Peptide inhibitors of the interleukin-23 receptor and their use for treating inflammatory diseases - Patent Application 20070122999

Abstract

Peptide inhibitors of the interleukin-23 receptor and their use for treating inflammatory diseases are provided. The present invention provides novel peptide inhibitors of the interleukin-23 receptor, as well as related compositions and methods for using these peptide inhibitors to treat or prevent various diseases and disorders, including inflammatory bowel disease. The interleukin-23 (IL-23) cytokine has been implicated as playing an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 447,778, filed January 18, 2017, which is incorporated herein by reference in its entirety.

[0002] Sequence Listing Description The sequence listing associated with this application is provided in text format in lieu of a paper copy and is incorporated herein by reference. The text file containing the sequence listing is named PRTH_027_01WO_ST25.txt. The text file is 255 KB, was created on January 18, 2018, and has been submitted electronically via EFS-Web.

[0003] The present invention relates to novel peptide inhibitors of the interleukin-23 receptor and their use to treat or prevent a variety of diseases and disorders, including inflammatory bowel disease, Crohn's disease, and psoriasis. [Background technology]

[0004] The interleukin-23 (IL-23) cytokine has been implicated as playing a key role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Studies of acute and chronic IBD mouse models have revealed a key role for IL-23R and downstream effector cytokines in pathogenesis. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are abundant in the intestine. At the intestinal mucosal surface, IL-23R gene expression and protein levels have been found to be elevated in IBD patients. IL-23 acts as a signaling pathway for pathogenic CD4 T cells, which produce IL-6, IL-17, and tumor necrosis factor (TNF). +It is thought to mediate this effect by promoting the development of T cell populations.

[0005] IL-23 production is abundant in the intestine and is thought to play a key role in regulating the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation through its effects on T helper 1 (Th1)- and Th17-associated cytokines, as well as suppressing regulatory T cell responses in the intestine in favor of inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to IBD, further establishing the critical role of the IL-23 pathway in intestinal homeostasis.

[0006] Psoriasis, a chronic skin disease affecting approximately 2% to 3% of the general population, has been shown to be mediated by the body's T cell inflammatory response. IL-23 is one of several interleukins implicated in playing a key role in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation through the induction of interleukin-17, modulation of T memory cells, and activation of macrophages. IL-23 and IL-23R expression have been shown to be increased in tissues of psoriasis patients, and IL-23-neutralizing antibodies have demonstrated IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0007] IL-23 is a heterodimer consisting of its own p19 subunit and the p40 subunit of IL-12, which is involved in the production of interferon-γ (IFN-γ)-producing T helper (T H 1) IL-23 and IL-12 are cytokines involved in the development of cells. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic characteristics. For example, animals lacking IL-12 are prone to inflammatory autoimmune diseases, while animals lacking IL-23 are presumably CD4+, which produces IL-6, IL-17, and TNF in the CNS of animals lacking IL-23. +Resistance is induced by a decrease in the number of T cells. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. IL-23 binding to IL-23R activates Jak-Stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, although Stat4 activation is substantially weaker and a different DNA-binding Stat complex is formed in response to IL-23 compared to IL-12. IL-23R associates constitutively with Jak2 and ligand-dependently with Stat3. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 selectively acts on memory CD4(+) T cells.

[0008] Efforts have been made to identify therapeutic moieties that inhibit the IL-23 pathway for use in treating IL-23-related diseases and disorders. Many antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, a humanized antibody that binds IL-23 and is approved for the treatment of psoriasis. More recently, polypeptide inhibitors that bind to IL-23R and inhibit IL-23 binding to IL-23R have been identified (see, e.g., U.S. Patent Application No. US2013 / 0029907). Clinical trials in Crohn's disease and psoriasis using ustekinumab and briakinumab (which target the common p40 subunit), as well as tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL-23) highlight the potential of IL-23 signaling blockade in the treatment of human inflammatory diseases. While these results are promising, challenges remain with regard to identifying stable and selective agents that selectively target the IL-23 pathway in the intestine that can be used for the treatment of intestinal inflammation, such as intestinal diseases including Crohn's disease, ulcerative colitis, and related disorders. Clearly, there remains a need in the art for new therapeutic agents that target the IL-23 pathway that can be used to treat and prevent IL-23-related diseases, including those associated with autoimmune inflammation in the intestinal tract. In addition, compounds and methods for specifically targeting IL-23R from the luminal side of the intestine may provide therapeutic benefit to IBD patients suffering from local inflammation of intestinal tissue. The present invention addresses these needs by providing novel peptide inhibitors that bind IL-23R, inhibit IL-23 binding and signaling, and are suitable for oral administration. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent Application No. US2013 / 0029907 Summary of the Invention [Means for solving the problem]

[0010] The present invention provides, inter alia, novel peptide inhibitors of IL-23R and related methods of use.

[0011] In a first aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, the peptide inhibitor having formula (II): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(II) (SEQ ID NO: 237), comprising or consisting of the amino acid sequence of X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Abu, (D)Pen, or Pen; X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or Aib; X13 is Glu, Cit, Gln, alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or absent; The peptide inhibitor is cyclized via the bond between X4 and X9, Peptide inhibitors inhibit the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0012] In a second aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, the peptide inhibitor having the formula (V): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(V) (Sequence number 238) comprising or consisting of the amino acid sequence of X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Lys(Ac), Lys(Y1-Ac), or absent, where Y1 is an amino acid; X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac); wherein Y2 is an amino acid; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, Ala, Asp, Tyr, Arg, Leu, Gln, Ser, Ile, 1-Nal, 2-Nal, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, (D)Ile, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or absent; The peptide inhibitors are cyclized via the bond between X4 and X9, and the peptide inhibitors inhibit the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0013] In certain embodiments, X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent. In certain embodiments, X3 is Lys(Ac) or Lys(Y1-Ac), where Y1 is an amino acid.

[0014] In certain embodiments, X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, or Pen. In certain embodiments, X4 is Pen(sulfoxide).

[0015] In certain embodiments, X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln. In certain embodiments, X5 is Asp or Cys.

[0016] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp. In certain embodiments, X8 is 1-Nal or 2-Nal.

[0017] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl Ala, Lys, or Aib. In certain embodiments, X12 is Ala, cyclohexyl Ala, or Lys.

[0018] In certain embodiments, X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys. In certain embodiments, X13 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid.

[0019] In certain embodiments, X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent. In certain embodiments, X16 is Ala, Asp, Tyr, Arg, Leu, Gln, Ser, He, 1-Nal, 2-Nal, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, or (D)Ile.

[0020] In certain embodiments of any of the peptide inhibitors disclosed herein, including peptide inhibitors comprising the amino acid sequence of Formula (I), Formula (II), or Formula (V), X4 is Pen, X9 is Pen, and the bond is a disulfide bond. In certain embodiments of any of the peptide inhibitors, X4 and X9 are Pen. In certain embodiments, X4 and X9 form a disulfide bond.

[0021] In certain embodiments of any of the peptide inhibitors disclosed herein, including peptide inhibitors comprising the amino acid sequence of Formula (I), Formula (II), or Formula (V), X4 is Abu and X9 is Cys. In certain embodiments, X4 is Abu and X9 is Cys. In certain embodiments, X4 and X9 form a thioether bond.

[0022] In certain embodiments, any of the peptide inhibitors described herein comprises one or more half-life extending moieties and / or one or more linker moieties conjugated to the peptide inhibitor. In certain embodiments, the half-life extending moiety is conjugated to the peptide inhibitor via one or more linker moieties.

[0023] In certain embodiments, any of the peptide inhibitors described herein further comprises a conjugated chemical substituent. In certain embodiments, the conjugated chemical substituent is a lipophilic substituent or polymer moiety, such as Ac, Palm, gamaGlu-Palm, isoGlu-Palm, PEG2-Ac, PEG4-isoGlu-Palm, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, Alexa488, Alexa647, or biotin. In certain embodiments, the conjugated chemical substituent is polyethylene glycol having a molecular weight of 400 Da to 40,000 Da. In certain embodiments, the peptide is conjugated at X8. In another specific embodiment, the peptide is conjugated at X9. In more specific embodiments, the peptide is conjugated at X10.

[0024] In another aspect, the present invention provides a compound of formula Z: R 1 -XR 2 (Z) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, and includes PEGylated forms alone or as a spacer for any of the above; R 2 is a bond, OH, or NH2; X is a peptide comprising any of the amino acid sequences described herein, including peptides comprising the amino acid sequences of formula (I), formula (II), formula (IIIa), (IVa), formula (V), formula (XII)-(XVIIIh), or any of the peptide acid sequences described in the tables herein.

[0025] In a related aspect, the present invention includes a peptide dimeric inhibitor of the interleukin-23 receptor, wherein the peptide dimeric inhibitor comprises two peptide monomer subunits connected via one or more linker moieties, each peptide monomer subunit comprising a sequence of Formula (I), Formula (II), Formula (V), or any other sequence or structure described herein. In certain embodiments, one or both peptide monomer subunits are cyclized via an intramolecular bond between X4 and X9. In certain embodiments, one or both intramolecular bonds are disulfide bonds or thioether bonds. In certain embodiments, the linker is any of the linkers shown in Table 2 or described herein. In certain embodiments, the linker moiety is a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker. In certain embodiments, the N-termini of each peptide monomer subunit are connected by a linker moiety. In certain embodiments, the C-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments, the linker connects at least one internal amino acid residue of a peptide monomer subunit to the N-terminus, C-terminus, or internal amino acid residue of another peptide monomer subunit.

