Lys_Me3, or Thr; X3 is Tba, Tie, or Vai; X4 is Thr or Glu; X5 is He; X6 is Oic or Pro; X7 is Cys or Lys_Ac; X8 is Asp; X9 is Leu or Ogl; X10 is INal or Trp; XI 1 is Cys or Lys_Ac; X12 is aMe_Trp or Trp; X13 is He; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; X16 is absent; wherein X7 and XI 1 are not both Cys or Lys_Ac; and wherein: (i) the cyclic structure of each monomer comprises X7 and XI 1 that are directly covalently linked through a thioether bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker or each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.D)).

[00373] Representative compounds of Formula (II.D) include: C51, C52, C54, C56, andC62.

[00374] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (IT.E):Ri -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15-X 16-R2, wherein: Rl is 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is Thr or Lys_Me3; X3 is Tba or Tie; X4 is Thr or Glu; X5 is Chg or He; X6 is Oic or Pro; X7 is Ala; X8 is Asp; X9 is Ogl; X10 is Cys; XI 1 is Asp or Glu; X12 is Trp; X13 is He; X14 is Lys or Orn_Ac; X15 is dR; X16 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; wherein: (i) the cyclic structure of each monomer comprises X10 and X14 that are directly covalently linked through a thioether bond; and (ii) each monomer is directly covalently linked to a PEG linker at X16Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X16Lys_PEG4_PEG4_NH2, X16Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.E)).

[00375] Representative compounds of Formula (II.E) include C136 and C137.

[00376] In some embodiments, the cyclic structure of a monomer of Formula (II) comprises the two amino acid residues directly covalently linked through: (a) a carbon-carbon single bond (-C-C-) at X5 and X13, X9-X13, X7-X11 , or X10-X14, wherein the residues of these pairs are individually or both O3S_Reduced, O3S_Methyl_Reduced, O4S_Reduced, or O4S_Methyl_Reduced; or (b) a carbon-carbon double bond (-C=C-) at X5 and XI 3, X9-X13, X7-X11, or XI 0-X 14, wherein the residues of these pairs are individually or both O2S, 03 S, O4S, O3S_methyl, or O4S_Methyl.

[00377] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II. F):R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxy], or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He, Vai, or Tba; X2 is Gin, His, Hse, Lys_Me3, or Thr; X3 is cyclopropyl_Ala, Tba, Tie, or Vai; X4 is Glu or Thr; X5 is O3S_Reduced or O4S_Reduced; X6 is Pro or Oic; X7 is Ala; X8 is Asp or Gia; X9 is Ogl; X10 is INal or Trp; XI 1 is Asp or Glu; X12 is Trp or Trp5Me; X13 is O3S_Reduced, O3S_Methyl_Reduced, O4S_Reduced; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; XI 5 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and XI 3 that are directly covalently linked through a carbon-carbon single bond (-C-C-); and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (ILF)).

[00378] Representative compounds of Formula (ILF) include: C135, C168, C169, C292, C349, C350, C367, C427, C528, C532, C533, C534, C566, C567, C568, C569, C570, C585, C586, C598, C699, C701, C758, C811, C813, C818, C819, C836, C837, C838, and C839.

[00379] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II. G):Ri -X00-X0-X 1 -X2-X3-X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13-X 14-X 15-X 16-R2, wherein: Rl is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is Chg, Vai, or He; X2 is His, Lys_Me3, or Thr; X3 is Ogl, Vai, Tba, or Tie; X4 is Thr or Glu; X5 is He or Chg; X6 is Oic or Pro; X7 is O3S_Me; X8 is Asp or Gia; X9 is Ogl; X10 is INal or Trp; XI 1 is O3S_Me; X12 is Trp; X13 is He; X14 is Asn; X15 is dR; and X16 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; wherein: (i)the cyclic structure of each monomer comprises X7 and XI 1 that are directly covalently linked through a carbon-carbon double bond (-C=C-); and (ii) each monomer is directly covalently linked to a PEG linker at X16Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X16Lys_PEG4_PEG4_NH2, X16Lys_PEG4_lPEG2_NH2, or X16Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II. G)).

[00380] Representative compounds of Formula (II.G) include Cl 19 and Cl 70.

[00381] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II.H):Ri -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15-X 16-R2, wherein Rl is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is Chg, Vai, or lie; X2 is His, Lys_Me3, or Thr; X3 is Ogl, Tba, Tie, or Vai; X4 is Thr or Glu; X5 is Chg or He; X6 is Oic or Pro; X7 is Ala or Cys; X8 is Asp or Gia; X9 is O3S; X10 is INal or Trp; XI 1 is Asp, Glu, or Lys_Ac; X12 is Trp; X13 is O3S; X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG4_PEG4_NH2, or Lys_PEG8_NH2; XI 5 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X9 and XI 3 that are directly covalently linked through a carbon-carbon double bond (-C=C-); and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.H)).

[00382] Representative compounds of Formula (II.H) include: C163, C164, C165, C166, C223, C257, C258, C259, C260, C261, C306, C307, and C408.

[00383] In some embodiments, when the two cross-linked amino acid residues are at X5 and XI 3, X7 and XI 1 , X9 and XI 3, or XI 0 and XI 4, the two amino acids are indirectly crosslinked through a cyclization linker that comprises an alkane or an alkene or at least two free methyl (CH3) or alkyl groups that can form covalent bonds with a thiol group from the side chains of the two amino acid residues, such as a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, a Ebutene_Linker, a Hexane_Linker, an Oxetane_Linker a Pentane_Linker, Propane_Linker, or a Xylene_Linker. The two amino acid residues crosslinked through a thioether bond with the cyclization linker can be, for example, individually or both Cys, dC, Hey, Hhc, Pen, or hhPen, their D-forms, and their a-methyl variants. Other amino acids with thiol containing side chains may be suitable.

[00384] In some embodiments of Formula (II), each monomer of the dimer has a cyclic structure comprising two amino acid residues that are indirectly covalently linked through: a thioether bond with one of the aforementioned linkers in the paragraph immediately above at: (a) X5 and X13, wherein X5 is Cys, Hey, Hhc, or Pen, and X13 is Cys, Hey, Hhc, or Pen; (b) X7 and XI 1, wherein both X7 and XI 1 are Cys, and with the a Xylene linker, or (c) X7 and XI 1 , wherein X7 and XI 1 are individually or both Cys or Hey and with the Propane_Linker.

[00385] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II.I):R 1 -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15-X 16-R2, wherein: R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is Cha, Cyclopropyl_Ala, DIP, He, Tba, or Vai; X2 is Gin, His, Hse, Lys_Me3, Lys_Dimethyl, Lys_PEG2_Me3, Lys2HyAc, LysMPA, LysNs, Orn_Ac, Orn2HyAc, OmPVA, Phe_2Ad, Phe_3Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, or Tetl ; X3 is AlaCF3, AlaCHF2, cyclopentyl_Ala, cyclopropyl_Ala, nVF3, Tba, Tie, or Vai; X4 is Asn, Glu, Glu_OMe, hE, Lys_Me3, Phe_4COOH, or Thr; X5 is Cys, Hey, or Pen; X6 is 4RBenzyloxyPro, 4RPhePro, 4S_Amp_Cyclohex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4SCyclohexPro, 5RPhePro, Oic, or Pro; X7 is Ala, Gin, His, Lys_lPEG2_lPEG2_lsoGlu_C18_diacid, Lys_Ac, Oic, or Pro; X8 is Asp, Gia, Glu,Phe_3C00H, or Phe_4COOH; X9 is Aoc, Dgl, or Ogl; X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Hph, Phe_4COOH, or Trp; XI 1 is Aib, Ala, Asn, Asp, aMe_Leu, aMe_Phe, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie; X12 is INal, aMe_Trp, Om_Bz, Trp_6Cl, or Trp; XI 3 is Cys, Hey, or Pen; X14 is dK, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and XI 3 that are indirectly covalently linked through a thioether bond with a Butane_Linker, a Carbonyl_Linker, Dimethylcyclopropane_Linker, EButene linker, Hexane_Linker, Oxetane_Linker, Pentane_Linker, Propane linker, oXylene linker, mXylene linker, or pXylene_ linker; and (ii) each monomer is directly covalently linked to a PEG linker at X14 through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (ILI)).

[00386] Representative compounds of Formula (11.1) include: C202, C203, C204, C268, C270, C282, C283, C284, C285, C299, C301, C337, C338, C346, C363, C386, C387, C391, C421, C422, C443, C444, C448, C449, C467, C472, C474, C493, C494, C495, C496, C497, C498, C499, C500, C508, C509, C510, C511, C513, C515, C517, C519, C520, C521, C522, C531, , C536, C537, C563, C572, C574, C575, C576, C577, C578, C579, C581, C583, C588, C589, C590, C591, C592, C593, C594, C595, C596, C597, C599, C600, C601, C686, C687, C688, C691, C693, C694, C695, C696, C697, C698, C703, C704, C705, C706, C707, C708, C709, C714, C715, C716, C717, C718, C719, C720, C721, C722, C723, C724, C725, C726, C727, C734, C735, C736, C737, C738, C739, C740, C741, C742, C743, C744, C745, C746, C747, C748, C749, C750, C751, C752, C753, C754, C760, C761, C764, C765, C789, C791 , C792, C793, C794, C795, C796, C807, C8O8, C816, C817, C820, C821, C822, C823, C824, C825, C826, C827, C828, C829, C830, C831, C832, C833, C834, C835, C840, C841, C842, C843, C844, C845, C846, and C847.

[00387] In some embodiments, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II. J):Ri -XOO-XO-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 1 O-X 11 -X 12-X 13 -X 14-X 15-X 16-R2,Wherein: Rl is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, XO is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent; XI is He or Vai; X2 is His, Lys_Me3, or Thr; X3 is Tie or Vai; X4 is Glu or Thr; X5 is He; X6 is Pro or Oic; X7 is Cys; X8 is Asp or Gia; X9 is Leu or Ogl; X10 is INal or Trp; XI 1 is Cys or Hey; X12 is Trp; X13 is He; X14 is Asn, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; and X16 is Lys, Lys_PEG4_PEG4_NH2, or absent; wherein: (i) the cyclic structure of each monomer comprises X7 and XI 1 that are indirectly covalently linked through a bis-thioether bond with the a Xylene linker (m-, o-, or p-) or a Propane_Linker; and(ii) each monomer is directly covalently linked to a PEG linker at X14 or XI 6 through an amide bond when X14 or X16 is Lys, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14 or XI 6 through an amide bond, wherein X14 or X16 is Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II. J)).

[00388] Representative compounds of Formula (II. J) include: C50 or C62.

[00389] In some embodiments, a peptide compound of the invention inhibits human IL-17AA, human IL-17AF, and human IL-17FF activity, or at least for each of hIL-17AA and hIL-17FF, with an IC50 for each isoform (IL- 17 — AA, -AF, -FF) or with an IC50 for at least the AA and FF isoforms, of about 10 nM or less in the human IL-17 HEK Blue assays, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (III):R1 -X00-X0-X 1 -X2-X3 -X4-X5-X6-X7-X8-X9-X 10-X 11 -X 12-X 13 -X 14-X 15-X 16-R2, wherein:R1 is lPip_AceticAcid, acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, Mor_propanoic_acid, or absent; R2 is NH2 or OH or absent;XOO is Cha, dH, Tie, or absent;XO is 2Pal, Asn, d2Pal, dE, dH, dQ, Gin, Glu, Glu.OMe, His, He, Lys, Lys_Me3, NMe_His, Om, Sar, Tie, or absent;XI is INal, Cha, Cyclopropyl_Ala, Dgl, DIP, hCha, hF, hhF, He, Ogl, Phe_4Me, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, Gin, Glu, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, Om_Ac, Orn2HyAc, OrnAc, OrnMs, OrnPVA, Phe_2Ad, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtoMe, Tetl, or Thr;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, hE, His, LysMe3, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, Lys_Ac, LysN3, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen;X6 is 4SCF3Pro, 4SCyclohexPro, Oic, or Pro;X7 is Acvc, Ala, Dab, Gin, Glu, His, Hpr, hR, Lys_Ac, Oic, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Aoc, Dgl, or Ogl;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, hCha, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe;XI I is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, O3S, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tie;X12 is aMe_Trp, Trp, Trp_56diCl, Trp_5Cl, Trp_5Me, or Trp_6Cl;X13 is Abu, Cys, Dab_Acetyl, Hey, Hhc, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen;X14 is Aib, Asn, Cys, dK, dL, dN, dQ, dR, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, Tba, or absent; XI 5 is dR, dE, or absent;X16 is dE, dQ, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein:(i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or(ii) the peptide is optionally conjugated with a half-life extension moiety.(Formula (III))