[0026] In a further related aspect, the invention includes a polynucleotide comprising a sequence encoding a peptide inhibitor of the invention, or one or both peptide monomer subunits of a peptide dimeric inhibitor of the invention. The invention also includes a vector comprising the polynucleotide.

[0027] In another aspect, the present invention includes a pharmaceutical composition comprising a peptide inhibitor or peptide dimer inhibitor of the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the pharmaceutical composition comprises an enteric coating. In certain embodiments, the enteric coating protects and releases the pharmaceutical composition within the lower gastrointestinal system of a subject.

[0028] and methods for treating or preventing a disease associated with IL-23 signaling in a subject, including, but not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as in leukocyte adhesion deficiency type 1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, or graft-versus-host disease, comprising providing to the subject a therapeutically effective amount of a peptide inhibitor or pharmaceutical composition of the invention. In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In certain embodiments, the peptide inhibitor or peptide dimer inhibitor inhibits the binding of interleukin-23 (IL-23) to the interleukin-23 receptor (IL-23R). In certain embodiments, the pharmaceutical composition is provided to a subject by oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vapor, spray, sublingual, buccal, parenteral, rectal, intraocular, inhalation, intravaginal, or topical administration. In certain embodiments, the pharmaceutical composition is provided orally to treat inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease. In certain embodiments, the pharmaceutical composition is provided topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously to treat psoriasis. DETAILED DESCRIPTION OF THE INVENTION

[0029] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. Generally, the terminology 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 well known and commonly used in the art.

[0030] As used herein, the following terms have the meanings ascribed to them unless otherwise specified.

[0031] It will be understood that throughout this specification, the use of "comprise" or variations such as "comprises" or "comprising" refers to the inclusion of a stated integer (or component) or group of integers (or components), but not to the exclusion of any other integer (or component) or group of integers (or components).

[0032] The singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0033] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0034] The terms "patient," "subject," and "individual" can 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., cows, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0035] The term "peptide," as used herein, refers broadly to a sequence of two or more amino acids joined together by peptide bonds. It should be understood that the term does not connote a specific length of a polymer of amino acids, nor is it intended to mean or distinguish whether the polypeptide is produced using recombinant techniques, chemical synthesis, enzymatic synthesis, or naturally occurring.

[0036] As used herein, the terms "sequence identity," "percent identity," "percent homology," or, for example, "50% identical sequence" refer to the degree to which sequences are identical nucleotide-by-nucleotide or amino acid-by-amino acid over a comparison window.Therefore, "percent sequence identity" can be calculated by comparing two optimally aligned sequences over a comparison window, determining the number of positions where the same nucleic acid base (e.g., A, T, C, G, I) or the same amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) occurs in both sequences to obtain the number of identical positions, and dividing the number of identical positions by the total number of positions within the comparison window (i.e., window size), and multiplying the result by 100 to obtain the percentage of sequence identity.

[0037] Calculation of sequence similarity or sequence identity (these terms are used interchangeably herein) between sequences can be performed as follows. To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In certain embodiments, the length of the 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%, or 100% of the length of the reference sequence. Then, amino acid positions, or nucleotides at corresponding amino acid positions, or nucleotide positions, are compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position.

[0038] 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 that need to be introduced for optimal alignment of the two sequences.

[0039] 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 is implemented in the GAP program of the GCG software package using either a Blossum 62 matrix or a PAM250 matrix, 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 of the GCG software package using a NWSgapdna.CMP matrix, 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 the Blossum 62 scoring matrix with a gap penalty of 12, a gap extension 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) with a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0040] The peptide sequences described herein can be used as "query sequences" to conduct searches against public databases, for example, to 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 using the NBLAST program, score = 100, word length = 12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention. BLAST protein searches can be performed using the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences homologous to the protein molecules of the present 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 (eg, XBLAST and NBLAST) can be used.

[0041] The term "conservative substitution," as used herein, refers to the replacement of one or more amino acids with another, biologically similar residue. Examples include the substitution of amino acid residues with similar characteristics, such as small, acidic, polar, basic, hydrophobic, and aromatic amino acids. See, for example, the table below. In some embodiments of the present invention, one or more Met residues are replaced with norleucine (Nle), which is a bioisostere of Met but, in contrast to Met, is not readily oxidized. Another example of a conservative substitution with a residue not normally found in endogenous mammalian peptides and proteins is the conservative substitution of Arg or Lys with, for example, ornithine, canavanine, aminoethylcysteine, or another basic amino acid. In some embodiments, one or more cysteines in the peptide analogs of the present invention may be replaced with another residue, such as serine. For more information on non-phenotypic substitutions in peptides and proteins, see, for example, Bowie et al., Science 247, 1306-1310, 1990. In the following scheme, conservative substitutions of amino acids are grouped by physicochemical properties: I: neutral, hydrophilic; II: acid and amide; III: basic; IV: hydrophobic; V: aromatic, bulky amino acids. [Table A]

[0042] In the following scheme, conservative substitutions of amino acids are grouped by physicochemical properties: VI: neutral or hydrophobic, VII: acidic, VIII: basic, IX: polar, X: aromatic. [Table B]

[0043] The term "amino acid" or "any amino acid," as used herein, refers to any and all amino acids, including naturally occurring amino acids (e.g., α-amino acids), unnatural amino acids, modified amino acids, and non-naturally occurring amino acids. This includes both D- and L-amino acids. Natural amino acids include those found in nature, such as the 23 amino acids that combine into peptide chains to form the building blocks of a wide variety of proteins. These are primarily L-stereoisomers, although several D-amino acids occur in bacterial envelopes and some antibiotics. The 20 "standard" naturally occurring amino acids are listed in the table above. "Non-standard" naturally occurring amino acids are pyrrolysine (found in methanogens and other eukaryotes), selenocysteine ​​(present in most eukaryotes as well as many non-eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). "Unnatural" or "non-naturally occurring" amino acids are non-proteinogenic amino acids (i.e., amino acids that are not naturally encoded, i.e., not found in the genetic code), either occurring in nature or synthesized chemically. Over 140 unnatural amino acids are known, with thousands more possible combinations. Examples of "unnatural" amino acids include the β-amino acids (β 3 and β 2), homo-amino acids, proline and pyruvate derivatives, tri-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. Non-natural or unnatural 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. According to certain embodiments, the peptide inhibitor comprises an intramolecular bond between two amino acid residues present in the peptide inhibitor. It is understood that the amino acid residues that form the bond change somewhat when bound to each other compared to when not bound to each other. Reference to a particular amino acid is intended to encompass the amino acid in both its unbound and bound states. For example, the unbound form of the amino acid residue homoserine (hSer) or homoserine (Cl) can take the form of 2-aminobutyric acid (Abu) when involved in an intramolecular bond according to the present invention. The present invention includes both peptide inhibitors that include a bridge between X4 and X9, as well as peptide inhibitors that do not include a bridge between X4 and X9, e.g., prior to bridge formation. Thus, the names hSer and Abu are intended to refer to the same amino acid and are used interchangeably.

[0044] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the nomenclature conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as presented in "Nomenclature of α-Amino Acids (Recommendations, 1974)" Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from these suggestions, they will be made clear to the reader. Some abbreviations useful in describing this invention are defined below in Table 1, below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0045] Throughout this 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 one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise specified, the three-letter or one-letter abbreviation of an amino acid refers 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., Dasp, (D)Asp, or D-Asp; Dphe, (D)Phe, or D-Phe). The D-isomeric form of an amino acid residue can be substituted for any L-amino acid residue, so long as the peptide retains the desired function. D-amino acids, when referred to using one-letter abbreviations, may conventionally be designated by lowercase letters.

[0046] For less common or non-naturally occurring amino acids, unless they are referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently used three- or four-letter codes are used for the residues, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (2-aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenylalanine) and Bip (β,β-diphenylalanine), and Ida (iminodiacetic acid).

[0047] As will be apparent to those skilled in the art, peptide sequences disclosed herein are presented from left to right, with the left-hand end of the sequence being the N-terminus of the peptide and the right-hand end of the sequence being the C-terminus of the peptide. Some sequences disclosed herein incorporate a "Hy-" moiety at the amino-terminus (N-terminus) of the sequence and either an "-OH" or "-NH2" moiety at the carboxy-terminus (C-terminus) of the sequence. In such cases, and unless otherwise indicated, the "Hy-" moiety at the N-terminus of the sequence indicates a hydrogen atom corresponding to the presence of a free primary or secondary amino group at the N-terminus, while the "-OH" or "-NH2" moiety at the C-terminus of the sequence indicates a hydroxy or amino group, respectively, corresponding to the presence of an amide (CONH2) group at the C-terminus. In each of the sequences of the invention, the C-terminal "-OH" moiety can be substituted for a C-terminal "-NH2" moiety, and vice versa.

[0048] Those skilled in the art will understand 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 forming an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogens may be removed or replaced by the bond. Thus, as used herein, a reference to an amino acid or modified amino acid present in a peptide dimer of the present invention (e.g., at position X4 or position X9) is intended to include the form of such amino acid or modified amino acid present in the peptide both before and after the formation of the intramolecular bond.

[0049] The term "dimer," as used herein, broadly refers to a peptide comprising two or more monomer subunits. Certain dimers comprise two monomer subunits comprising Formula (I) or a sequence described herein. Dimers of the present invention include homodimers and heterodimers. The monomer subunits of a dimer can be linked at their C- or N-termini, or they can be linked via internal amino acid residues. Each monomer subunit of a dimer can be linked through the same site, or each can be linked through a different site (e.g., the C-terminus, N-terminus, or internal site).

[0050] The term "NH2", as used herein, can refer to the free amino group present at the amino terminus of a polypeptide. The term "OH", as used herein, can refer to the free carboxy group present at the carboxy terminus of a peptide. Furthermore, the term "Ac", as used herein, refers to acetyl protection through acylation of the C- or N-terminus of a polypeptide. In certain peptides shown herein, the NH2 located at the C-terminus of the peptide refers to an amino group.

[0051] The term "carboxy" as used herein refers to -CO2H.

[0052] The term "isosteric substitution," as used herein, refers to any amino acid or other analog moiety that has chemical and / or structural properties similar to a particular amino acid. In certain embodiments, an isosteric substitution is a conservative substitution or analog of a particular amino acid.

[0053] The term "cyclization," as used herein, refers to the linking of one portion of a polypeptide molecule to another portion of a polypeptide molecule to form a closed ring, such as by forming a disulfide bridge or a thioether bond.

[0054] The term "subunit," as used herein, refers to one of a pair of polypeptide monomers that are linked to form a dimeric peptide composition.

[0055] The term "linker moiety," as used herein, broadly refers to a chemical structure that is capable of linking or binding two peptide monomer subunits together to form a dimer.

[0056] The term "pharmaceutically acceptable salt," as used herein, refers to a salt or zwitterionic form of a peptide or compound of the present invention that is water- or oil-soluble or dispersible, suitable for the treatment of disease without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. Salts can be prepared during the final isolation and purification of the compound 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-hydroxyethanesulfonate (isethionate), lactate, maleate, mesitylene, and the like. The salts of the amino groups in the compounds of the present invention include sulfonate, 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. The amino groups in the compounds of the present invention can also be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. The pharmaceutically acceptable salt may suitably be, for example, a salt selected from acid addition salts and base salts. Examples of acid addition salts include chloride salts, citrate salts, and acetate salts.Examples of basic salts include salts in which the cation is selected from among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, and substituted ammonium ions, such as ions of the N(R1)(R2)(R3)(R4) type, where R1, R2, R3, and R4 independently typically represent hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C2-6 alkenyl. Examples of relevant C1-6 alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl groups. Examples of potentially relevant C2-6 alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in "Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (Ed.), "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66:2 (1977). Also, for a review of 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 can also be formed, such as hemisulfate and hemicalcium salts.

[0057] The term "N(alpha) methylation," as used herein, describes the methylation of the alpha amine of an amino acid, also commonly referred to as N-methylation.

[0058] The term "symmetric methylation" or "Arg-Me-sym" as used herein describes the symmetric methylation of the two nitrogens of the guanidine group of arginine. Additionally, the term "asymmetric methylation" or "Arg-Me-asym" describes the methylation of a single nitrogen of the guanidine group of arginine.

[0059] The term "acylating organic compound," as used herein, refers to various compounds having a carboxylic acid functionality that are used to acylate the N-terminus of an amino acid or monomer or dimer, e.g., a monomer subunit, prior to forming a C-terminal dimer. Non-limiting examples of acylating organic compounds include cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclopentanecarboxylic acid, 3,3,3-trifluoropropionic acid, 3-fluoromethylbutyric acid, and tetrahedro-2H-pyran-4-carboxylic acid.

[0060] The term "alkyl" includes straight-chain or branched, acyclic or cyclic, saturated aliphatic hydrocarbons containing 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, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-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, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

[0061] The term "mammal" refers to any mammalian species, such as humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, farm animals, etc.

[0062] As used herein, a "therapeutically effective amount" of a peptide inhibitor of the invention is intended to describe a sufficient amount of the peptide inhibitor to treat an IL-23 / IL-23R-associated disorder (e.g., to reduce inflammation associated with IBD), including, but not limited to, any of the diseases and disorders described herein. In certain embodiments, a therapeutically effective amount achieves a desirable benefit / risk ratio applicable to any treatment.

[0063] An "analog" of an amino acid, e.g., a "Phe analog" or a "Tyr analog," refers to an analog of the referenced amino acid. A variety of amino acid analogs, including Phe and Tyr analogs, are known and available in the art. In certain embodiments, an amino acid analog, e.g., a Phe analog or a Tyr analog, contains one, two, three, four, or five substitutions compared to Phe or Tyr, respectively. In certain embodiments, the substitutions are in the side chain of the amino acid. In certain embodiments, a Phe analog has the structure Phe(R 2 ), wherein R 2 is Hy, OH, CH, COH, CONH, CONHOCHCHNH, t-Bu, OCHCHNH, phenoxy, OCH, OAllyl, Br, Cl, F, NH, N, or guanadino. 2is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3, or CO2H. Examples of Phe analogs include hPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH2), Phe(4-phenoxy), Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F), Phe(4-F), Phe(3,5 Examples of Tyr analogs include, but are not limited to, hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N), and βhTyr.

[0064] Peptide inhibitors of IL-23R Genome-wide association studies (GWAS) have demonstrated a significant association of the IL-23 receptor (IL-23R) gene with inflammatory bowel disease (IBD), suggesting that perturbations in IL-23 signaling may be involved in the pathogenesis of this disease as well as other inflammatory diseases and disorders. The present invention provides compositions and methods for modulating the IL-23 pathway through antagonism of IL-23R.

[0065] The present invention generally relates to peptides with IL-23R antagonist activity, including both peptide monomers and peptide dimers. In certain embodiments, the present invention demonstrates a new paradigm for the treatment of IBD and other diseases and disorders through oral delivery of IL-23 antagonists. IBD manifests as local inflammation in intestinal tissue; therefore, advantageous therapeutic agents would act from the luminal side of the intestine, resulting in high drug concentrations in affected tissues, minimizing systemic availability and improving efficacy and safety compared to systemic approaches. Oral administration of the compounds of the present invention is expected to maximize drug levels in affected intestinal tissues while limiting drug concentrations in the blood circulation, thereby providing effective, safe, and sustained delivery for lifelong treatment of IBD and other diseases and disorders.

[0066] In certain embodiments, the present invention relates to peptide dimers comprising various peptides or hetero- or homo-monomer subunits that form a cyclized structure through a disulfide bond or other bond. In certain embodiments, the disulfide bond or other bond is an intramolecular bond. The cyclized structure of the monomer subunits of peptide monomer inhibitors and peptide dimer inhibitors has been shown to increase the potency and selectivity of the peptide inhibitors. In certain embodiments, the peptide dimer inhibitor may contain one or more intermolecular bonds connecting two monomer peptide subunits within the peptide dimer inhibitor, for example, an intermolecular bridge between two Pen residues (one in each peptide monomer subunit).

[0067] The present invention provides peptide inhibitors that bind to IL-23R, which can be monomeric or dimeric. In certain embodiments, the peptide inhibitors inhibit the binding of IL-23 to IL-23R. In certain embodiments, the IL-23R is human IL-23R and the IL-23 is human IL-23. In certain embodiments, the peptide inhibitors of the present invention reduce the binding of IL-23 to IL-23R by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to a negative control peptide. Methods for determining binding are known in the art and include ELISA assays, as described in the accompanying Examples.

[0068] In certain embodiments, peptide inhibitors of the invention have an IC50 of less than 1 mM, less than 1 mM, 500 nM-1000 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 10 nM, less than 5 nM, less than 2 nM, less than 1 nM, or less than 5 mM, for example, to inhibit binding of IL-23 to IL-23R (e.g., human IL-23 and human IL-23R). Methods for determining activity are known in the art and include any of those described in the accompanying Examples.

[0069] In certain embodiments, the peptide inhibitors of the present invention have increased stability, increased stability in the gastrointestinal tract, increased stability in simulated intestinal fluid (SIF) or simulated gastric fluid (SGF) and / or under redox conditions (DTT) compared to a control peptide. In certain embodiments, the control peptide is an unrelated peptide of the same or similar length. In certain embodiments, the control peptide is a peptide having the same or highly related amino acid sequence (e.g., greater than 90% sequence identity) as the peptide inhibitor. In certain embodiments, the control peptide is a peptide having the same or highly related amino acid sequence (e.g., greater than 90% sequence identity) as the peptide inhibitor, but not having a cyclized structure, for example, through an intramolecular bond between two amino acid residues in the control peptide, or not being dimerized, or not containing a stabilizing conjugate. In certain embodiments, the only difference between the peptide inhibitor and the control peptide inhibitor is that the peptide inhibitor contains one or more amino acid substitutions that introduce one or more amino acid residues into the peptide inhibitor, such that the introduced amino acid residue(s) form an intrasulfide disulfide or thioether bond with another amino acid residue in the peptide inhibitor. An example of a control for a peptide dimeric inhibitor is a monomer having the same sequence as one of the monomeric subunits present in the peptide dimeric inhibitor. An example of a control for a peptide inhibitor that includes a conjugate is a peptide having the same sequence but without the conjugate moiety. In certain embodiments, the control peptide is a peptide (e.g., a non-naturally occurring peptide) corresponding to a region of IL-23 that binds to IL-23R.

[0070] The method for determining the stability of peptide is known in the art.In certain embodiments, the stability of peptide inhibitor is determined using SIF assay, for example, as described in Example 3.In certain embodiments, the stability of peptide inhibitor is determined using SGF assay, for example, as described in Example 3.In certain embodiments, under a given set of conditions (for example, temperature), when exposed to SIF or SGF or DTT, the peptide inhibitor has a half-life (for example, in SIF or SGF or DTT) of more than 1 minute, more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 60 minutes, more than 90 minutes, more than 120 minutes, more than 3 hours, or more than 4 hours.In certain embodiments, the temperature is about 25 ℃, about 4 ℃, or about 37 ℃, and pH is physiological pH, i.e., pH of about 7.4.