[00390] Representative compounds of Formula (III) include: C203, C217, C219, C222, C225,C270, C271, C283, C285, C289, C291, C292, C294, C295, C296, C298, C299, C301 , C302,C303, C304, C305, C307, C309, C310, C312, C313, C314, C315, C316, C317, C318, C320,C321 , C322, C323, C331 , C332, C333, C334, C335, C336, C337, C340, C341 , C349, C350,C351, C352, C356, C357, C358, C363, C367, C457, C488, C491, C494, C495, C496, C497,C498, C499, C500, C501, C502, C5O3, C504, C5O5, C508, C509, C510, C511, C513, C515,C517, C519, C520, C521, C522, C525, C528, C529, C530, C531, C532, C533, C534, C535,C536, C537, C538, C539, C540, C541, C542, C543, C544, C545, C546, C547, C548, C557,C559, C560, C561, C562, C566, C567, C568, C569, C570, C571, C572, C574, C575, C576,C577, C578, C579, C580, C581, C583, C584, C585, C586, C587, C588, C589, C590, C591,C592, C593, C594, C595, C596, C597, C598, C599, C600, C601, C604, C605, C606, C607,C608, C609, C610, C611, C612, C613, C614, C615, C617, C618, C620, C621, C629, C631,C632, C634, C647, C648, C650, C651, C654, C658, C659, C660, C661, C662, C672, C675,C677, C682, C686, C687, C688, C689, C690, C691, C693, C694, C695, C696, C697, C698,C699, C700, C701, C702, C703, C704, C705, C706, C707, C708, C709, C710, C711, C712,C713, C714, C715, C716, C717, C718, C719, C721, C722, C723, C724, C726, C727, C728,C729, C730, C731, C732, C733, C734, C735, C736, C737, C738, C739, C740, C741, C742,C743, C744, C746, C747, C748, C750, C751, C752, C754, C755, C756, C757, C758, C759,C760, C761, C762, C763, C764, C767, C765, C768, C769, C770, C771, C772, C774, C777,C778, C780, C781, C782, C783, C784, C785, C786, C787, C788, C789, C791, C792, C793,C794, C795, C796, C797, C798, C799, C800, C801, C802, C8O3, C804, C8O5, C806, C807,C808, C809, C810, C811, C812, C813, C814, C816, C817, C818, C819, C820, C821 , C822,C823, C824, C825, C826, C827, C828, C829, C830, C831, C832, C833, C834, C835, C836, C837, C838, C839, C840, C841 , C842, C843, C844, C845, C846, and C847.

[00391] It should be noted that representative compounds of the Formulas can be determined through the information provided in Figure 1. Figure 1 provides the necessary cyclization, dimerization, potency, and stability information to determine which compounds fall under a particular Formula. The representative compounds of the Formulas listed herein is not necessarily comprehensive relative to Figure 1.

[00392] In some embodiments of Formula (III), the peptides comprise X5Hhc and X13Hhc, wherein these two residues are directly covalently linked through a disulfide bond. Other pairs can be any combination of Hhc, Cys, Hey, Pen, HhPen, and their D-isoforms, or X5 and X13 can both be any one of these residues.

[00393] In some embodiments, Formula (III) peptides comprise X5Lys_Ac and X13Cys, or X5Hhc and XI 3 is Dab_Acetyl, wherein these two residues are directly covalently linked through a thioether bond. Other pairs include Lys_Ac, Om_Ac or Dab_Ac, for one residue of the pair, and Hhc, Cys, Pen, HhPen, and Hey as the other residue of the pair.

[00394] In another embodiment of Formula (111), X5 is Lys and XI 3 is hE (or vice versa), and these two residues are directly covalently linked through an amide bond (lactam).

[00395] In another embodiment of Formula (III), X5 is LysN3 and X13 is Abu (or vice versa), and these two residue are directly covalently linked as shown in paragraph

[00324] .

[00396] In some embodiments, Formula (III) peptides comprise O3S_Reduced at both X5 and X13.

[00397] In some embodiments, Formula (III) peptides comprise Hey, Hhc, Cys, or Pen at X5 and XI 3, wherein these two residues are indirectly covalently linked through an Ebutene_Linker or a Propane_Linker, such that each of X5 and X 13 form a thioether bond with a terminal end of the Ebutene_Linker or the Propane_Linker. In some embodiments, X5 and X13 can be D-isoforms of Hey, Cys, Hhc, or Pen. Residues with a free thiol in its side chain can be covalently attached to a cyclization linker with two free and separated alkyl groups (one for each thiol). Such cyclization linkers include, for example, a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene linker, a Hexane_Linker, aMethylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane linker, an oXylene linker, an mXylene linker, or a pXylene linker.

[00398] In some embodiments of Formula (III), the peptide is a monomer of a homodimer compound, wherein X14K of each monomer is covalently linked to a dimerization linker. The dimerization linker can be, for example, a PEG linker comprising functional moieties at its terminal ends, e.g., see Table for PEGDA linkers, including PEG21DA and PEG25DA.

[00399] In some embodiments of Formula (III), the peptide is a monomer of a homodimer compound, wherein X14Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2, of each monomer is covalently linked to a DIG dimerization linker.

[00400] In some embodiments of Formula (III), the peptide compound, whether a monomer or a dimer, has a half-life (T1 / 2) of at least 0.5 hours, or between 1-1.5 hours, 1.5-2, or greater than 2 hours in an SGF and / or SIF assay.

[00401] In another embodiment, the invention provides a peptide compound that has an IC50 for hIL-17AA that is less than about InM, and has an IC50 for hIL-17FF that is less than about 10 nM, in a human IL-17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprises or consists of the sequence of Formula (IV):R'-XOO-XO-X I-X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2,R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH, Tie, or absent;X0 is 2Pal, d2Pal, Asn, dE, dH, dQ, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, NMe_His, Om, Sar, Thr, Tie, or absent;XI is INal, Cha, Cyclopropyl_Ala, Dgl, DIP, hCha, hF, hhF, He, Ogl, Phe_4Me, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, E, Gin, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, OmAc, Om2HyAc, OrnMs, OmPVA, Phe_2Ad, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl, or Thr;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, hE, His, LysMe3, Phe_4C00H, or Thr;X5 is Cys, Hey, Hhc, Lys_Ac, LysN3, O2S, O3S, O3S_Reduced, 03S_Me, 03S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen;X6 is 4SCF3Pro, 4SCyclohexPro, Oic, or Pro;X7 is Acvc, Ala, Dab, Gin, Glu, His, hR, Lys_Ac, Oic, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Aoc, Dgl, or Ogl;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, hCha, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4COOH, Trp_4Me, Trp_5CONH2, Trp_6CONH2, Trp_6Me, Trp_7Me, or Trp_7Phe;XI 1 is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Ser, Tba, or Tie;X12 is aMe_Trp, Trp, Trp_56diCl, Trp_5Cl, Trp_5Me, or Trp_6Cl;X13 is Abu, Cys, Dab_Acetyl, Hey, Hhc, O2S, O3S, O3S_Reduced, 03S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S, or Pen;X14 is Aib, Asn, Cys, dK, dN, dQ, dR, Gin, Lys, Lys_Ac, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, Tba, or absent;XI 5 is dE, dR, or absent; andXI 6 is dE, dQ, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety (Formula (IV)).

[00402] In one embodiment of Formula (IV), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00403] In another embodiment of Formula (IV), X5 is Lys_Ac and XI 3 is Cys, and these two residues are directly covalently linked through a thioether bond.

[00404] In another embodiment of Formula (IV), X5 is Hhc and XI 3 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[00405] In another aspect of Formula (IV), X5 is O5S_Reduced and XI 3 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[00406] In another aspect of Formula (IV), X5 is O5S_Reduced and X13 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00407] In another embodiment of Formula (IV), X5 is Lys and XI 3 is hE, or vice versa, and these two residues are directly covalently linked through a lactam.

[00408] In another embodiment of Formula (IV), X5 is LysN3 or Lys and X13 is Abu or hE, and these two residues are directly covalently linked as shown in paragraph

[00324] .

[00409] In another aspect of Formula (IV), both X5 and XI 3 are individually, or both, O3S_Reduced, O3S_Methyl_Reduced, or O4S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00410] In another aspect of Formula (IV), X5 and X13 are individually, or both, O2S, O3S, O3S_Me, or O4S, and these two residues are directly covalently linked through a carboncarbon double bond.

[00411] In another aspect of Formula (IV), X5 and X13 are individually, or both, Cys, Hey, Hhc, or Pen, wherein X5 and X13 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, or a pXylene_Linker

[00412] In another embodiment of Formula (IV), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at XI 4 through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA. X14 can be Lys, dK, Lys_Hexy, Lys_PEG12_NH, or a Lys analog with a side chain comprising a free amine.

[00413] In another embodiment of Formula (IV), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, throughan amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00414] In another embodiment of Formula (IV), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00415] Representative Formula (IV) peptide compounds include: C203, C219, C225, C270, C271, C283, C285, C288, C289, C291, C292, C294, C295, C296, C298, C299, C301, C302,C303, C304, C305, C307, C309, C310, C312, C313, C314, C315, C316, C317, C318, C320,C321, C322, C323, C331, C332, C333, C334, C335, C336, C337, C340, C341, C349, C350,C351, C352, C356, C357, C358, C363, C367, C457, C488, C491, C494, C495, C496, C497,C498, C499, C500, C501, C502, C5O3, C504, C5O5, C508, C509, C510, C511, C513, C515,C517, C519, C520, C521, C522, C525, C528, C529, C530, C531, C532, C533, C534, C535,C536, C537, C538, C539, C540, C541, C542, C543, C544, C545, C546, C547, C548, C557,C559, C560, C561, C562, C566, C567, C568, C569, C570, C571, C572, C574, C575, C576,C577, C578, C579, C580, C581, C583, C584, C585, C586, C587, C588, C589, C590, C591,C592, C593, C594, C595, C596, C597, C598, C599, C600, C601, C605, C606, C607, C608,C609, C610, C611, C612, C613, C614, C615, C617, C618, C620, C621, C629, C631, C632,C634, C647, C648, C650, C651, C654, C658, C659, C660, C661, C662, C664, C667, C672,C675, C677, C682, C686, C687, C688, C689, C690, C691, C693, C694, C695, C696, C697,C698, C699, C700, C701, C702, C703, C704, C705, C706, C707, C708, C709, C710, C711,C712, C713, C714, C715, C716, C717, C718, C719, C721, C722, C723, C724, C726, C727,C728, C729, C730, C731, C732, C733, C734, C735, C736, C737, C738, C739, C740, C741,C742, C743, C744, C746, C747, C748, C750, C751, C752, C754, C755, C756, C757, C758,C759, C760, C761, C762, C763, C764, C765, C767, C769, C770, C771, C772, C774, C777,C778, C780, C781, C782, C783, C784, C785, C786, C788, C789, C791, C792, C793, C794,C795, C796, C797, C798, C799, C800, C801, C802, C803, C804, C805, C806, C808, C809,C810, C811, C812, C813, C814, C816, C817, C818, C819, C820, C821, C822, C823, C824,C825, C826, C827, C828, C829, C830, C831, C832, C833, C834, C835, C836, C837, C838,C839, C840, C841, C842, C843, C844, C845, C846, and C847.

[00416] In one embodiment, the invention provides a peptide compound that has an IC50 for hIL-17AA that is less than about InM, and has an IC50 for hIL-17FF that is less than about 5 nM, in a human IL- 17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprises or consists of the sequence of Formula (V):R'-XOO-XO-X I-X2-X3-X4-X5-X6-X7-X8-X9-X 10-X I I -X 12-X 13-X 14-X 15-X 16-R2, wherein:R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH, Tie or absent;XO is dE, dH, dQ, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, Orn, Sar, Thr, Tie, or absent;XI is Cha, Cyclopropyl_Ala, Dgl, DIP, hhF, He, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, Gin, Glu, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, LyslPEG2Ac, Lys2HyAc, LysMPA, LysMs, OmAc, Orn2HyAc, OmMs, OmPVA, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tetl , or Thr;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Tba, Tie, or Vai;X4 is Asn, Gin, Glu, Glu_OMe, hE, His, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, Lys_Ac, LysN3, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S_Reduced, or Pen;X6 is 4SCF3Pro or Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Oic, Pro, Ser, or Tba;X8 is aMe_Glu, Asp, Gia, Glu, or Tetl;X9 is Aoc, Dgl, or Ogl;X10 is INal, 2Nal, Aoc, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4COOH, Trp_6CONH2, Trp_6Me, Trp_7Me, or Trp_7Phe;XI I is Aib, Ala, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Ser, Tba, or Tie;X12 is aMe_Trp, Trp, Trp_56diCl, or Trp_6Cl;X13 is Abu, Cys, Dab_Acetyl, Hey, Hhc, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, or Pen;X14 Asn, dK, Gin, Lys, Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or absent;XI 5 is dE, dR, or absent; andXI 6 is dE or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety.Formula (V).