[0071] In some embodiments, half-life is measured in vitro using any suitable method known in the art, for example, in some embodiments, the stability of peptides of the invention is determined by incubating the peptides with pre-warmed human serum (Sigma) at 37° C. Samples are taken at various time points, typically up to 24 hours, and the stability of the samples is analyzed by separating the peptide or peptide dimer from serum proteins and then analyzing for the presence of the peptide or peptide dimer using LC-MS.

[0072] In some embodiments, the peptide inhibitors of the present invention exhibit improved solubility or improved aggregation properties compared to a control peptide. Solubility can be determined by any suitable method known in the art. In some embodiments, suitable methods known in the art for determining solubility include buffering various buffers (acetate pH 4.0, acetate pH 5.0, phosphate / citrate pH 5.0, phosphate citrate pH 6.0, phosphate pH 6.0, phosphate pH 7.0, phosphate pH 7.5, strong PBS). These include incubating peptides in pH 7.5, Tris pH 7.5, Tris pH 8.0, glycine pH 9.0, water, acetic acid (pH 5.0 and others known in the art), and testing for aggregation or solubility using standard techniques. These include, but are not limited to, visible precipitation, dynamic light scattering, circular dichroism, and fluorescent dyes to measure surface hydrophobicity and detect aggregation or fibrillation. In some embodiments, improved solubility means that the peptide is more soluble in a given liquid than a control peptide. In some embodiments, improved solubility means that the peptide has less aggregation than a control peptide in a given liquid under a given set of conditions.

[0073] In certain embodiments, which are advantageous for achieving high compound concentrations in intestinal tissues when delivered orally, the peptide inhibitors of the present invention are stable in the gastrointestinal (GI) environment. Proteolytic metabolism in the GI tract is facilitated by enzymes secreted into the lumen by the pancreas or produced as brush border enzymes, including pepsin, trypsin, chymotrypsin, elastase, aminopeptidase, and carboxypeptidase A / B. Proteases typically cleave peptides and proteins in extended conformations. In the reducing environment of intestinal fluids, disulfide bonds can be broken, resulting in linear peptides and rapid protein degradation. The redox environment of the lumen is primarily determined by the Cys / CySS redox cycle. In enterocytes, relevant activities include many digestive enzymes, such as CYP450 and UDP-glucuronyltransferase. Finally, 1010 ~10 12 Bacteria present in the large intestine at concentrations in the CFU / mL range constitute another metabolic barrier. In certain embodiments, peptide inhibitors are stable across a range of pHs, from strongly acidic in the stomach (pH 1.5-1.9) to more basic in the small intestine (pH 6-7.5), and then slightly acidic in the colon (pH 5-7). Such peptide inhibitors are stable during their transit through the various GI compartments, a process estimated to take 3-4 hours in the intestine and 6-48 hours in the colon.

[0074] In some embodiments, the peptide inhibitors of the present invention exhibit less degradation (i.e., higher degradation stability) than a control peptide, e.g., by about 10% or more, about 20% or more, about 30% or more, about 40% or more, or about 50% or more, over a period of time. In some embodiments, degradation stability is determined by any suitable method known in the art. In some embodiments, degradation is enzymatic degradation. For example, in certain embodiments, the peptide inhibitor has reduced susceptibility to degradation by trypsin, chymotrypsin, or elastase. In some embodiments, suitable methods known in the art for determining degradation stability include those described in Hawe et al., J Pharm Sci, VOL. 101, No. 3, 2012, pp. 895-913, incorporated herein in its entirety. Such methods are, in some embodiments, used to select potent peptide sequences with improved shelf life. In certain embodiments, peptide stability is determined using a SIF assay or an SGF assay, for example, as described in PCT Publication No. WO2016 / 011208.

[0075] In certain embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated inflammation. In related embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated secretion of one or more cytokines, for example, by binding to IL-23R on the cell surface and thus inhibiting IL-23 binding to cells. In certain embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3, Stat4, or Stat5. Methods for determining inhibition of cytokine secretion and inhibition of signaling molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling can be determined by measuring inhibition of phospho-Stat3 levels in cell lysates, as described, for example, in PCT Publication No. WO2016 / 011208.

[0076] In certain embodiments, the peptide inhibitors have increased redox stability compared to a control peptide. Various assays that can be used to determine redox stability are known and available in the art. Any of these can be used to determine the redox stability of the peptide inhibitors of the present invention.

[0077] In certain embodiments, the present invention provides various peptide inhibitors that bind or associate with IL-23R in vitro or in vivo and disrupt or block the binding between IL-23 and IL-23R. In certain embodiments, the peptide inhibitors bind and / or inhibit human IL-23R. In certain embodiments, the peptide inhibitors bind and / or inhibit both human IL-23R and rodent IL-23R. In certain embodiments, the peptide inhibitors bind and / or inhibit both human IL-23R and rat IL-23R. In certain embodiments, the peptide inhibitors inhibit rat IL-23R by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, as determined, for example, by the assays described herein, and they bind and / or inhibit human IL-23R. In certain embodiments, the peptide inhibitors selectively bind to and / or inhibit human IL-23R and / or rat IL-23R compared to mouse IL-23R. In certain embodiments, the peptide inhibitors selectively bind to rat IL-23R compared to mouse IL-23R. In certain embodiments, the peptide inhibitors selectively bind to human IL-23R compared to mouse IL-23R. In certain embodiments, the binding of the peptide inhibitors to mouse IL-23R is less than 75%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the binding of the same peptide inhibitor to human IL-23R and / or rat IL-23R. In certain embodiments of peptide inhibitors that selectively bind to and / or inhibit human IL-23R and / or rat IL-23R compared to mouse IL-23R, the peptide inhibitor binds to a region of IL-23R that is disrupted by the presence of additional amino acids present in mouse IL-23R but not in human IL-23R or rat IL-23R. In one embodiment, the additional amino acids present in mouse IL-23R are within a region corresponding to about amino acid residue 315 to about amino acid residue 340 of the mouse IL23R protein, eg, the amino acid region NWQPWSSPFVHQTSQETGKR (SEQ ID NO: 239).In certain embodiments, the peptide inhibitor binds to a region of human IL-23R from about amino acid 230 to about amino acid residue 370.

[0078] In certain embodiments, peptide inhibitors show GI-limited localization after oral administration.In certain embodiments, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of orally administered peptide inhibitors are localized in digestive organs and tissues.In certain embodiments, the plasma level of orally administered peptide inhibitors is less than 20%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of the level of peptide inhibitors found in small intestinal mucosa, colonic mucosa, or proximal colon.

[0079] The various peptide inhibitors of the present invention may be constructed solely from natural amino acids. Alternatively, the peptide inhibitors may contain unnatural amino acids, including, but not limited to, modified amino acids. In certain embodiments, modified amino acids include natural amino acids that have been chemically modified to include a group, groups, or chemical moiety that is not naturally present on the amino acid. The peptide inhibitors of the present invention may additionally include one or more D-amino acids. Furthermore, the peptide inhibitors of the present invention may also include amino acid analogs.

[0080] In certain embodiments, the peptide inhibitors of the present invention comprise one or more modified or unnatural amino acids. In some embodiments of the present invention, the peptide inhibitors comprise one or more unnatural amino acids shown in Table 1A. In certain embodiments, the peptide inhibitors of the present invention include any of those described herein, including, but not limited to, any of those comprising an amino acid sequence or peptide inhibitor structure shown in any one of the tables herein.

[0081] The present invention also includes any of the peptide inhibitors described herein, in either free or salt form. Accordingly, embodiments of any of the peptide inhibitors described herein (and related methods of use thereof) include pharmaceutically acceptable salts of the peptide inhibitors.

[0082] The present invention also includes variants of any of the peptide inhibitors described herein, including, but not limited to, one comprising a sequence shown in any one of the tables herein, in which one or more L-amino acid residues are replaced with the D-isomer form of the amino acid residue, e.g., L-Ala is replaced with D-Ala.

[0083] The peptide inhibitors described herein include peptide inhibitors labeled with isotopes.In certain embodiments, the present disclosure provides peptide inhibitors that have the various formulas and structures presented herein or are identical to any of those listed therein, except that one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is usually found in nature.The examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds described herein, for example, 3 H and 14 Incorporating radioactive isotopes such as 1C are useful in drug and / or substrate tissue distribution assays. Additionally, deuterium, i.e. 2 Substitution with isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0084] The present invention also includes any of the peptide monomer inhibitors described herein linked to a linker moiety, including any of the specific linker moieties described herein. In certain embodiments, the linker is attached to the N- or C-terminal amino acid, while in other embodiments, the linker is attached to an internal amino acid. In certain embodiments, the linker is attached to two internal amino acids, for example, to each internal amino acid of two monomer subunits that form a dimer. In some embodiments of the present invention, the peptide inhibitor is attached to one or more linker moieties as shown.

[0085] The present invention also includes peptides and peptide dimers comprising peptides having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the peptide sequences of the peptide inhibitors described herein. In certain embodiments, the peptide inhibitors of the present invention comprise a core peptide sequence and one or more N-terminal and / or C-terminal modifications (e.g., Ac and NH), and / or one or more conjugated linker moieties and / or half-life extending moieties. As used herein, a core peptide sequence is the amino acid sequence of a peptide without such modifications and conjugations. For example, for the peptide inhibitor: [Palm]-[isoGlu]-[PEG4]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 240), the core peptide sequence is [Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN (SEQ ID NO: 240).