[00417] In one embodiment of Formula (V), both X5 and X 13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00418] In another embodiment of Formula (V), X5 is Lys_Ac and XI 3 is Cys, and these two residues are directly covalently linked through a thioether bond.

[00419] In another embodiment of Formula (V), X5 is Hhc and X13 is Dab_Acetyl, and these two residues are directly covalently linked through a thioether bond.

[00420] In another aspect of Formula (V), X5 is O5S_Reduced and XI 3 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00421] In another embodiment of Formula (V), X5 is LysN3 and X13 is Abu, and these two residues are directly covalently linked as shown in paragraph

[00324] .

[00422] In another embodiment of Formula (V), X5 is O2S, O3S, or O4S, and X13 is O2S, O3S, O4S, or O3S_Me, and these two residues are directly covalently linked through a carboncarbon double bond.

[00423] In another embodiment of Formula (V), X5 is O3S Reduced and XI 3 is O3S_Reduced or O3S_Me_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00424] In another embodiment of Formula (V), X5 is Cys or Hey, and X13 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, an Oxetane_Linker, a Pentane_Linker, Propane_Linker, or a pXylene_Linker.

[00425] In other embodiments of Formula (V), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00426] In another embodiment of Formula (V), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00427] In other embodiments of Formula (V), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00428] Representative Formula (V) peptides include: C219, C225, C270, C271, C283, C285, C291, C292, C294, C295, C296, C298, C299, C301, C302, C3O3, C304, C3O5, C307, C309,C310, C312, C313, C314, C315, C316, C317, C320, C321, C331, C332, C333, C334, C335,C336, C337, C341, C349, C350, C351, C363, C367, C457, C488, C491, C494, C495, C496,C497, C498, C500, C501, C503, C5O5, C508, C509, C510, C511, C513, C515, C517, C519,C520, C521, C522, C528, C529, C530, C531, C532, C533, C534, C535, C536, C537, C538,C539, C540, C541, C542, C543, C544, C545, C546, C547, C548, C559, C560, C561, C562,C564, C565, C566, C567, C568, C569, C570, C571, C572, C574, C575, C576, C577, C578,C579, C581, C583, C584, C585, C586, C587, C589, C590, C591, C592, C593, C594, C597,C598, C599, C600, C601, C605, C606, C607, C608, C609, C610, C611, C612, C613, C614,C617, C618, C647, C675, C686, C687, C688, C689, C690, C691, C693, C694, C695, C696,C697, C698, C699, C700, C701, C702, C703, C704, C705, C706, C707, C708, C709, C710,C711, C712, C713, C715, C716, C717, C718, C719, C721, C722, C723, C724, C726, C727,C728, C729, C730, C731, C732, C733, C734, C735, C737, C738, C739, C741, C742, C743,C744, C746, C747, C748, C750, C751, C752, C754, C755, C756, C757, C758, C759, C760,C761, C762, C763, C764, C765, C768, C771, C783, C785, C786, C787, C788, C791, C792,C793, C794, C795, C796, C797, C798, C799, C800, C801, C802, C803, C804, C805, C806, C808, C809, C810, C81 1 , C812, C813, C814, C816, C817, C818, C819, C820, C821 , C822, C823, C824, C825, C826, C827, C828, C829, C830, C831, C832, C833, C834, C835, C836, C837, C838, C839, C840, C841, C842, C843, C844, C845, C846, and C847.

[00429] In one embodiment, the invention provides a peptide compound that has an ICso for hIL- 17 AA that is less than about 1 nM and for hIL- 17FF that is less than about 1 nM in a human IL- 17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (VI):R'-X00-X0-X I-X2-X3-X4-X5-X6-X7-X8-X9-X I0-X I 1-X 12-X I 3-X I4-X L5-X I6-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH or absent;X0 is dE, dH, Gin, Glu, Glu_OMe, His, He, Lys_Me3, Sar, Tie, or absent;XI is Cyclopropyl_Ala, He, Tba, or Vai;X2 is Dab_Ac, Gin, Glu, His, Hse, Lys_Ac, Lys_Me3, LyslPEG2Ac, Lys2HyAc, LysMs, Om2HyAc, OmAc, Q_NHMe, Q_NMe2, Q_EtOMe, or Thr;X3 is Cyclopropyl_Ala, Ogl, Tba, Tie, or Vai;X4 is Asn, Glu, Glu_OMe, hE, Phe_4COOH, or Thr;X5 is Cys, Hey, Hhc, O2S, O3S, O3S_Reduced, or O4S;X6 is Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba;X8 is Asp or Gia;X9 is Dgl, or Ogl;XIO is INal, 2Nal, or Trp;XI I is Aib, Asp, or Glu;X12 is aMe_Trp or Trp;X13 is Cys, Hey, Hhc, O2S, O3S, O3S_Me, O3S_Me_Reduced, O3S_Reduced, or O4S;X14 Asn, Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2;X15 is dR; andXI 6 is dE or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety (Formula (VI)).

[00430] In one embodiment of Formula (VI), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00431] In another embodiment Formula (VI), X5 is O2S, O3S, or O4S, and X13 is O2S, O3S, O4S, or O3S_Me, and these two residues are directly covalently linked through a carboncarbon double bond.

[00432] In another embodiment of Formula (VI), X5 is O3S_Reduced and X13 is O3S_Reduced or O3S_Me_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00433] In another embodiment of Formula (VI), X5 is Cys or Hey, and X13 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an EButene_Linker, an Oxetane_Linker, a Pentane_Linker, or a Propane_Linker.

[00434] In other embodiments of Formula (VI), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00435] In another embodiment of Formula (VI), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG\8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00436] In other embodiments of Formula (VI), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00437] In another embodiment of Formula (VI), R1 is Acetyl or isovaleric acid, and R2 is an amine.

[00438] Representative Formula (VI) compounds include: C270, C271, C302, C304, C3O5, C315, C316, C331, C332, C335, C494, C496, C5O3, C515, C517, C519, C520, C522, C529, C530, C531, C532, C533, C534, C535, C536, C537, C542, C543, C544, C545, C546, C547, C548, C566, C567, C570, C571, C574, C575, C581, C583, C584, C585, C586, C587, C590, C591, C592, C593, C598, C599, C600, C601, C604, C686, C687, C688, C690, C691, C693, C694, C695, C696, C699, C700, C701, C702, C703, C704, C705, C707, C708, C709, C710, C711, C712, C713, C722, C730, C731, C734, C737, C738, C742, C743, C744, C746, C747, C750, C751, C755, C756, C757, C758, C759, C760, C761, C762, C763, C764, C765, C787, C788, C789, C791, C792, C793, C796, C810, C811, C812, C813, C814, C816, C817, C818, C819, C820, C821, C823, C824, C825, C826, C827, C828, C829, C830, C831, C832, C833, C834, C835, C836, C837, C838, C839, C840, C841, C842, C844, C845, and C846.

[00439] In one embodiment, the invention provides a peptide compound that has an IC50 for hIL-17AA that is less than about InM, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (VII):R’-xoo-xo-xi^-xs-xd-xs-xe^-xs-xg-xio-xii-x^-xis-xM-xis-xie-xn-xis- XI 9-X20-X21 -X22-X23-X24-R2,wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, glycolic acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2 or OH or absent;X00 is bA, dH, dK, Tie or absent;X0 is 2Pal, Aib, Asn, d2Pal, d3Pal, dA, dE, dH, dL, dQ, dS, Gia, Gin, Glu, Glu_OMe, His, He, Lys, Lys_Me3, NMe_His, Orn, Pro, Sar, Thr, Tie, or absent;XI is INal, Aph, Dgl, hCha, hF, hhF, He, Lys_lPEG2_lPEG2_IsoGluC12, Ogl, Phe_4Me, Tba, Tie, or Vai;X2 is 2Pal, 3Pal, Gin, His, Hse, Lys_lPEG2_lPEG2_IsoGluC12, Lys_Me3, Orn, Phe_3Ad, Phe_4_2ae, or Phe_4ad;X3 is Cpg, Cyclopropyl_Ala, Dgl, Ogl, Phe_4tBu, Tba, Tie, or Vai;X4 is Asn, Glu, or Thr;X5 is Cys, Hey, Hhc, He, Lys_Ac, O3S, O3S_Reduced, or O5S_Reduced;X6 is Oic or Pro;X7 is Ala, Aze, Dab, His, Lys_Ac, 03S_Me, or Tic;X8 is Asp or Gia;X9 is Dgl, Ogl, or O3S;X10 is INal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, Gin, hCha, Hph, O3S, Phe_4Ad, Phe_4COOH, Tba, Tie, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5Me, Trp_6Cl, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe;XI 1 is Asp, dA, Glu, or O3S_Me;X12 is aMe_Trp, Trp, Trp_5Cl, Trp_5Me, or Trp_6Cl;X13 is Cys, Hey, Hhc, He, O3S, O3S_Me, O3S_Reduced, or O4S;X14 Aib, Arg, Asn, Asp, Cys, dE, dK, dN, dQ, dR, Gin, Glu, Gly, Lys, Lys_lPEG2_lPEG2_IsoGlu_C12, Lys_Ac, 03S_Me, Tba, or absent;XI 5 is Ala, Asn, dE, dQ, dR, Gin, Gly, Leu, Pro, Ser, or absent;X16 is Aad, dE, dH, dQ, PEG4, PEG6, PEG8, Ser, Thr, Vai, or absent;X17 is Asp, Gly, Glu, His, He, Pro, or absent;X18 is His, He, Ser, Tie, Vai, or absent;X19 is His, lie, Vai, or absent;X20 is His, Thr, Vai, or absent;X21 is He, Thr, Vai, or absent;X22 is He, Thr, or absent;X23 is He or absent;X24 is Oic, Pro, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3, X9 and XI 3, or X7 and XI 1, are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker.(Formula (VII)).

[00440] In one embodiment of Formula (VII), the peptide compound is a monomer (not a multimer).

[00441] In one embodiment of Formula (VII), both X5 and XI 3 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00442] In one embodiment of Formula (VII), X5 is Lys_Ac and X13 is Cys, and these two residues are directly covalently linked through a thioether bond

[00443] In one embodiment of Formula (VII), X5 is O5S_Reduced and X13 is Hhc, and these two residues are directly covalently linked through a thioether bond.

[00444] In another embodiment of Formula (VII), both X5 and X13 are O3S, or X5 and X13 are individually or both O3S, O4S, or O3S_Methyl, and these two residues are directly covalently linked through a carbon-carbon double bond.

[00445] In another embodiment of Formula (VII), both X5 and XI 3 are O3S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00446] In another embodiment of Formula (VII), X5 is Cys or Hey, and XI 3 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Butane_Linker, Dimethylcyclopropane_Linker, an EButene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, or a Xylene_Linker.

[00447] In another embodiment of Formula (VII), X9 and X13 are both O3S, which are directly covalently linked through a carbon-carbon single bond.

[00448] In another embodiment of Formula (VII), X7 and XI 1 are both O3S_Me, which are directly covalently linked through a carbon-carbon double bond.

[00449] In another embodiment, each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00450] In other embodiments, a peptide of Formula (VII) can be a monomer in a homodimer compound. As described herein, the monomer can be dimerized in multiple ways, such ashaving a lysine at a residue prior to or after the cyclization residues. In one embodiment, a homodimer comprising a monomer of Formula (VII) can he dimerized by covalently attaching a PEG linker to each monomer through an amide bond to the side chain of a lysine.

[00451] In another embodiment, a homodimer comprising a monomer of Formula (VII) can be modified to have a lysine with a modified side-chain that comprises PEG units and a free amine, such that the amine can form an amide bond with a linker having free COOH groups, such as the DIG_Linker.

[00452] In other embodiments of Formula (VII), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF and / or SIF stability assay.

[00453] In another embodiment of Formula (VII), the compound has an IC50 for hIL-17AA that is less than about InM and an IC50 for hIL-17FF that is less than about 10 nM, wherein the peptide comprises the following:R1 is acetyl, glutaric acid, glycolic acid, or isovaleric acid; R2 is NH2;X00 is bA or absent;X0 is 2Pal, d2Pal, dE, dH, Gia, Glu, His, NMe_His, Tie, or absent;XI is INal, Aph, Dgl, hF, hhF, lie, Tie, or Vai;X2 is 2Pal, 3Pal, or His;X3 is Tba or Tie;X4 is Thr;X5 is Cys, Hey, Hhc, or O3S;X6 is Oic;X7 is Ala or Lys_Ac;X8 is Asp;X9 is Dgl or Ogl;X10 is Cys, Trp, Trp_7Me, or Trp_7Phe;XI I is Asp or Glu;X12 is aMe_Trp or Trp;X13 is Hey, Hhc, O3S, O3S_Me, or O4S;X14 Aib, Asn, Asp, Cys, Gin, Gly, Lys_lPEG2_lPEG2_IsoGlu_C12, or Lys_Ac;X15 is Ala, Asn, dQ, dR, Gin, Gly, Leu, Ser, or absent;XI 6 is Aad, dE, Ser, Thr, Vai, or absent;XI 7 is Asp, His, or absent; andXI 8 is Ser, Val, or absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker.

[00454] In another embodiment of Formula (VII), the compound has an IC50 for ML-17AA that is less than about InM and an IC50 for hIL-17FF that is less than about 10 nM, and the compound exhibits a half-life in both an SGF and an SIF assay greater than about 2 hours, wherein the peptide comprises the following:R1 is acetyl, glutaric acid, glycolic acid, or isovaleric acid; R2 is NH2;X00 is bA or absent;X0 is 2Pal, d2Pal, dE, dH, Glu, His, NMe_His, Tie, or absent;XI is INal, Aph, Dgl, hF, hhF, He, Tie, or Val;X2 is 2Pal, 3Pal, or His;X3 is Tba or Tie;X4 is Thr;X5 is Cys, Hey, Hhc, or O3S;X6 is Oic;X7 is Ala or Lys_Ac;X8 is Asp;X9 is Dgl or Ogl;X10 is Cys, Trp, Trp_7Me, or Trp_7Phe;XI I is Asp or Glu;X12 is aMe_Trp or Trp;X13 is Hey, Hhc, O3S, O3S_Me, or O4S;X14 Aib, Asn, Cys, Gin, Lys_lPEG2_lPEG2_IsoGlu_C12, or Lys_Ac;XI 5 is Ala, dQ, dR, Gin, or absent;XI 6 is Aad, dE, or absent;X17-X24 are absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker.

[00455] Representative monomer peptide compounds (i.e., not representative homodimer compounds that could fall under Formula (VII)) include: C218, C231, C269, C271, C273, C286, C288, C290, C342, C344, C348, C351, C352, C353, C354, C355, C357, C360, C362, C374, C375, C376, C378, C384, C397, C399, C402, C403, C406, C407, C409, C410, C411, C436, C438, C441, C447, C456, C457, C458, C459, C461, C462, C463, C468, C471, C482, C483, C484, C514, C529, C530, C538, C539, C540, C541, C549, C550, C551, C552, C553, C573, C582, C596, C597, C602, C603, C604, C605, C606, C607, C608, C609, C610, C611, C612, C613, C614, C615, C616, C617, C618, C619, C620, C621, C622, C623, C624, C625, C626, C627, C628, C629, C630, C631, C632, C633, C634, C635, C636, C637, C638, C639, C640, C641, C642, C643, C644, C645, C646, C647, C648, C649, C650, C641, C652, C653, C654, C655, C657, C658, C659, C660, C661, C662, C663, C664, C665, C666, C667, C668, C670, C671, C672, C673, C674, C675, C676, C677, C678, C679, C680, C681, C682, C683, C684, C685, C766, C767, C768, C769, C770, C771, C772, C773, C774, C775, C776, C777, C778, C779, C780, C781, C782, C783, C784, C785, C786, C790, C797, C798, C799, C800, C801, C802, C803, C804, C805, C806, C809, C855, C856, C857, C858, C859, C860, C861, C862, C863, C864, C865, C866, C867, C868, C869, C870, C871, C872, C873, C874, C875, C876, C877, C878, C879, C880, C881, C882, C883, C884, C885, C886, C887, C888, C889, C890, C891, C892, C893, C894, C895, C896, and C897..

[00456] In one embodiment, the invention provides a peptide compound that has an IC50 for hIL-17AA and FF that is less than about InM in a human IL- 17 HEK Blue assay, wherein the peptide compound exhibits a half-life in an SIF assay greater than about 2 hours, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (VIII):R'-X00-X0-X I-X2-X3-X4-X5-X6-X7-X8-X9-X I0-X I 1-X 12-X I 3-X I4-X 15-X I6-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;XOO is dH or absent;XO is dE, dH, Gin, Glu, His, lie, Lys_Me3, Sar, Tie, or absent;XI is Cyclopropyl_Ala, He, Tba, or Vai;X2 is Dab_Ac, Gin, His, Lys_Ac, Lys_Me3, LyslPEG2Ac, Lys2HyAc, Orn2HyAc, OrnAc, or Thr;X3 is Cyclopropyl_Ala, Ogl, Tba, Tie, or Vai;X4 is Asn, Glu, Glu_OMe, hE, or Thr;X5 is Cys, Hey, Hhc, O2S, O3S, O3S_Reduced, or O4S;X6 is Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba;X8 is Asp or Gia;X9 is Dgl, or Ogl;X10 is INal, 2Nal, or Trp;XI I is Aib, Asp, or Glu;X12 is aMe_Trp or Trp;X13 is Cys, Hey, Hhc, O2S, O3S, O3S_Me, O3S_Reduced, or O4S;X14 is Asn, Lys, , Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2;XI 5 is dR; andXI 6 is absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety (Formula (VIII)).

[00457] In one embodiment of Formula (VIII), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00458] In another embodiment of Formula (VIII), both X5 and XI 3 are individually or both O2S, O3S, O3S_Methyl, or O4S, and these two residues are directly covalently linked through a carbon-carbon double bond.

[00459] In another embodiment of Formula (VIII), both X5 and XI 3 are O3S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00460] In another embodiment of Formula (VIII), X5 is Cys or Hey, and XI 3 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Dimethylcyclopropane_Linker, an Oxetane_Linker, a Pentane_Linker, or a Propane_Linker.

[00461] In other embodiments of Formula (VIII), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00462] In other embodiments, a peptide of Formula (VIII) can be a monomer in a homodimer compound. As described herein, the monomer can be dimerized in multiple ways, such as having a lysine at a residue prior to or after the cyclization residues. In one embodiment, a homodimer comprising a monomer of Formula (VIII) can be dimerized by covalently attaching a PEG linker to each monomer through an amide bond to the side chain of a lysine.

[00463] In another embodiment, a homodimer comprising a monomer of Formula (VII) can be modified to have a lysine with a modified side-chain that comprises at least one PEG unit and a free amine, such that the amine can form an amide bond with a linker having free COOH groups at its terminal ends, such as the DIG_Linker. Thus, in one embodiment, X14 is Lys_PEG4_PEG4_NH2, Lys_PEG4_lPEG2_NH2, or Lys_PEG8_NH2, and the dimerization linker is a DIG_Linker.

[00464] In other embodiments of Formula (VIII), the compound exhibits a half-life greater than about 0.5 hours, 1.0 hours, 1.5 hours, or 2.0 hours, in an SGF stability assay.

[00465] Representative Formula (VIII) compounds include: C271, C302, C304, C331, C332, C335, C494, C496, C515, C517, C519, C530, C531, C532, C533, C534, C535, C537, C542,C543, C544, C545, C546, C547, C548, C566, C567, C570, C571, C574, C575, C581 , C583,C584, C585, C586, C587, C590, C591, C592, C593, C598, C599, C600, C601, C604, C690,C693, C699, C700, C701, C702, C707, C708, C709, C710, C711, C712, C713, C722, C734,C737, C738, C742, C743, C744, C747, C750, C756, C757, C758, C760, C761, C762, C763,C764, C765, C787, C788, C789, C791, C792, C793, C796, C816, C817, C818, C819, C820, C821 , C823, C824, C825, C826, C827, C828, C829, C830, C831 , C832, C833, C834, C835, C836, C837, C838, C839, C840, C841, C842, C844, C845, and C846.

[00466] In one embodiment, the invention provides a peptide compound that has an IC50 for hIL-17AA that is less than about 1 nM and for IL-17FF that is less than about 5nM, wherein the peptide compound exhibits a half-life in both an SGF and an SIF assay greater than about 2 hours, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (IX):R'-X00-X0-X I-X2-X3-X4-X5-X6-X7-X8-X9-X I0-X I 1-X 12-X I 3-X I4-X E5-X I6-R2, wherein:R1 is acetyl, 3 -hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2 or OH or absent;X00 is dH or absent;X0 is dE, dH, Glu, His, He, Lys_Me3, Sar, Tie, or absent;XI is He or Vai;X2 is His, Lys_Me3, or Gin;X3 is Tba, Tie, or Vai;X4 is Asn, Glu, Glu_OMe, hE, or Thr;X5 is Cys, Hey, Hhc, O3S, or O3S_Reduced;X6 is Oic;X7 is Acvc, Ala, Gin, Glu, Lys_Ac, Pro, Ser, or Tba;X8 is Asp or Gia;X9 is Dgl or Ogl;X10 is INal, 2Nal, or Trp;XI I is Aib, Asp, or Glu;X12 is aMe_Trp or Trp;X13 is Cys, Hey, Hhc, O3S, O3S_Me, or O3S_Reduced;X14 is Lys, Lys_PEG4_lPEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_ NH2;X15 is dR; andX16 is absent;wherein the peptide comprises a cyclic structure wherein X5 and XI 3 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is a monomer in a homodimer complex, wherein each monomer is covalently linked to a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety (Formula (IX)).

[00467] In one embodiment of Formula (IX), both X5 and X13 are Hhc, and these two residues are directly covalently linked through a disulfide bond.

[00468] In another embodiment of Formula (IX), both X5 and XI 3 are 03 S and these two residues are directly covalently linked through a carbon-carbon double bond.

[00469] In another embodiment of Formula (IX), X5 is 03 S and X13 is O3S or O3S_Me and these two residues are directly covalently linked through a carbon-carbon double bond.

[00470] In another embodiment of Formula (IX), both X5 and X13 are O3S_Reduced, and these two residues are directly covalently linked through a carbon-carbon single bond.

[00471] In another embodiment of Formula (IX), X5 is Cys or Hey, and X13 is Cys or Hey, wherein X5 and XI 3 are indirectly covalently linked through a thioether bond, wherein these two residues are indirectly covalently linked through a thioether bond with a terminal end of a Dimethylcyclopropane_Linker, a Pentane_Linker, or a Propane_Linker.

[00472] In other embodiments of Formula (IX), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

[00473] In another aspect of Formula (IX), the peptide is a monomer in a homodimer compound, and wherein each monomer is directly covalently linked to a DIG_linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2 (or its D-form, i.e., dK_PEG4_PEG4_NH2 et al.) through an amide bond, wherein one monomer is linked to one terminal end of this linker and the other monomer is linked to the other terminal end.

[00474] In other embodiments of Formula (IX), the peptide is a monomer in a homotrimer compound, and wherein the amine at the terminal end of the side chain ofX14Lys_PEG12_NH, X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_lPEG2_NH2, or X14Lys_PEG8_NH2,_ in each monomer is covalently linked to the same multimerization linker, TAEP, through an amide bond. The PEG portion in a lysine analog side-chain can be modified to increase or decrease the number of PEG units.

[00475] In other embodiments, any monomer peptide of the invention can be part of a homotrimer through this multimerization approach, i.e., X14Lys_PEG12_NH (or another Lys analog comprising a PEG unit and a free NH2 it is side-chain) with a TAEP multimerization linker.

[00476] In other embodiments, any monomer peptide of the invention can be part of a homotetramer compound, herein the methyl at the terminal end of the side chain of a residue (for example, X14Lys_Hexy) in each monomer is covalently linked to the same multimerization linker, TetN3, through a carbon-carbon single bond.

[00477] Representative Formula (IX) compounds include: C292, C313, C314, C317, C349, C351, C498, C500, C513, C517, C533, C537, C542, C543, C544, C545, C546, C547, C548,C551, C564, C565, C570, C571, C572, C574, C575, C577, C581, C586, C587, C592, C593,C599, C601, C690, C693, C699, C722, C734, C737, C738, C707, C708, C709, C712, C713,C742, C743, C744, C750, C758, C760, C761, C762, C763, C764, C765, C787, C789, C791,C792, C793, C796, C816, C817, C818, C819, C820, C821, C822, C823, C824, C825, C826,C827, C828, C829, C830, C831, C832, C833, C834, C835, C836, C837, C838, C839, C840,C841, C842, C843, C844, C845, C846, and C847.