[0086] In certain embodiments, a peptide inhibitor or a monomeric subunit of a peptide inhibitor of the invention comprises, consists essentially of, or consists of 7-35 amino acid residues, 8-35 amino acid residues, 9-35 amino acid residues, 10-35 amino acid residues, 7-25 amino acid residues, 8-25 amino acid residues, 9-25 amino acid residues, 10-25 amino acid residues, 7-20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 10-20 amino acid residues, 7-18 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues, and optionally one or more additional non-amino acid moieties such as a conjugated chemical moiety, e.g., PEG or a linker moiety. In certain embodiments, a peptide inhibitor (or monomeric subunit thereof) of the present invention, including but not limited to any embodiment of Formula I, is more than 10, more than 12, more than 15, more than 20, more than 25, more than 30, or more than 35 amino acids, e.g., 35-50 amino acids. In certain embodiments, a peptide inhibitor (or monomeric subunit thereof) is less than 50, less than 35, less than 30, less than 25, less than 20, less than 15, less than 12, or less than 10 amino acids. In certain embodiments, a monomeric subunit of a peptide inhibitor (or peptide monomeric inhibitor) comprises or consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acid residues. In certain embodiments, the monomeric subunits of the peptide inhibitors of the invention comprise or consist of 10-23 amino acid residues, and optionally one or more additional non-amino acid moieties, such as conjugated chemical moieties, e.g., PEG or linker moieties. In various embodiments, the monomeric subunits comprise or consist of 7-35 amino acid residues, 7-20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 10-20 amino acid residues, 8-18 amino acid residues, 8-19 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues.In certain embodiments of any of the various formulas described herein, X comprises or consists of 7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues.

[0087] Certain exemplary peptide inhibitors described herein contain 12 or more amino acid residues. However, the present invention also includes peptide inhibitors comprising fragments of any of the peptide sequences described herein, including peptide inhibitors having 7, 8, 9, 10, or 11 amino acid residues. For example, peptide inhibitors of the present invention include peptides comprising or consisting of X4-X9, X4-X10, X4-X11, X4-X12, X4-X13, X4-X14, X4-X15, or X4-X16. In certain embodiments, the present invention includes peptide inhibitors having any of the sequences described herein, including, but not limited to, any of the formulas described herein or those shown in any of the tables provided herein, where one or more of X15, X16, X17, X18, X19, X20, X21, X22, or X23 are absent.

[0088] In certain embodiments of the invention, the amino acid sequence of the peptide inhibitor is not present within the antibody or is located within the V H or V L Not present in the region.

[0089] Peptide inhibitors The peptide inhibitors of the present invention include peptides having any of the amino acid sequences described herein, compounds having any of the structures described herein, including compounds comprising any of the peptide sequences described herein, and dimers of any of these peptides and compounds.Peptide inhibitors of the present invention include both peptides that do not have a bond between X4 and X9 and peptides that do have a bond between X4 and X9, for example, before and after a bridge is introduced between X4 and X9.Exemplary peptides of the present invention include the amino acid sequences or structures described in any of the attached tables.

[0090] In certain embodiments, the present invention comprises a peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor has the formula (I): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(I) (Sequence number 241) wherein: X0 is any amino acid or is absent X1 is any amino acid or is absent; X2 is any amino acid or is absent; X3 is any amino acid or is absent; X4 is Cys, (D)Cys), alpha-MeCys, Pen, (D)Pen, Abu, or (D)Abu; X5 is any amino acid; X6 is any amino acid; X7 is any amino acid; X8 is any amino acid; X9 is Cys, (D)Cys), alpha-MeCys, Pen, (D)Pen, Abu, or (D)Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is Trp, Trp(5-F), 1-Nal, Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 2-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or Aib; X13 is Glu, Cit, Gln, alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys; X14 is any amino acid; X15 is any amino acid or is absent, X16 is any amino acid or is absent; X17 is any amino acid or is absent; X18 is any amino acid or is absent; X19 is any amino acid or is absent; X20 is any amino acid or is absent,

[0091] wherein X4 and X9 are capable of forming a bond with each other.

[0092] In a related embodiment, the invention comprises a peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor has the formula (II): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23 (II) (SEQ ID NO: 237) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, or Pen; X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or Aib; X13 is Glu, Cit, Gln, alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or absent; wherein X4 and X9 are capable of forming a bond with each other.

[0093] In another aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, the peptide inhibitor having the formula (V): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(V) (Sequence number 238) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Lys(Ac), Lys(Y1-Ac), or absent, where Y1 is an amino acid; X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, Ala, Asp, Tyr, Arg, Leu, Gln, Ser, Ile, 1-Nal, 2-Nal, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, (D)Ile, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or absent; The peptide inhibitors are cyclized via the bond between X4 and X9, and the peptide inhibitors inhibit the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0094] In certain embodiments of peptide inhibitors of Formula (V) or any other formula disclosed herein, X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent. In certain embodiments, X3 is Lys(Ac) or Lys(Y1-Ac), where Y1 is an amino acid.

[0095] In certain embodiments of peptide inhibitors of Formula (V) or any other formula disclosed herein, X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, or Pen. In certain embodiments, X4 is Pen(sulfoxide).

[0096] In certain embodiments of the peptide inhibitor of formula (V) or any other formula disclosed herein, X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln. In certain embodiments, X5 is Asp or Cys.

[0097] In certain embodiments of peptide inhibitors of Formula (V) or any other formula disclosed herein, X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp. In certain embodiments, X8 is 1-Nal or 2-Nal.

[0098] In certain embodiments of the peptide inhibitors of Formula (V) or any other formula disclosed herein, X is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl Ala, Lys, or Aib. In certain embodiments, X is Ala, cyclohexyl Ala, or Lys.

[0099] In certain embodiments of peptide inhibitors of Formula (V) or any other formula disclosed herein, X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys. In certain embodiments, X13 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid.

[0100] In certain embodiments of peptide inhibitors of Formula (V) or any other formula disclosed herein, X is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent. In certain embodiments, X is Ala, Asp, Tyr, Arg, Leu, Gln, Ser, He, 1-Nal, 2-Nal, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, or (D)Ile.

[0101] In certain embodiments of a peptide of Formula (I), Formula (II), or Formula (V), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, the peptide inhibitor is cyclized via the bond between X4 and X9. In certain embodiments, the bond is a disulfide bond or a thioether bond. In certain embodiments, the peptide inhibitor inhibits binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0102] In some embodiments, X4 and X9 of the peptides of Formulas (I), (II), and (V) (or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein) are Cys, alpha-Me-Cys, Pen, or D-Pen, and the intramolecular bond is a disulfide bond. In certain embodiments, both X4 and X9 are Cys, or both X4 and X9 are Pen, and the intramolecular bond is a disulfide bond.

[0103] In one embodiment of a peptide of Formula (I), (II), or (V), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, X4 is Abu, Cys, Pen, D-Pen, or D-Abu, X9 is Abu, Cys, Pen, D-Pen, or D-Abu, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu or D-Abu, X9 is Cys, and the intramolecular bond is a thioether bond, wherein the S of Cys is attached to the γ-C of Abu. In certain embodiments, X4 is Abu or D-Abu, X9 is Cys, the intramolecular bond is a thioether bond, and the intermolecular bond forms -X3-N(H)-C(H)(CH2CH2-S*-)C(O)-X5-, where "S*" is S of Cys.

[0104] In certain embodiments of a peptide of Formula (I), (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, X7 is (Trp(5-F)).

[0105] In certain embodiments of any of the peptide inhibitors or monomeric subunits described herein, including peptides of Formula (I), Formula (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or those having one or both monomeric subunits of a peptide dimer disclosed herein, X7 and X11 are both W. In certain embodiments of any of the peptide inhibitors or monomeric subunits, X7 and X11 are not both Trp. In certain embodiments, X7 is Trp and X11 is not Trp. In certain embodiments, X7 is Trp and X11 is 2-NaI or Trp(5-F). In certain embodiments, X7 and X11 are both W and X10 is Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(4-OMe), or alpha-MeTyr. In certain embodiments, X7 and X11 are both W, X10 is Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(4-OMe), or alpha-Me-Tyr, and X11 is 2-Nal or Trp(5-F). In certain embodiments, X7 is Trp, X11 is 2-Nal or Trp(5-F), and X10 is Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(4-OMe), or alpha-Me-Tyr. In certain embodiments, X7 is Trp, X10 is Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-OMe), or alpha-Me-Tyr, and X11 is 2-Nal or Trp(5-F).

[0106] In certain embodiments, X7 and X11 are both W, or X7 is Trp, X11 is 2-Nal or Trp(5-F), X10 is Phe[4-(2-acetylaminoethoxy)], Phe[4-(2-aminoethoxy)], Phe(CONH2), or alpha-Me-Tyr, and X4 and X9 are amino acid residues capable of forming a thioether bond or a disulfide bond. In certain embodiments, both X4 and X9 are Pen, and the intramolecular bond is a disulfide bond. In certain embodiments, X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond.

[0107] In certain embodiments of a peptide of Formula (I), Formula (II), Formula (V), Formula (IIIa), or Formula (IVa), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, X5-X8 are selected from any of the following tetrapeptide sequences: QTWQ (SEQ ID NO: 242), NDWQ (SEQ ID NO: 243), N(Dab)WQ (SEQ ID NO: 244), NT(1-Nal)Q (SEQ ID NO: 245), NT(2-Nal)Q (SEQ ID NO: 246), NTWE (SEQ ID NO: 247), NTWF (SEQ ID NO: 248), NTWQ (SEQ ID NO: 249), NT[Trp(5-F)]Q (SEQ ID NO: 250). In certain embodiments of a peptide of Formula (I), Formula (II), Formula (V), Formula (IIIa), or Formula (IVa), X5-X8 are selected from the following tetrapeptide sequences: QTWQ (SEQ ID NO: 242), QTWE (SEQ ID NO: 251), ETWQ (SEQ ID NO: 252), ETWE (SEQ ID NO: 253), QTW-(alpha-MeLeu) (SEQ ID NO: 254), QTW-(alpha-MeLys) (SEQ ID NO: 255), QTW-(alpha-MeLeu) (SEQ ID NO: 256), QTW-(alpha-MeLys) (SEQ ID NO: 257), QTW-(alpha-MeLys) (SEQ ID NO: 258), QTW-(alpha-MeLeu) (SEQ ID NO: 259), QTW-(alpha-MeLys) (SEQ ID NO: 260), QTW-(alpha-MeLys) (SEQ ID NO: 261), QTW-(alpha-MeLeu) (SEQ ID NO: 262), QTW-(alpha-MeLys) (SEQ ID NO: 263), QTW-(alpha-MeLeu) (SEQ ID NO: 264), QTW-(alpha-MeLys) (SEQ ID NO: 265), QTW-(alpha-MeLys) (SEQ ID NO: 266), QTW-(alpha-MeLys) (SEQ ID NO: 267), QTW-(alpha-MeLys) (SEQ ID NO: 268), QTW-(alpha-MeLeu) (SEQ ID NO: 269), QTW-(alpha-MeLys) (SEQ ID NO: 270), QTW-(alpha-MeLys) (SEQ ID NO: 271), QTW-(alpha-MeLeu) (SEQ ID NO: 2 QTW-[(D)Gln-MeLys(Ac)) (SEQ ID NO: 256), QTW-((D)Gln) (SEQ ID NO: 257), QTW-(B-homoGln) (SEQ ID NO: 258), QTWF (SEQ ID NO: 259), QTWW (SEQ ID NO: 260), QTW-[Aib] (SEQ ID NO: 261), QTWT (SEQ ID NO: 262), QTWV (SEQ ID NO: 263), or QT-[Trp(5-F)]-Q (SEQ ID NO: 264).

[0108] In certain embodiments, a peptide of Formula (I), (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, comprises an Asn residue at both X14 and X15.

[0109] In certain embodiments, a peptide of Formula (I), (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, comprises at least one, at least two, at least three, or at least four amino acid residues N-terminal to X4. In certain embodiments, at least one, at least two, at least three, or at least four of the amino acid residues N-terminal to X4 are the same amino acid residue as each other. In certain embodiments, they are all the same residue as each other. In certain embodiments, at least one, at least two, at least three, or at least four of the amino acid residues N-terminal to X4 are selected from G, R, F, E, Q, T, and (D)-Arg. In certain embodiments, X0-X3 are the same as any of the corresponding residues shown in any of the peptides in Tables 2-5.

[0110] In certain embodiments, a peptide of Formula (I), (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, comprises at least two, at least three, at least four, at least five, or at least six amino acid residues carboxyl side to X14. In certain embodiments, at least two, at least three, at least four, at least five, or at least six of the amino acid residues carboxyl side to X14 are the same amino acid residue as each other. In certain embodiments, they are all the same residue as each other. In certain embodiments, X14 and X15 are both N. In certain embodiments, at least two, at least three, or at least four of the amino acid residues carboxyl side to X14 are selected from N, E, F, K, W, G, T, P, K, F, or Q. In certain embodiments, X14 through X23 are the same as any of the corresponding residues shown in any of the peptides in Tables 2-5.

[0111] In certain embodiments, a peptide of Formula (I), (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or one or both monomeric subunits of a peptide dimer disclosed herein, comprises an N-terminal Ac group. In certain embodiments, a peptide of Formula (I), (II), (V), (IIIa), or (IVa), and any peptide inhibitor disclosed herein, comprises a C-terminal NH group.

[0112] In certain embodiments, peptide inhibitors of the invention comprise or consist of an amino acid sequence shown herein, e.g., in Tables 2-6. In certain embodiments, peptide inhibitors of the invention have a structure shown herein, e.g., in Tables 2-6. In certain embodiments, any of the Phe[4-(2-aminoethoxy)] residues present in the peptide inhibitors described herein can be replaced by Phe[4-(2-acetylaminoethoxy)].

[0113] In additional embodiments, the present invention includes peptide inhibitors, including peptides comprising variants of any of Formula (I), (II), (V), (IIIa), or (IVa), or the sequences set forth in Tables 2-6, comprising an isosteric substitution of one or more amino acid residues X0-X23. In certain embodiments, the isosteric substitution is a conservative amino acid substitution, and in certain embodiments, the isosteric substitution is a substitution of an amino acid with an analog.

[0114] In additional embodiments, the present invention includes peptide inhibitors, including peptides comprising variants of any of Formula (I), (II), (V), (IIIa), or (IVa), or the sequences set forth in Tables 2-6, which contain different amino acid residues (or chemical entities) at one or both of amino acid residues X4 and X9, but in which the amino acid residues at X4 and X9 are capable of linking with each other, e.g., to form an intramolecular bond or a triazole ring within the peptide. In certain embodiments, the linkage is a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefinic bond.

[0115] For example, in certain embodiments, X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propionic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, or 3-chloro-isobutyric acid; X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys; and the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu, X9 is Pen, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is a 2-methylbenzoyl moiety capable of forming a thioether bond with X9; and X9 is selected from Cys, N-Me-Cys, D-Cys, hCys, Pen, and D-Pen. In certain embodiments, X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain cases, in a peptide monomer, dimer, or subunit thereof of any of the formulas and peptides described herein, X4 is selected from the group consisting of modified Ser, modified hSer (e.g., Homo-Ser-Cl), a suitable isostere, and a corresponding D-amino acid. In other cases, X4 is an aliphatic acid having 1 to 4 carbons that forms a thioether bond with X9. In some cases, X4 is a 5- or 6-membered alicyclic acid having a modified 2-methyl group that forms a thioether bond with X9. In some embodiments, X4 is a 2-methylbenzoyl moiety. In certain embodiments, X4 is selected from Cys, hCys, Pen, and a 2-methylbenzoyl moiety. In certain embodiments, X4 is selected from the group consisting of modified Ser, modified hSer, a suitable isostere, and a corresponding D-amino acid. In one embodiment, X4 is hSerCl (before a thioether bond is formed with X9, thereby removing the Cl), or an hSer precursor (e.g., homoSer(O-TBDMS)). In other cases, X4 is an aliphatic acid having 1-4 carbons that forms a thioether bond with X9. In some cases, X4 is a 5- or 6-membered alicyclic acid with a modified 2-methyl group that forms a thioether bond with X9. In some cases, X4 is a 2-methylbenzoyl moiety.In certain embodiments where X4 is not an amino acid but is a chemical moiety attached to X9, X1, X2, and X3 are absent, and X4 is conjugated or bonded to X5. In some embodiments, the amino acid directly carboxyl to X9 is an aromatic amino acid. In certain embodiments, X4 is an amino acid, while in other embodiments, X4 is another chemical moiety capable of being attached to X9, e.g., to form a thioether bond. In certain embodiments, X4 is another chemical moiety selected from any of the non-amino acid moieties described herein relative to X4. In certain embodiments where X4 is another chemical moiety, X1, X2, and X3 are absent, and the other chemical moiety is attached or conjugated to X5. In certain embodiments, X4 is defined as a chemical moiety containing a group such as chloride, e.g., in 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-choropropanoic acid, 4-chlorobutyric acid, or 3-chloroisobutyric acid. However, those skilled in the art will understand that once the peptide undergoes ring-closing cyclization to form a thioether bond between X4 and X9, the chloride group is no longer present. Thus, a description of a chemical moiety at X4 containing a reactive group such as chloride refers to both the group bearing the chloride and the group without the chloride, i.e., after formation of the bond with X9. The present invention also includes peptides containing the same structures as those shown in any of the other formulas or tables described herein, but in which the thioether bond is in the reverse orientation. In such embodiments of the invention, it can generally be considered that the amino acid residue or other chemical moiety depicted at X4 is instead present at X9, and the amino acid residue depicted at X9 is instead present at X4, i.e., the amino acid residue containing the sulfur of the resulting thioether bond is located at X4 instead of X9, and an amino acid residue or other moiety having a carbon side chain capable of forming a thioether bond with X4 is located at X9. However, in this reverse orientation, the amino acid or chemical moiety at position X9 is one that contains a free amine. For example, in certain embodiments, the amino acid at X9 is a protected homoserine, such as homoserine (OTBDMS).Thus, in certain reverse orientation embodiments of peptide inhibitors of any of the formulas described herein, X9 is an amino acid residue having a one- or two-carbon side chain that forms a thioether bond with X4, where X4 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, and D-Pen. Specific examples of amino acid residues and other chemical moieties present at corresponding positions in other formulas and tables are described herein.