[00478] In some embodiments, a peptide compound comprising a monomer of any of the Formulas herein (including SEQ ID NO formulas) has an IC5o less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, or 1 nM in a 3T3 Cell Line IL-6 secretion assay (see Example 3).2D. Prodrug Forms of IL- 17 Antagonist Peptides

[00479] A prodrug is a compound that undergoes chemical conversion by an enzymatic or non-enzymatic chemical process in vivo resulting in liberation of the parent drug. Herein, the parent drug is an IL-17 antagonist peptide of the invention, i.e., a peptide according to one of Formulas (I) et al., a peptide according to one of the compounds of Figure 1, or a peptide according to any of the SEQ ID NOs. An intact prodrug is not substantially pharmacologically active. Rather, herein, a dipeptide-based amide or ester extension is attached to the N-terminus, C-terminus, or side chain, of an IL- 17 antagonist peptide of the invention, whereupon in vivo, the extension is cleaved from the peptide of the invention, resulting in the liberation of the peptide in its free form.

[00480] Dipeptides are known in the art for prodrug development for targeting or targeted transport as they are substrates for enzymes or biotransport systems or for the non-enzymatic route for dipeptide prodrug formation, namely the ability to undergo intramolecular cyclization to form the corresponding diketopiperazine (DKP) or diketomorpholine (DKM) and release the active drug. See, e.g., US20110237493A1 and US20130137849A1, both of which are hereby incorporated-by-reference for their teachings on suitable dipeptide moieties that can be attached to the IL- 17 antagonist peptides described herein. Potential susceptibility of dipeptide-based prodrugs to peptidases may be addressed by incorporating at least one non-natural amino acid in the dipeptide motif.

[00481] Such dipeptides may be attached to a drug via ester bonds. In this case, the cyclization reaction consists of a nucleophilic attack of the N-terminal amine of the peptide on the ester carbon atom to form a tetrahedral intermediate. This is followed by a proton transfer from the amine to the leaving group oxy anion with simultaneous formation of a peptide bond to give the cyclic DKP product and free drug. The reaction has been described for ester prodrugs for example for cyclosporin A (Hamel, A R; Hubler, F; Carrupt, A; Wenger, R M; Mutter, M, J. Pept. Res., vol. 63, num. 2 (2004), p. 147-154). WO-A 2009 / 99763 describes ester based dipeptide prodrugs of bioactive peptides such as GLP-1 capable of releasing the peptide through diketopiperazine formation of the dipeptidic extension.

[00482] DKP formation reaction also results from amide prodrugs. U.S. Pat. No. 5,952,294 details prodrug activation using diketopiperazine formation for dipeptidyl amide prodrugs of cytarabine. In this case, the temporary linkage was formed between the carbonyl of a dipeptide and the aromatic amino group of cytarabine. In another study, the utility of diketopiperazine activation was demonstrated for even more stable aliphatic amide prodrugs (Suaifan et al., Tetrahedron 62 (2006) 1 1245-11266).

[00483] Thus, in one embodiment, the invention provides DKP-forming or DKM-forming prodrugs of the peptides of the invention, wherein a DKP-forming moiety or a DKM-forming moiety, i.e., a dipeptide, is attached to the N-terminus, C-terminus, or a side-chain of the peptides of the invention. The dipeptide can be attached through an ester bond or an amide bond.

[00484] In one embodiment, the dipeptide can be attached via an amide bond between the dipeptide and an aliphatic amino group of an IL-17 antagonist peptide of the invention (e.g., a primary amine such as the N-terminal amine or the amino group of an amino acid side chain or via a linking moiety that comprises a primary amine bearing an acyl group or alkyl group).In a related embodiment, the R1 or R2 group of an IL- 17 antagonist peptide of the invention can be absent or modified to comprise an acyl or alkyl group with a free amine moiety.

[00485] The prodrug dipeptides can also have one or more biocompatible polymers attached to a side chain of one of the residues of the dipeptide. Polymers can have, for example, a size selected from a range of about 20,000 to 120,000 Daltons. In one embodiment the polymer has a size selected from a range of about 40,000 to 100,000 or about 40,000 to 80,000 Daltons. In one embodiment the polymer has a size of about 40,000, 50,000, 60,000, 70,000 or 80,000 Daltons. Suitable polymers include but are not limited to dextrans, polylactides, polyglycolides, caprolactone-based polymers, poly(caprolactone), polyanhydrides, polyamines, polyesteramides, poly orthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyesters, polybutylene terephthalate, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof, and biodegradable polymers and their copolymers including caprolactone-based polymers, polycaprolactones and copolymers which include polybutylene terephthalate. In one embodiment the polymer is selected from the group consisting of polyethylene glycol, dextran, polylactic acid, polyglycolic acid and a copolymer of lactic acid and glycolic acid. In one embodiment, the polymer is polyethylene glycol, and the polymer can comprise one or more polyethylene glycol chains linked to the dipeptide element wherein the combined molecular weight of polymer(s) is 40,000 to 80,000 Daltons.

[00486] In one embodiment, the attachment between the dipeptide and a peptide of the invention comprises an amide bond and the dipeptide can comprise a structure according to Dipeptide Formula (I): wherein Rl, R2, R4 and R8 are independently selected from the group consisting of H, Cl-C18 alkyl, C2-C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (Cl-C4 alkyl)CONH2, (C1-C4 alkyDCOOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or Rl and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or aryl; or R4 and R8 together with the atoms to which they are attached form a C3-C6 cycloalkyl; R3 is selected from the group consisting of Cl -Cl 8 alkyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)NH2, (Cl -Cl 8 alkyl)SH, (C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, and (C1-C4 alkyl)(C3-C9 heteroaryl) or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R5 is NHR6 or OH; R6 is H, Cl-C8 alkyl or R6 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; and R7 is selected from the group consisting of H and OH, with the proviso that when R4 and R3 together with the atoms to which they are attached form a 5 or 6 member heterocyclic ring, then at least one of R1 and R2 are other than hydrogen.(Dipeptide Formula (I).)

[00487] In another embodiment, the dipeptide structure that is attached to a peptide of the invention through an amide bond comprises a structure according to Dipeptide Formula (II): wherein(I) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (C1 -C 18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1 -C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is Cl -Cl 8 alkyl; R4 and R8 are each H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to an IL- 17 antagonist peptide of the invention through an amide bond between the dipeptide and an aliphatic amino group (e.g., a primary amine such as the N-terminal amine or the amino group of an amino acid side chain or via a linking moiety that comprises a primary amine bearing acyl group or alkyl group) of the IL-17 antagonist peptide; with the proviso that when both R1 and R2 are H, R3 is C5-C18 alkyl;(II) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is Cl -Cl 8 alkyl; R4 is selected from the group consisting of CH3, CH2(C1 -C1O alkyl), CH2(C2-C10 alkenyl), CH2(C0-C10 alkyl)OH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)SCH3, CH2(C0-C3 alkyl)CONH2 CH2(C0-C3 alkyl)COOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH2+)NH2 CH2(C0-C3 alkyl)(C3-C6 cycloalkyl), CH2(C0-C3 alkyl)(C2-C5 heterocyclic), CH2(C0-C3 alkyl)(C6-C10 aryl)R7, CH2(C1-C3 alkyl)(C3-C9 heteroaryl), and CH2(C0-C12 alkyl)(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C 1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to an IL- 17 antagonist peptide of the invention through an amide bond between the dipeptide and an aliphatic amino group (e.g., a primary amine such as the N-terminal amine or the amino group of an amino acid side chain or via a linking moiety that comprises a primary amine bearing acyl group or alkyl group) of the IL- 17 antagonist peptide; with the proviso that when either R1 or R2 are H, then R4 and R3 together with the atoms to which they are attached do not form a 4, 5 or 6 member heterocyclic ring;(III) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (Cl -Cl 8 alkyDOH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 is independently selected from the group consisting of CH(C1-C8 alkyl)2, CH(C2-C8 alkenyl)2, CH(C1-C8 alkyl)(OH), CH(C1-C8 alkyl)((Cl-C8 alkyl)SH), and CH(C1-C3 alkyl)((Cl-C8 alkyl)(NH2); R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to an IL- 17 antagonist peptide of the invention through an amide bond between the dipeptide and an aliphatic amino group of the IL- 17 antagonist peptide;(IV) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, alkyl)(C3-C9 heteroaryl), and C12 alkyl(Wl )Cl -C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 and R8 are each H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein A-B is linked to an IL-17 antagonist peptide of the invention through an amide bond between A-B and an aromatic amino group on an amino acid side chain of an IL- 17 antagonist peptide;(V) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, alkyl)COOH, alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 is selected from the group consisting of CH3, CH2(C1-C1O alkyl), CH2(C2-C10 alkenyl), CH2(C0-C10 alkyDOH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)SCH3, CH2(C0-C3 alkyl)CONH2, CH2(C0-C3 alkyDCOOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH2+)NH2, CH2(C0-C3 alkyl)(C3-C6 cycloalkyl), CH2(C0-C3 alkyl)(C2-C5 heterocyclic), CH2(C0-C3 alkyl)(C6-C10 aryl)R7, CH2(C1-C3 alkyl)(C3-C9 heteroaryl), and CH2(C0-C12 alkyl)(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH. wherein the dipeptide is linked to an IL- 17 antagonist peptide of the invention through an amide bond between the dipeptide and an aromatic amino group on an amino acid side chain of the IL- 17 antagonist peptide of the invention;(VI) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2 +)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; or R1 and R2 together with the atoms to which they are attached form a C3-C 12 cycloalky]; R3 is C1 -C 18 alkyl; R4 is independently selected from the group consisting of CH(C1-C8 alkyl)2, CH(C2-C8 alkenyl)2, CH(C1-C8 alkyl)(OH), CH(C1-C8 alkyl)((Cl-C8 alkyl)SH), and CH(C1-C3 alkyl)((Cl-C8 alkyl)(NH2); R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C 1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to an IL- 17 antagonist peptide of the invention through an amide bond between the dipeptide and an aromatic amino group on an amino acid side chain of the IL- 17 antagonist peptide of the invention.

[00488] Suitable amino acids for the dipeptide (which can be referred to herein as “A-B”) include, but are not limited to:(1) for the first residue of the dipeptide (N-terminal residue of the dipeptide), or the “A” residue: Aib, Gly, Ala, Leu, Met, Asn, Glu, Asp, Gin, His, Lys, Arg, Ser, Cys, Pro, Phe, Tyr, Trp, He, Vai, Thr, their corresponding D-forms, their N-methyl variant forms (N-methyl amino acids have a methyl group attached to the nitrogen), and D-forms of the N-methyl variants;(2) for the second residue of the dipeptide, or the “B” residue, modified amino acids are contemplated, where the modification comprises attaching an alkyl group to the amino group of the core amino acid structure, for example: Gly(N — Cl-C8alkyl), Gly(N — Cl-C8alkyl), Ala(N— Cl -C8alkyl), Leu(N— C l-C8alkyl), Met(N— Cl-C8alkyl), Asn(N— Cl-C8alkyl), G1U(N— Cl-C8alkyl), Asp(N— Cl-C8alkyl), Gln(N— Cl-C8alkyl), His(N— Cl-C8alkyl), Lys(N— Cl-C8alkyl), Arg(N— Cl-C8alkyl), Ser(N— Cl-C8alkyl), Cys(N— Cl-C8alkyl), Pro, Phe(N— Cl-C8alkyl), Tyr(N— Cl-C8alkyl), Trp(N— Cl-C8alkyl), Val(N— Cl-C8alkyl), Thr(N — Cl-C8alkyl), Gly(N-methyl), Ala(N-methyl), Leu(N-methyl), Met(N-methyl), Asn(N-methyl), Glu(N-methyl), Asp(N-methyl), Gln(N-methyl), His(N-methyl), Lys(N-methyl), Arg(N-methyl), Ser(N-methyl), Cys(N-methyl), Phe(N-methyl), Tyr(N-methyl), Trp(N-methyl), Ile(N-methyl), Val(N-methyl), Thr(N-methyl), Gly(N-hexyl), Ala(N-hexyl), Leu(N-hexyl), Met(N-hexyl), Asn(N-hexyl), Glu(N-hexyl), Asp(N-hexyl), Gln(N-hexyl), His(N-hexyl), Lys(N-hexyl), Arg(N-hexyl), Ser(N-hexyl), Cys(N-hexyl), Phe(N-hexyl),Tyr(N-hexyl), Trp(N-hexyl), Ile(N-hexyl), Val(N-hexyl), Thr(N-hexyl), and their corresponding D-isoforms.

[00489] In some embodiments, the half-life of the prodrug, e.g., the chemical cleavage halflife (tl / 2) of A-B from a peptide of the invention under physiological conditions, is dependent on the presence and length of the N-alkyl substituent on the B amino acid. For example, a prodrug that has a shorter N-alkyl substituent on the B amino acid (e.g. Gly(N-methyl)), will undergo a slower rate of cleavage of A-B, and have a longer half-life, than a prodrug that has a longer N-alkyl substituent on the B amino acid (e.g., Gly(N-hexyl)).

[00490] In some embodiments, the half-life of the prodrug is dependent on the presence or absence of an alkyl side chain, and the degree of substitution at the beta position of the alkyl side chain, of the B amino acid of the dipeptide prodrug element. For example, a prodrug that has an N-alkylated B amino acid that is disubstituted at the beta position (e.g., N-alkylated isoleucine) will undergo slower cleavage of A-B, and have a longer ha...

Claims

1. A peptide comprising or consisting of a sequence of Formula (I): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2, wherein: R1 is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, 1Pip_AceticAcid, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, glutaric_acid, isovaleric acid, methanesulfonyl acetic acid, Mor_propanoic_acid, pivalic acid (PVA), 1PEG2_1PEG2_IsoGlu_C12, 1PEG2_1PEG2_IsoGlu_C12_Diacid, 1PEG2_1PEG2_IsoGlu_C18_diacid, 1PEG2_1PEG2_IsoGlu_Palm, 1PEG2_1PEG2_Ahx_C18_Diacid, 1PEG2_PEG2_Ahx_Palm, or absent; R2 is NH2 or OH or absent; X00 is Cha, dH, dK, Ogl, Tle or absent;X0 is 2Pal, 3Pal, Aib, Asn, d2Pal, d3Pal, dA, dE, dF, dH, dK, dL, dQ, dS, Gln, Glu, Glu_OMe, His, Ile, Lys, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_Palm, Lys_Me3, NMe_His, Orn, Pro, Sar, Thr, Tle, or absent;X1 is 1Nal, Bip, Cha, Chg, Cyclopropyl_Ala, Dgl, DIP, dI, hCha, hF, hhF, Ile, Lys, Lys_1PEG2_1PEG2_IsoGlu_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_Palm, Ogl, Phe_4Me, Tba, Tle, Val, or absent;X2 is 2Pal, 3Pal, aMe_Arg, Agb, Agp, bhF, Cit, Dab, Dab_Ac, Dab_2HyAc, Dab_Ms, Dab_Ts, dDab2HyAc, dH, dT, Glu, Gln, His, hR, Hse, Lys, Lys_1PEG2_Ac, Lys_1PEG2_1PEG2_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, Lys_1PEG2Ac, Lys_2HyAc, LysMPA, Lys_Ms, Lys_Ns, Lys_Ts, NMe_Thr, Orn, Orn_Ac, Orn_Ms, OrnPVA, Orn_Ts, Phe_2Ad, Phe_3Ad, Phe_4Ad, Phe_4_2ae, Phe_4_COOH, Phe_4_Cl, Phe_4guan, Phe_4OMe, Phe_4_Morph, Phe_pentaF, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Q_MecPro, Tet1, Thr, or Thi;X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, bhV, Cha, Chg, Cprg, Cpg, cyclopentyl_Ala, cyclopropyl_Ala, Cys, Dgl, DiethylGly, dL, dV, H_Cha, Hcy, hL, Hph, Igl, Nle, NMe_Leu, nVF3, O4S, O5S, Ogl, Phe_4tBu, Phe_4Cl, Phe_4_OMe, Phe_4_Me, Phe_3_4_Cl2, Phe_4_CF3, Peptoid_CH2_V, Pra, Tba, Tle, or Val;X4 is Asn, dT, Dab, Gln, Glu, Glu_OMe, hE, His, hR, Lys_Me3, Orn, Phe4_COOH, Phe_4_Morph, Tet1, Thr, or Thr_Me;X5 is Abu, aMe_Lys_Ac, Cha, Cys, Chg, Dab_Acetyl, dI, dLys_Ac, Glu, Hcy, hE, Hhc, HhPen, Ile, Lys, Lys_Ac, LysN3, LysPhAc, NMe_Lys_Ac, O2S, O3S, O3S_Reduced, O4S_Reduced, O5S, O5S_Reduced, Orn_Acetyl, or Pen;X6 is 4R_BenzyloxyPro, 4RPhePro, 4S_Amp, 4S_Amp_Cyclhex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4ScyclohexPro, 5RPhePro, Azetidinone, Dfp, dP, Hpr, Oic, or Pro;X7 is Acvc, Aib, Ala, aMe_Phe, Arg, Aze, Cys, Dab, dC, Gln, Glu, His, Hpr, hR, Lys_1PEG2_1PEG2_Ahx_C18_Diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_C18_ diacid, Lys_1PEG2_1PEG2_IsoGlu_Palm, Lys_Ac, O3S, O3S_Me, O4S, Pro, Ser, Tba, or Tic;X8 is aMe_Asp, aMe_Glu, Asp, dD, Gla, Gln, Glu, Phe_3COOH, Phe_4COOH, Tet1, or Tet2;X9 is Aoc, Cha, Cys, Dgl, hCha, Hcy, Leu, Nle, O3S, O3S_Reduced, O6S, Ogl, Phe_34diF, Phe_4CF3, or Tba;X10 is 1Nal, 2Nal, Aib, aMe_Phe, aMe_Trp, Aoc, Cys, DIP, dW, hCha, Gln, Hph, Lys_1PEG2_1PEG2_IsoGlu_C12, Phe, Phe_34diCl, Phe_3Ad, Phe_4ad, Phe4_COOH, Phe_4OMe, Phg, Tba, Tle, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, Trp_7Phe, or Trp; X11 is Aib, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Cys, Chg, dA, dS, Gln, Glu, Hcy, Leu, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_Me3, O3S, O3S_Me, O4S, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tle;X12 is 1Nal, aMe_Trp, Hph_34diCl, Orn_Bz, Trp, Trp_4Cl, Trp_5Br, Trp_5Cl, Trp_5Et, Trp_5Me, Trp_56diCl, Trp_56diMe, Trp_6Cl, Trp_6CF3, Trp_6Me, or Trp_7Cl;X13 is Abu, aMe_Cys, aMe_Lys_Ac, Cys, Cha, Dab_Acetyl, Glu, Hcy, hE, Hhc, HhPen, Ile, Lys, Lys_Ac, LysN3, O2S, O3S, O3S_Me, O3S_Me_Reduced, O3S_Reduced, O4S_Reduced, Orn_Acetyl, or Pen;X14 is Aib, Arg, Asn, Cys, dE, dF, dH, dK, dL, dN, dQ, dR, Gln, Glu, Lys, Lys_1PEG2_1PEG2_NH2, Lys_1PEG2_1PEG2_1PEG2 NH2, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_Hexy, Lys_PEG12_NH, Lys_PEG4_1PEG2_NH2, Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, O3S, O3S_Me, Orn_Acetyl, PEG12, Tba, or absent; X15 is dE, dK, dR, Glu, Lys, Lys_PEG4_PEG4_NH2, Lys_Dimethyl, Pro, or absent; andX16 is dE, dF, dH, dK, dL, dR, dQ, Lys, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_Palm, Lys_PEG4_PEG4_NH2, Lys_Ac, or absent; wherein:(i) the peptide optionally comprises a cyclic structure wherein at least two amino acid residues in the peptide (monomer) are either: (a) directly covalently linked, or (b) indirectly covalently linked through a cyclization linker;(ii) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other, or indirectly covalently linked to each other through a dimerization linker; and / or(iii) the peptide is optionally conjugated with a half-life extension moiety. Formula (I).

2. The peptide of claim 1, wherein the peptide comprises a cyclic structure characterized by an intramolecular cross-link between residues X5 and X13 (X5-X13), X7 and X11 (X7-X11), X9 and X13 (X9-X13), or X10 and X14 (X10-X14).

3. The peptide of claim 2, wherein the intramolecular cross-link comprises a covalent bond directly or indirectly between the cross-linked residues, wherein the covalent bond comprises an amide bond, a disulfide bond, a thioether bond, a carbon-carbon single bond, or a carbon-carbon double bond.

4. The peptide of claim 3, wherein the intramolecular cross-link is a direct covalent bond between the cross-linked residues.

5. The peptide of claim 4, wherein the two cross-linked amino acid residues are at X5 and X13 or X9 and X13, and the two amino acids are directly covalently linked through a disulfide bond.

6. The peptide of claim 5, wherein the two amino acid residues cross-linked through a disulfide bond are both, or individually, Cys, Hcy, Hhc, Pen, or HhPen.

7. The peptide of claim 4, wherein the two directly cross-linked amino acid residues are at X5 and X13, X7 and X11, X9 and X13, or X10 and X14, and wherein these two amino acids are directly covalently linked through a thioether bond.

8. The peptide of claim 7, wherein the two amino acid residues directly cross-linked through a thioether bond are: Cys, Hcy, Hhc, Pen, or hhPen, their D-forms, and their a-methyl variants, for one residue of the pair; and aMe_Lys_Ac, Dab_Acetyl, Dap_Ac, dLys_Ac, NMe_Lys_Ac, Lys_Ac, Lys_PEG12_Ac, LysPhAc, or Orn_Acetyl, for the other residue of the pair, in either order.

9. The peptide of claim 4, wherein the two directly cross-linked amino acid residues are at X5 and X13, and the two amino acids are directly covalently linked through a cyclic amide bond (lactam).

10. The peptide of claim 9, wherein the two amino acid residues cross-linked through a cyclic amide bond are Lys paired with Glu, hE, or Asp.

11. The peptide of claim 4, wherein the two directly cross-linked amino acid residues are at X5 and X11, or X9 and X13, and the two amino acids are directly covalently linked through a carbon-carbon double bond.

12. The peptide of claim 11, wherein the two amino acid residues cross-linked through a carbon-carbon double bond are both, or individually, O2S, O3S, O3S_Me, O4S, O5S, or O6S.

13. The peptide of claim 4, wherein the two directly cross-linked amino acid residues are at X5 and X13, or at X9 and X13, and the two amino acids are directly covalently linked through a carbon-carbon single bond.

14. The peptide of claim 13, wherein the two amino acid residues cross-linked through a carbon-carbon single bond are both, or individually, O3S_Reduced, O3S_Me_Reduced, or O4S_Reduced.

15. The peptide of claim 3, wherein the intramolecular cross-link is an indirect covalent bond between the cross-linked residues, wherein each of the cross-linked residues form a direct covalent bond with a cyclization linker.

16. The peptide of claim 15, wherein the two amino acid residues are indirectly covalently linked through a thioether bond with a cyclization linker.

17. The peptide of claim 16, wherein the cyclization linker comprises an alkane or an alkene with two free alkyl groups, a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, an mXylene_Linker, a pXylene_Linker, or an oXylene_Linker..

18. The peptide of claim 17, wherein the cyclization linker comprises one of the Xylene_Linkers, and wherein the two amino acid residues cross-linked through a thioether bond with the cyclization linker are at X5 and X13, X7 and X11, X9 and X13, or X10 and X14, wherein the residues are both, or individually, Cys or dC.

19. The peptide of claim 17, wherein the cyclization linker comprises a Carbonyl_Linker, a Dimethylcyclopropane_Linker, a Ebutene_Linker, a Hexane_Linker, an Oxetane_Linker a Pentane_Linker, or a Propane_Linker, and wherein the two amino acid residues cross-linked through a thioether bond with the cyclization linker can be both, or individually, Cys, dC, Hcy, Hhc, Pen, or HhPen.

20. The peptide of any one of claims 1-19, wherein the peptide is a monomer of a homodimer or heterodimer.

21. The peptide of claim 20, wherein the homodimer comprises each monomer having a direct covalent attachment to a dimerization linker.

22. The peptide of claim 21, wherein each monomer comprises Lys or dK at X14, X15, or X16 that is directly covalently linked to a PEG linker, or wherein each monomer comprises Lys_PEG4_PEG4_NH2, Lys_PEG4_1PEG2_NH2, or Lys_PEG8_NH2, at X14, X15, or X16 that is directly covalently linked to a DIG_Linker.

23. The peptide of claim 22, wherein the PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25.

24. The peptide of claim 23, wherein each monomer is directly covalently linked to the PEG linker through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker.

25. The peptide of claim 24, wherein the PEG linker is PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

26. The peptide of any one of claims 1-25, wherein the monomer or homodimer exhibits an IC50 value of less than about 20 nM in a human IL-17 HEK Blue assay.

27. The peptide of any one of claims 1-25, wherein the monomer or homodimer exhibits a half-life greater than 0.5 hours in an SGF and / or SIF stability assay.