[0116] In certain peptides that form a thioether bond between X4 and X9, X4 is an amino acid, an aliphatic acid, an alicyclic acid, or a modified 2-methylaromatic acid having a carbon side chain capable of forming a thioether bond with X9, and X9 is a sulfur-containing amino acid capable of forming a thioether bond with X4. In certain embodiments, X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propionic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propionic acid (3-chloro-propanoic acid). acid), 4-chlorobutyric acid, 3-chloroisobutyric acid, Abu, β-azido-Ala-OH, propargylglycine, 2-(3'-butenyl)glycine, 2-allylglycine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine, 2-(5'-hexenyl)glycine, and X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCy X4 is s, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-allylglycine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine, or 2-(5'-hexenyl)glycine. In certain embodiments, X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propionic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propionic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, and X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys.

[0117] In one embodiment, X4 and X9 are each Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, or D-Lys, and the intramolecular bond is a lactam bond.

[0118] In certain embodiments, X4 and X9 are each β-azido-Ala-OH or propargylglycine, and the peptide inhibitor (or monomeric subunit) is cyclized through the triazole ring.

[0119] In certain embodiments, X4 and X9 are each 2-allylglycine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine, or 2-(5'-hexenyl)glycinem, and the peptide inhibitor (or monomeric subunit) is cyclized via ring closing methathesis to provide the corresponding olefin / "staple peptide."

[0120] In certain embodiments, X4 is 2-chloromethylbenzoic acid, mercapto-propionic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, or hSer(Cl), X9 is hSer(Cl), Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is 2-chloromethylbenzoic acid or hSer(Cl), X9 is Cys or Pen, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu, and X9 is Cys or Pen.

[0121] In certain embodiments, X4 is 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu, or Sec, X9 is Abu or Sec, and the intramolecular bond is a selenoether bond.

[0122] In certain embodiments, the intramolecular bond between X4 and X9 is a diselenide bond.

[0123] In some embodiments, with respect to any of the formulas described herein, X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent. In other embodiments, X3 is Lys(Ac) or Lys(Y1-Ac), where Y1 is an amino acid. In one embodiment, Y1 is a natural amino acid. In another embodiment, Y1 is a (D)amino acid. In certain embodiments, Y1 is Glu, Phe, Tyr, Ser, Arg, Leu, or Pro.

[0124] In some embodiments, for any of the formulas described herein, X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln. In other embodiments, X5 is Asp or Cys.

[0125] In some embodiments, for any of the formulas described herein, X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp. In other embodiments, X8 is 1-Nal or 2-Nal.

[0126] In some embodiments, with respect to any of the formulas described herein, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or Aib. In other embodiments, X12 is Ala, or cyclohexyl Ala, or Lys. In certain embodiments, X12 is cyclohexyl Ala. In certain embodiments, X12 is, for example, conjugated to a chemical substituent. In certain embodiments, X12 is Lys, and Lys is, for example, conjugated to a chemical substituent.

[0127] In some embodiments, with respect to any of the formulas described herein, X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys. In other embodiments, X13 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), and Y2 is an amino acid. In one embodiment, Y2 is a natural amino acid. In another embodiment, Y2 is a (D) amino acid. In certain embodiments, Y2 is Glu, Phe, Asn, Thr, Asp, Tyr, Ser, Arg, Leu, or Pro. In certain embodiments, Y2 is (D)Glu, (D)Phe, (D)Asn, (D)Thr, (D)Asp, (D)Tyr, (D)Ser, (D)Arg, or (D)Leu.

[0128] In some embodiments, with respect to any of the formulas described herein, X is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent. 16 is Ala, Asp, Tyr, Arg, Leu, Gln, Ser, Ile, 1-Nal, 2-Nal, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, or (D)Ile.

[0129] In certain embodiments, the present invention comprises a peptide inhibitor of the interleukin-23 receptor, the peptide inhibitor having formula XI: R 1 -XR 2 (XI) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, alkylsulfonate, acid, γ-Glu, or pGlu, and is attached to the N-terminus and includes PEGylated forms (e.g., 200 Da to 60,000 Da) alone or as a spacer for any of the above; R 2 is a bond, OH, or NH2; X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 amino acids.

[0130] In one embodiment, R 1 is a bond, hydrogen, or C1-C20 alkanoyl. 1 is a bond, hydrogen, or Ac. In certain embodiments, R 1 is Ac. In another particular embodiment, R 1 is PEGylated.

[0131] In one embodiment, R 2 is OH. In certain embodiments, R 2 is NH2.

[0132] In certain embodiments of the peptide inhibitor of formula XI, X is a group represented by formula XII: X2-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(XII) (Sequence number 275) wherein: X2 is Arg, (D)Arg, Gln, or absent; X3 is (D)Arg, Phe, (D)Phe, Lys, (D)Lys, Lys(Y1-Ac), (D)Lys(Y1-Ac), or absent, wherein Y1 is an amino acid or Y1 is absent; X4 is Cys, (D)Cys), alpha-MeCys, Abu, (D)Pen, Pen, (D)Pen sulfoxide, or Pen sulfoxide; X5 is Cit, Lys, Asn, Asp, Glu, Lys(Ac), or Gln; X7 is Trp, substituted Trp, or 1-Nal; X8 is Gln, Lys, Lys(Ac), a-MeLeu, Cit, Glu, 1-Nal, 2-Nal, Trp, substituted Trp, or Lys(Peg12); X9 is Cys, Abu, or Pen; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe(Cmd), or Phe[4-(2-acetylaminoethoxy)]; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is alpha-MeLeu, Aib, Lys, cyclohexyl Ala, tetrahydropyran Ala, or Lys(Peg12); X13 is Glu, b-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or (D)Lys(Y2-Ac); wherein Y2 is an amino acid or Y2 is absent; X14 is Asn, Asp, Cit, or Lys(Ac); X15 is Asn, Lys, Lys(Ac), Cit, Asp, Gly, Ala, b-Ala, or Sarc; X16 is an amino acid or is absent; the substituted Trp is a Trp substituted with a halo- or aza-Trp; wherein X4 and X9 are capable of forming a disulfide bond or a thioether bond or are linked via a disulfide bond or a thioether bond.

[0133] In one embodiment, the substituted Trp is fluoro-substituted Trp. In another embodiment, the substituted Trp is aza-Trp. In a particular embodiment, the substituted Trp is (5-F)Trp. In another particular embodiment, the substituted Trp is (7-aza)Trp.

[0134] In one embodiment, X2 is Arg, (D)Arg, or absent. In certain embodiments, X2 is absent.

[0135] In one embodiment, X7 is Trp or Trp(5-F). In certain embodiments, X7 is Trp.

[0136] In one embodiment, X10 is Phe[4-(2-aminoethoxy)].

[0137] In one embodiment, X11 is 2-Nal.

[0138] In one embodiment, X15 is Asn.

[0139] In certain embodiments, with respect to formula XI, X is formula XIII: X3-X4-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XIII) (SEQ ID NO: 276) wherein X3, X4, X5, X8, X9, X12, X13, X14, or X16 is as described for formula XII.

[0140] In one embodiment, X4 and X9 are linked together to form a disulfide bond. In one embodiment, X4 and X9 are linked together to form a thioether bond.

[0141] In one embodiment, X4 is Abu or Pen. In one embodiment, X4 is Abu; X4 and X9 are linked together to form a thioether bond. In another embodiment, X4 is Pen, and X4 and X9 are linked together to form a disulfide bond.

[0142] In certain embodiments, with respect to formula XI, X is formula XIVa or XIVb: X3-Abu-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XIVa) (SEQ ID NO: 277); or X3-Pen-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XIVb) (SEQ ID NO: 278); wherein X3, X5, X8, X9, X12, X13, X14, or X16 is as described for formula XII.

[0143] In one embodiment, X5 is Asn or Gln.

[0144] In certain embodiments, with respect to formula XI, X is selected from formula XVa, XVb, XVc, or XVd: X3-Abu-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVa) (SEQ ID NO: 279); X3-Pen-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVb) (SEQ ID NO: 280); X3-Abu-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVc) (SEQ ID NO: 281); or X3-Pen-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVd) (SEQ ID NO: 282); wherein X3, X8, X9, X12, X13, X14, or X16 is as described for formula XII.

[0145] In one embodiment, X4 and X9 are linked together to form a disulfide bond or a thioether bond.

[0146] In one embodiment, X9 is Cys or Pen.

[0147] In certain embodiments, with respect to formula XI, X is selected from formula XVIa, XVIb, XVIc, XVId, XVIe, XVIf, XVIg, or XVIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIa) (SEQ ID NO: 283); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIb) (SEQ ID NO: 284); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIc) (SEQ ID NO: 285); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVId) (SEQ ID NO: 286); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIe) (SEQ ID NO: 287); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIf) (SEQ ID NO: 288); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIg) (SEQ ID NO: 289); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIh) (SEQ ID NO: 290); wherein X3, X8, X12, X13, X14, or X16 is as described for formula XII.

[0148] In one embodiment, with respect to Formulas XVIa-XVIh, Abu and Cys, Pen and Cys, Abu and Pen, or Pen and Pen are linked together to form a disulfide bond or a thioether bond.

[0149] In one embodiment, with respect to formulae XI-XVIh, X12 is tetrahydropyran-Ala (THP-Ala) or a-MeLeu.

[0150] In one embodiment, with respect to formulae XI-XVIh, X14 is Lys(Ac) or Asn. In certain embodiments, X14 is Asn.