28. The peptide of claim 26, wherein the homodimer exhibits at least a 2-fold improvement in its IC50 value in a human IL-17 HEK Blue assay as compared to its monomeric form.

29. The peptide of claim 27, wherein the homodimer exhibits at least an improvement in its half-life in an SGF and / or an SIF stability assay as compared to its monomeric form.

30. A homodimer peptide compound that exhibits an IC50 equal to or less than 10 nM in a HEK Blue IL-17 assay, wherein the compound has two monomer cyclic peptides both comprising or consisting of the same amino acid sequence from Formula (II):R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2, R1 is acetyl (Ac), 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, 1PEG2_1PEG2_IsoGlu_Palm, 1PEG2_1PEG2_IsoGlu_C18_Diacid, 1PEG2_1PEG2_IsoGlu_C12, or absent; R2 is NH2, OH, or absent; X00 is dH or absent;X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Cha, Chg, Cyclopropyl_Ala, DIP, Ile, Lys_1PEG2_1PEG2_IsoGlu_C12, Ogl, Tba, or Val;X2 is 2Pal, 3Pal, Agb, Agp, Cit, Dab_Ac, Dab2HyAc, DabMs, DabTs, dDab2HyAc, Gln, Glu, His, hR, Hse, Lys, Lys_1PEG2_1PEG2_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, Lys1PEG2Ac, Lys2HyAc, LysMPA, LysMs, LysNs, LysTs, OrnAc, Orn2HyAc, OrnMs, OrnPVA, OrnTs, Phe_2Ad, Phe_3Ad, Phe_4_Morph, Phe_4Ad, Phe_4COOH, Phe_4Guan, Phe_4OMe, Phe_pentaF, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, Tet1, Thi, or Thr;X3 is AlaCF3, AlaCHF2, Ala_cycBu, Aoc, Cha, Chg, Cpg, cyclopentyl_Ala, cyclopropyl_Ala, Cys, dV, H_Cha, Hcy, Hph, Igl, nVF3, Ogl, Phe_34diCl, Phe_4CF3, Phe_4Cl, Phe_4Me, Phe_4OMe, Phe_4tBu, Tba, Tle, or Val;X4 is Asn, Gln, Glu, Glu_OMe, His, hE, hR, Lys_Me3, Phe4_COOH, Thr, or Thr_Me;X5 is Abu, Cys, Cha, Chg, Dab_Acetyl, Glu, Hcy, hE, Hhc, Ile, Lys, Lys_Ac, LysN3, LysPhAc, O2S, O3S, O3S_Reduced, O4S, O4S_Reduced, Orn_Acetyl, or Pen;X6 is 4RBenzyloxyPro, 4RPhePro, 4S_Amp_Cyclohex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4SCyclohexPro, 5RPhePro, Azetidinone, Hpr, Oic, or Pro;X7 is Ala, Acvc, Aib, aMe_Phe, Arg, Cys, Gln, Glu, His, hR, Lys_1PEG2_1PEG2_Ahx_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_Palm, Lys_Ac, O3S_Me, Oic, Pro, Ser, or TbaX8 is aMe_Glu, Asp, dD, Gla, Glu, Phe_3COOH, Phe_4COOH, Tet1, or Tet2;X9 is Aoc, Dgl, Hcy, Leu, O3S, O3S_Reduced, or Ogl; X10 is 1Nal, 2Nal, aMe_Phe, aMe_Trp, Cys, Hph, Lys_1PEG2_1PEG2_IsoGlu_C12, Phe_4COOH, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, Trp_7Phe, or Trp; X11 is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Cys, Chg, Gln, Glu, Leu, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_Me3, O3S_Me, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tle;X12 is 1Nal, aMe_Trp, Orn_Bz, Trp, Trp_56diCl, Trp_56diMe, Trp_5Br, Trp_5Cl, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, or Trp6Me;X13 is Abu, aMe_Cys, aMe_Lys_Ac, Cys, Cha, Dab_Acetyl, Glu, Hcy, hE, Hhc, Ile, Lys, Lys_Ac, LysN3, O2S, O3S, O3S_Me, O3S_Me_Reduced, O3S_Reduced, O4S, O4S_Reduced, Orn_Acetyl, or Pen;X14 is Asn, dK, dR, Lys, Lys_Ac, Lys_PEG4_PEG4_NH2, Orn_Acetyl, or PEG12; X15 is dR, dK, Lys, Lys_PEG4_PEG4_NH2, or Lys_Dimethyl, or absent;X16 is dK, Lys, Lys_Ac, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_Palm, Lys_PEG4_PEG4_NH2, or absent;wherein:(i) the monomer comprises a cyclic structure wherein two amino acid residues in the peptide monomer are directly covalently linked or indirectly covalently linked through a through an amide bond, a disulfide bond, a thioether bond, a carbon-carbon single bond, or a carbon-carbon double bond, wherein the two amino acid residues are at X5 and X13, X7 and X11, X9 and X13, or X10 and X14; and(ii.a) each monomer is directly covalently linked to a polyethylene glycol (PEG) linker at X14, X15, or X16 through an amide bond, wherein the PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25, and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, wherein X14, X15, or X15 is Lys or dK, or (ii.b) each monomer is directly covalently linked to a DIG_linker (diglycolic acid linker) at X14, X15, or X16 through an amide bond, where X14, X15, or X16 is Lys_PEG4_PEG4_NH2, Lys_PEG4_1PEG2_NH2, or Lys_PEG8_NH2. (Formula (II).)31. The homodimer compound of claim 30, wherein the cyclic structure of each monomer comprises two amino acid residues directly or indirectly covalently linked at X5 and X13.

32. The homodimer compound of claim 30, wherein a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.A): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is NH2, OH, or absent;X00 is dH or absent,X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Chg, Ile, Lys_1PEG2_1PEG2_IsoGlu_C12, Ogl, or Val; X2 is 2Pal, 3Pal, Agb, Agp, Dab_Acetyl, Dab_2HyAc, Dab_Ms, Dab_Ts, dDab_2HyAc, Gln, Glu, His, hR, Hse, Lys, Lys_1PEG2_1PEG2_C18_Diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys1PEG2Ac, Lys2HyAc, LysMs, LysTs, OrnAc, OrnMs, OrnTs, Phe_2Ad, Phe_3Ad, Phe_4Ad, Phe_4Guan, Q_NHMe, Q_NMe2, Q_Pyro, Tet1, or Thr;; X3 is Ala_cycBu, Aoc, Cha, Chg, Cpg, cyclopropyl_Ala, dV, H_Cha, Hph, Igl, Ogl, Phe_34diCl, Phe_4CF3, Phe_4Cl, Phe_4Me, Phe_4OMe, Phe_4tBu, Tba, Tle, or Val; X4 is Glu, hR, or Thr; X5 is Hhc; X6 is Oic or Pro; X7 is Ala, Acvc, aMe_Phe, Gln, Glu, His, hR, Lys_Ac, Pro, Ser, or Tba; X8 is aMe_Glu, Asp, dD, Gla, Glu, Tet1, or Tet2; X9 is Leu or Ogl; X10 is 1Nal, aMe_Trp, Trp_7Phe, or Trp; X11 is aMe_Phe, Asp, or Glu; X12 is aMe_Trp, Trp_5Br, Trp_5Cl, Trp_5Me, Trp_6Cl, Trp_6Me, or Trp; X13 is Hhc; X14 is Asn, dR, dK, Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR, Lys, or absent; X16 is absent;wherein: (a) X5 and X13 are directly covalently linked through a disulfide bond; wherein each monomer is directly covalently linked to a PEG linker at X14 or X15 through an amide bond, and (b) X14 or X15 is dK or Lys, and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or X2 is dK or Lys and wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker, or X14 is Lys_PEG4_PEG4_NH2, Lys_PEG8_NH2, or Lys_PEG4_1PEG2_NH2, and wherein one monomer is linked to one terminal end of a DIG_Linker and the other monomer is linked to the other terminal end of the DIG_Linker. (Formula (II.A)).

33. The homodimer compound of claim 30, wherein a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.B): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent; X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Ile or Val; X2 is His or Lys_Me3; X3 is Tba or Val; X4 is Thr; X5 is Chg, Ile, or Tle; X6 is Azetidinone, Oic, or Pro; X7 is Ala; X8 is Asp or Gla; X9 is Hcy; X10 is Trp; X11 is Asp or Glu; X12 is Trp; X13 is Hhc; X14 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X9 and X13 that are directly covalently linked through a disulfide bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_1PEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.B)).

34. The homodimer compound of claim 30, wherein the cyclic structure of each monomer comprises the two amino acid residues directly covalently linked through a thioether bond at: (a) X5 and X13, wherein X5 is Cys, Dab_Acetyl, Hcy, Hhc, Lys_Ac, LysPhAc, Orn_Acetyl, or Pen, and X13 is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, Hcy, Hhc, Lys_Ac, Orn_Acetyl, or Pen; (b) X7 and X11, wherein X7 is Cys or Lys_Ac and X11 is Cys or Lys_Ac; or (c) X10 and X14, wherein X10 is Cys and X14 is Lys_Ac or Orn_Acetyl; and wherein aMe_Cys, Cys, Hcy, Hhc, or Pen is paired with aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Orn_Acetyl, and vice versa.

35. The homodimer compound of claim 30, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.C): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Lys_Me3, Sar, Tle, or absent; X1 is Chg, Ile, Lys_1PEG2_1PEG2_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_Palm, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_C18_Diacid, Ogl, or Val; X2 is 2Pal, 3Pal, Agb, Agp, aMe_Arg, Cit, Dab_Ac, Dab2HyAc, DabMs, DabTs, dDab2HyAc, Gln, Glu, His, hR, Hse, Lys, Lys_1PEG2_1PEG2_C18_diacid, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_1PEG2_1PEG2_IsoGlu_C18_Diacid, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys1PEG2Ac, Phe_4_Morph, Phe_4COOH, Phe_4OMe, Phe_pentaF, Thr, or Thi; or Thr; X3 is Cha, H_Cha, Ogl, Phe_4tBu, Tba, or Tle, or Val; X4 is Asn, Gln, Glu, His, Phe_4COOH, Thr, or Thr_Me; X5 is Cys, Dab_Acetyl, Hcy, Lys_Ac, LysPhAc, Orn_Acetyl, or Pen; X6 is Oic, or Pro; X7 is Aib, Ala, Arg, His, Lys_1PEG2_1PEG2_Ahx_C18_Diacid, Lys_1PEG2_1PEG2_IsoGlu_C18_Diacid, Lys_1PEG2_1PEG2_IsoGlu_Palm; X8 is aMe_Glu, Asp, Gla, Glu, or Tet1; X9 is Ogl; X10 is 1Nal, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe; X11 is aMe_Asp, Asp, Gln, or Glu; X12 is Trp, Trp_56diCl, Trp_56diMe, Trp_5Et, Trp_5Me, Trp_6CF3, Trp_6Cl, or Trp_6Me; X13 is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, Hcy, Hhc, Lys_Ac, Orn_Acetyl, or Pen; X14 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and X13 that are directly covalently linked through a thioether bond; wherein aMe_Cys, Cys, Hcy, Hhc, or Pen is paired with aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Orn_Acetyl, and vice versa; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker or each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG8_NH2, or X14Lys_PEG4_1PEG2_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II.C)).

36. The homodimer compound of claim 30, wherein a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.D): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Ile or Val; X2 is His, Lys_Me3, or Thr; X3 is Tba, Tle, or Val; X4 is Thr or Glu; X5 is Ile; X6 is Oic or Pro; X7 is Cys or Lys_Ac; X8 is Asp; X9 is Leu or Ogl; X10 is 1Nal or Trp; X11 is Cys or Lys_Ac; X12 is aMe_Trp or Trp; X13 is Ile; X14 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; X16 is absent; wherein X7 and X11 are not both Cys or Lys_Ac; and wherein: (i) the cyclic structure of each monomer comprises X7 and X11 that are directly covalently linked through a thioether bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker or each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_1PEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II.D).)37. The homodimer compound of claim 30, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.E): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Ile or Val; X2 is Thr or Lys_Me3; X3 is Tba or Tle; X4 is Thr or Glu; X5 is Chg or Ile; X6 is Oic or Pro; X7 is Ala; X8 is Asp; X9 is Ogl; X10 is Cys; X11 is Asp or Glu; X12 is Trp; X13 is Ile; X14 is Lys or Orn_Ac; X15 is dR; X16 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; wherein: (i) the cyclic structure of each monomer comprises X10 and X14 that are directly covalently linked through a thioether bond; and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X164Lys_PEG4_PEG4_NH2, X16Lys_PEG4_1PEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.E)).

38. The homodimer compound of claim 30, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.F): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Ile, Val, or Tba; X2 is Gln, His, Hse, Lys_Me3, or Thr; X3 is cyclopropyl_Ala, Tba, Tle, or Val; X4 is Glu or Thr; X5 is O3S_Reduced or O4S_Reduced; X6 is Pro or Oic; X7 is Ala; X8 is Asp or Gla; X9 is Ogl; X10 is 1Nal or Trp; X11 is Asp or Glu; X12 is Trp or Trp5Me; X13 is O3S_Reduced, O3S_Methyl_Reduced, O4S_Reduced; X14 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and X13 that are directly covalently linked through a carbon-carbon single bond (-C-C-); and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_1PEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.F)).

39. The homodimer compound of claim 30, a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.G): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Chg, Val, or Ile; X2 is His, Lys_Me3, or Thr; X3 is Ogl, Val, Tba, or Tle; X4 is Thr or Glu; X5 is Ile or Chg; X6 is Oic or Pro; X7 is O3S_Me; X8 is Asp or Gla; X9 is Ogl; X10 is 1Nal or Trp; X11 is O3S_Me; X12 is Trp; X13 is Ile; X14 is Asn; X15 is dR; and X16 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; wherein: (i) the cyclic structure of each monomer comprises X7 and X11 that are directly covalently linked through a carbon-carbon double bond (-C=C-); and (ii) each monomer is directly covalently linked to a PEG linker at X16Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X16Lys_PEG4_PEG4_NH2, X16Lys_PEG4_1PEG2_NH2, or X16Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end.(Formula (II.G)).

40. The homodimer compound of claim 30, a monomer peptide of a homodimer compound comprises or consists of an amino acid sequence of Formula (II.H): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Chg, Val, or Ile; X2 is His, Lys_Me3, or Thr; X3 is Ogl, Tba, Tle, or Val; X4 is Thr or Glu; X5 is Chg or Ile; X6 is Oic or Pro; X7 is Ala or Cys; X8 is Asp or Gla; X9 is O3S; X10 is Trp or 1Nal; X11 is Asp, Glu, or Lys_Ac; X12 is Trp; X13 is O3S; X14 is Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG4_PEG4_NH2, or Lys_PEG8_NH2; X15 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X9 and X13 that are directly covalently linked through a carbon-carbon double bond (-C=C-); and (ii) each monomer is directly covalently linked to a PEG linker at X14Lys through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2 X14Lys_PEG4_1PEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.H)).

41. The homodimer compound of claim 30, wherein each monomer of the dimer has a cyclic structure comprising two amino acid residues with a side-chain comprising a free thiol that are indirectly covalently linked through a thioether bond with a Butane_Linker, a Carbonyl_Linker, a Dimethylcyclopropane_Linker, an Ebutene_Linker, a Hexane_Linker, a Methylene_Linker, an Oxetane_Linker, a Pentane_Linker, a Propane_Linker, an mXylene_Linker, a pXylene_Linker, or an oXylene_Linker. at: (a) X5 and X13, wherein the residues are individually or both, Cys, Hcy, Hhc, or Pen, (b) X7 and X11, wherein both X7 and X11 are Cys, and with a Xylene linker, or (c) X7 and X11, wherein X7 and X11 are individually or both Cys or Hcy and with the Propane_Linker.

42. The homodimer compound of claim 30, wherein a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.I): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Ile, Lys_Me3, Sar, Tle, or absent; X1 is Cha, Cyclopropyl_Ala, DIP, Ile, Tba, or Val; X2 is Gln, His, Hse, Lys_Me3, Lys_Dimethyl, Lys_PEG2_Me3, Lys2HyAc, LysMPA, LysNs, Orn_Ac, Orn2HyAc, OrnPVA, Phe_2Ad, Phe_3Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtOMe, or Tet1; X3 is AlaCF3, AlaCHF2, cyclopentyl_Ala, cyclopropyl_Ala, nVF3, Tba, Tle, or Val; X4 is Asn, Glu, Glu_OMe, hE, Lys_Me3, Phe_4COOH, or Thr; X5 is Cys, Hcy, or Pen; X6 is 4RBenzyloxyPro, 4RPhePro, 4S_Amp_Cyclohex, 4S_Amp_Hex, 4S_Amp_IVA, 4S_Amp_tBu, 4SCF3Pro, 4SCyclohexPro, 5RPhePro, Oic, or Pro; X7 is Ala, Gln, His, Lys_1PEG2_1PEG2_IsoGlu_C18_diacid, Lys_Ac, Oic, or Pro; X8 is Asp, Gla, Glu, Phe_3COOH, or Phe_4COOH; X9 is Aoc, Dgl, or Ogl; X10 is 1Nal, 2Nal, aMe_Phe, aMe_Trp, Hph, Phe_4COOH, or Trp; X11 is Aib, Ala, Asn, Asp, aMe_Leu, aMe_Phe, Chg, Glu, Leu, Lys_Me3, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tle; X12 is 1Nal, aMe_Trp, Orn_Bz, Trp_6Cl, or Trp; X13 is Cys, Hcy, or Pen; X14 is dK, Lys, , Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; and X16 is absent; wherein: (i) the cyclic structure of each monomer comprises X5 and X13 that are indirectly covalently linked through a thioether bond with a Butane_Linker, a Carbonyl_Linker, Dimethylcyclopropane_Linker, EButene linker, Hexane_Linker, Oxetane_Linker, Pentane_Linker, Propane linker, oXylene linker, mXylene linker, or pXylene_ linker; and (ii) each monomer is directly covalently linked to a PEG linker at X14 through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14Lys_PEG4_PEG4_NH2, X14Lys_PEG4_1PEG2_NH2, or X14Lys_PEG8_NH2, through an amide bond, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.I)).

43. The homodimer compound of claim 30, wherein a monomer peptide of the homodimer compound comprises or consists of an amino acid sequence of Formula (II.J): R1-X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein R1 is acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, or absent; R2 is amine, hydroxyl, or absent; X00 is dH or absent, X0 is dE, dH, Gln, Glu, Glu_OMe, His, Lys_Me3, Sar, Tle, or absent; X1 is Ile or Val; X2 is His, Lys_Me3, or Thr; X3 is Tle or Val; X4 is Glu or Thr; X5 is Ile; X6 is Pro or Oic; X7 is Cys; X8 is Asp or Gla; X9 is Leu or Ogl; X10 is 1Nal or Trp; X11 is Cys or Hcy; X12 is Trp; X13 is Ile; X14 is Asn, Lys, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or Lys_PEG4_PEG4_NH2; X15 is dR; and X16 is Lys, Lys_PEG4_PEG4_NH2, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, or absent; wherein: (i) the cyclic structure of each monomer comprises X7 and X11 that are indirectly covalently linked through a bis-thioether bond with the a Xylene linker (m-, o-, or p-) or a Propane_Linker; and (ii) each monomer is directly covalently linked to a PEG linker at X14 or X16 through an amide bond when X14 or X16 is Lys, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker; or each monomer is directly covalently linked to a DIG linker at X14 or X16 through an amide bond, wherein X14 or X16 is Lys_PEG4_PEG4_NH2, Lys_PEG4_1PEG2_NH2, or Lys_PEG8_NH2, wherein one monomer is linked to one terminal end of the DIG linker and the other monomer is linked to the other terminal end. (Formula (II.J)).

44. The homodimer compound of any one of claims 30-43, wherein the PEG linker is PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA.

45. The homodimer compound of any one of claims 30-43, wherein the homodimer exhibits an IC50 value of less than about 5 nM in a human IL-17 HEK Blue assay.

46. The homodimer compound of any one of claims 30-45, wherein the homodimer exhibits a half-life greater than 0.5 hours in an SGF and / or SIF stability assay.

47. The homodimer compound of any one of claims 30-46, wherein R1 is acetyl, glutaric acid, or isovaleric acid, and R2 is an amine.

48. A peptide compound that has an IC50 for each of hIL-17AA, hIL-17AF, and hIL-17FF, or at least for each of hIL-17AA and hIL-17FF, that is less than about 10 nM in a human IL-17 HEK Blue assay, wherein the peptide compound comprises a monomer peptide comprising or consisting of the sequence of Formula (III):R1- X00-X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2,wherein: R1 is 1Pip_AceticAcid, acetyl, 3-hydroxypropionic acid, C6_diacid, cyclopropanecarboxylic acid, glutaric acid, isovaleric acid, methanesulfonyl acetic acid, Mor_propanoic_acid, or absent; R2 is NH2 or OH or absent; X00 is Cha, dH, or TleX0 is 2Pal, Asn, d2Pal, dE, dH, dQ, Gln, Glu, Glu_OMe, His, Ile, Lys, Lys_Me3, NMe_His, Orn, Sar, Tle, or absent;X1 is 1Nal, Cha, Cyclopropyl_Ala, Dgl, DIP, hCha, hF, hhF, Ile, Ogl, Phe_4Me, Tba, Tle, or Val; X2 is 2Pal, 3Pal, Dab_Ac, Dab2HyAc, DabMs, DabTs, Gln, Glu, His, Hse, Lys_Ac, Lys_Dimethyl, Lys_Me3, Lys_PEG2_Me3, Lys1PEG2Ac, Lys2HyAc, LysMPA, LysMs, Orn_Ac, Orn2HyAc, OrnAc, OrnMs, OrnPVA, Phe_2Ad, Phe_3Ad, Phe_4Ad, Q_NHMe, Q_NMe2, Q_Pyro, Q_EtoMe, Tet1, or Thr; X3 is Ala_cycBu, AlaCF3, AlaCHF2, Aoc, Cha, Chg, Cyclopentyl_Ala, Cyclopropyl_Ala, hCha, nVF3, Ogl, Phe_4tBu, Tba, Tle, or Val;X4 is Asn, Gln, Glu, Glu_OMe, hE, His, LysMe3, Phe_4COOH, or Thr; X5 is Cys, Hcy, Hhc, Lys_Ac, LysN3, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen; X6 is 4SCF3Pro, 4SCyclohexPro, Oic, or Pro; X7 is Acvc, Ala, Dab, Gln, Glu, His, Hpr, hR, Lys_Ac, Oic, Pro, Ser, or Tba; X8 is aMe_Glu, Asp, Gla, Glu, or Tet1; X9 is Aoc, Dgl, or Ogl; X10 is 1Nal, 2Nal, aMe_Phe, aMe_Trp, Aoc, Cys, hCha, Hph, Phe_4COOH, Trp, Trp_4Cl, Trp_4Me, Trp_5Cl, Trp_5CONH2, Trp_5Et, Trp_5Me, Trp_6Cl, Trp_6CONH2, Trp_6Me, Trp_7Cl, Trp_7Me, or Trp_7Phe; X11 is Aib, Ala, aMe_Asp, aMe_Leu, aMe_Phe, Asn, Asp, Chg, Glu, Leu, Lys_Me3, O3S, Phe_4Ad, Phe_4tBu, Ser, Tba, or Tle; X12 is aMe_Trp, Trp, Trp_56diCl, Trp_5Cl, Trp_5Me, or Trp_6Cl; X13 is Abu, Cys, Dab_Acetyl, Hcy, Hhc, O2S, O3S, O3S_Reduced, O3S_Me, O3S_Me_Reduced, O4S, O4S_Reduced, O5S, O5S_Reduced, or Pen; X14 is Aib, Asn, Cys, dK, dL, dN, dQ, dR, Gln, Lys, Lys_1PEG2_1PEG2_IsoGlu_C12, Lys_Ac, Lys_PEG4_PEG4_NH2, Lys_PEG4_1PEG2_NH2, Lys_PEG8_NH2, Tba, or absent; X15 is dR, dE, or absent; X16 is dE, dQ, or absent; wherein the peptide comprises a cyclic structure wherein X5 and X13 are either: (a) directly covalently linked or (b) indirectly covalently linked through a cyclization linker; and wherein: (i) the peptide is optionally a monomer in a homodimer or heterodimer complex, wherein each monomer is directly covalently linked to each other or indirectly covalently linked to each other through a dimerization linker; and / or (ii) the peptide is optionally conjugated with a half-life extension moiety. (Formula (III)).

49. The peptide compound of claim 48, wherein both X5 and X13 are Hhc, and wherein these two residues are directly covalently linked through a disulfide bond 50. The peptide compound of claim 48, wherein X5 is Lys_Ac and X13 is Cys, or X5 is Hhc and X13 is Dab_Acetyl, and wherein these two residues are directly covalently linked through a thioether bond.

51. The peptide compound of claim 48, wherein X5 is Lys and X13 is hE (or vice versa), and these two residues are directly covalently linked through an amide bond (lactam).  

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