[0151] In certain embodiments, with respect to formula XI, X is selected from formula XVIIa, XVIIb, XVIIc, XVIId, XVIIe, XVIIf, XVIIg, or XVIIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIa) (SEQ ID NO: 291); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIb) (SEQ ID NO: 292); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIc) (SEQ ID NO: 293); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIId) (SEQ ID NO: 294); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIe) (SEQ ID NO: 295); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIf) (SEQ ID NO: 296); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIg) (SEQ ID NO: 297); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIh) (SEQ ID NO: 298); wherein X3, X8, X12, X13, or X16 is as described for formula XII.

[0152] In certain embodiments, with respect to formula XI, X is selected from formula XVIIIa, XVIIIb, XVIIIc, XVIIId, XVIIIe, XVIIIf, XVIIIg, or XVIIIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIa) (SEQ ID NO: 299); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIb) (SEQ ID NO: 300); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16 (XVIIIc) (SEQ ID NO: 301); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16 (XVIIId) (SEQ ID NO: 302); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVIIIe) (SEQ ID NO: 303); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIf) (SEQ ID NO: 304); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16 (XVIIIg) (SEQ ID NO: 305); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIh) (SEQ ID NO: 306); wherein X3, X8, X13, or X16 is as described for formula XII.

[0153] In certain embodiments, with respect to Formulas XI-XVIIIh, X3 is (D)Arg, Phe, (D)Phe, Lys, (D)Lys, Lys(Y1-Ac), (D)Lys(Y1-Ac), or absent, and Y1 is an amino acid or absent. In one embodiment, Y1 is a natural amino acid. In another embodiment, Y1 is a (D)amino acid. In certain embodiments, Y1 is Glu, Phe, Tyr, Ser, Arg, Leu, or Pro. In certain embodiments, X3 is absent. In another specific embodiment, X3 is (D)Arg. In more specific embodiments, X3 is Lys(Y1-Ac) or (D)Lys(Y1-Ac). In one embodiment, Y1 is Leu. In another embodiment, Y1 is Glu. In another embodiment, Y1 is Phe. In another embodiment, Y1 is Tyr. In another embodiment, Y1 is Pro. In another embodiment, Y is Ser. In another embodiment, Y is Arg.

[0154] In certain embodiments, with respect to Formulas XI-XVIIIh, X8 is Gln, Lys, Lys(Ac), a-MeLeu, Cit, or Glu. In particular embodiments, X8 is Gln, Glu, Lys(Ac), or a-MeLeu. In another particular embodiment, X8 is Gln or Lys(Ac). In more specific embodiments, X8 is Gln.

[0155] In certain embodiments, with respect to Formulas XI-XVIIIh, X13 is Glu, b-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or (D)Lys(Y2-Ac); Y2 is an amino acid or Y2 is absent. In certain embodiments, X13 is Glu, Cit, Lys, or Lys(Ac). In more specific embodiments, X13 is Glu or Lys(Ac).

[0156] In certain embodiments, with respect to Formulae XI-XVIIIh, X16 is absent or an amino acid. In certain embodiments, X16 is absent. In more specific embodiments, X16 is an amino acid. In one embodiment, the amino acid is Sar, Lys, (D)Lys, Ahx, b-Ala, Gly, Arg, (D)Arg, Ile, Gln, (D)Gln, Tyr, Ser, (D)Ser, (D)Tyr, Ala, Trp, Asp, or (D)Asp.

[0157] In certain embodiments of peptide inhibitors comprising variants of any of Formulas (I), (II), (V), (IIIa), or (IVa), if X4 is not an amino acid, then X1, X2, and X3 are absent. In certain embodiments, X1 is a D-amino acid or is absent. In certain embodiments, X2 is a D-amino acid or is absent. In certain embodiments, X3 is a D-amino acid or is absent. In certain embodiments, X16 is a D-amino acid or is absent. In certain embodiments, X17 is a D-amino acid or is absent. In certain embodiments, X18 is a D-amino acid or is absent. In certain embodiments, X19 is a D-amino acid or is absent. In certain embodiments, X20 is a D-amino acid or is absent.

[0158] In certain embodiments, peptides of Formula (I), (II), (V), (IIIa), or (IVa) are conjugated to one or more chemical substituents, such as lipophilic substituents and polymer moieties, which may be referred to herein as half-life extending moieties. In certain embodiments, peptides of Formula (I), (II), (V), (IIIa), or (IVa) are conjugated to one or more detectable markers or dyes.

[0159] In some embodiments, when a peptide of the present invention is conjugated to an acidic compound, such as, for example, isovaleric acid, isobutyric acid, valeric acid, etc., the presence of such conjugate is referred to in its acidic form. Thus, for example, and in no way limiting, in some embodiments, instead of referring to the conjugation of isovaleric acid to a peptide by reference to isovaleryl (e.g., isovaleryl-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 307), the present application refers to a conjugate such as isovaleric acid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 307).

[0160] In certain embodiments, the peptide inhibitor does not include compounds disclosed in any or all of PCT Application No. PCT / US2014 / 030352, PCT Application No. PCT / US2015 / 038370, PCT Application No. PCT / US2015 / 040658, or PCT Application No. PCT / US2016 / 042680.

[0161] Exemplary Peptide Inhibitors Containing a Pen-Pen Disulfide Bond In certain embodiments, the present invention comprises a peptide inhibitor of the interleukin-23 receptor, the peptide inhibitor having Formula III: R 1 -XR 2 (III)

[0162] or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, alkylsulfonate, acid, γ-Glu, or pGlu, and is attached to the N-terminus and includes PEGylated forms (e.g., 200 Da to 60,000 Da) alone or as a spacer for any of the above;

[0163] R 2 is a bond, OH, or NH2;

[0164] X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 amino acids.

[0165] In certain embodiments of the peptide inhibitor of formula III, X is a group of formula IIIa: X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(IIIa) (Sequence number 265) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X4 is Cys, (D)Cys), alpha-MeCys, (D)Pen, or Pen; X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Pen, or Pen; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or Aib; X13 is Glu, Cit, Gln, alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or absent; wherein X4 and X9 are capable of forming a disulfide bond.

[0166] In certain embodiments of the peptide of formula (IIIa), the peptide inhibitor is cyclized via a disulfide bond between X4 and X9. In certain embodiments, both X4 and X9 are Cys, or both X4 and X9 are Pen, and the intramolecular bond is a disulfide bond.

[0167] In certain embodiments, the peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0168] In certain embodiments, X7 and X11 are both W, or X7 is Trp, X11 is 2-Nal or Trp(5-F), X10 is Phe[4-(2-acetylaminoethoxy)], Phe[4-(2-aminoethoxy)], Phe(CONH2), or alpha-MeTyr, and X4 and X9 are amino acid residues capable of forming a disulfide bond. In certain embodiments, both X4 and X9 are Pen, and the intramolecular bond is a disulfide bond.

[0169] In certain embodiments of a peptide of Formula (IIIa), X5-X8 are selected from any of the following tetrapeptide sequences: QTWQ (SEQ ID NO: 242), NDWQ (SEQ ID NO: 243), N(Dab)WQ (SEQ ID NO: 244), NT(1-Nal)Q (SEQ ID NO: 245), NT(2-Nal)Q (SEQ ID NO: 246), NTWE (SEQ ID NO: 247), NTWF (SEQ ID NO: 248), NTWQ (SEQ ID NO: 249), and NT[Trp(5-F)]Q (SEQ ID NO: 250).

[0170] In certain embodiments, peptides of Formula (IIIa) contain Asn residues at both X14 and X15. In related embodiments, these peptides further contain at least two, at least three, or at least four amino acid residues carboxyl to X15. In certain embodiments, the carboxy amino acid residues are the same as each other.

[0171] In certain embodiments of peptide inhibitors of Formula (III), one or more, two or more, three or more, or all four of X0, X1, X2, and X3 are absent. In certain embodiments, X0 is absent and / or X1 is absent. In certain embodiments, X0, X1, and X2 are absent. In certain embodiments, X0, X1, X2, and X3 are absent. In certain embodiments of peptide inhibitors of Formula III, one or more, two or more, three or more, or all four of X0, X1, X2, and X3 are present, i.e., not absent. In certain embodiments, X3 is present, in certain embodiments, X3 and X2 are present, in certain embodiments, X3, X2, and X1 are present, and in certain embodiments, X3, X2, X1, and X0 are present, i.e., an amino acid is present at each position.

[0172] In certain embodiments of peptide inhibitors of Formula III, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or all nine of X15, X16, X17, X18, X19, X20, X21, X22, and X23 are absent. In certain embodiments of peptide inhibitors of Formula III, one or more, two or more, three or more, or all of X17, X18, X19, and X20 are absent. In certain embodiments, one or more, two or more, or all three of X17, X19, and X20 are absent. In certain embodiments of peptide inhibitors of Formula III, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or all nine of X15, X16, X17, X18, X19, X20, X21, X22, and X23 are absent. In certain embodiments of peptide inhibitors of Formula III, one or more, two or more, three or more, four or more, five or more, six or more, or all seven of X17, X18, X19, X20, X21, X22, and X23 are present. In certain embodiments, one or more, two or more, or all three of X18, X19, and X20 are present.

[0173] In certain embodiments of any of the peptide inhibitors described herein, any of the amino acids of the peptide inhibitor are connected by a linker moiety, eg, PEG.

[0174] In certain embodiments, the N-terminus of the peptide inhibitor comprises an Ac group.

[0175] In certain embodiments, the C-terminus of the peptide inhibitor comprises an NH2 group.

[0176] In certain embodiments of the peptide inhibitors of formula III, X10 is not Tyr.

[0177] In certain embodiments, the peptide of formula (IIIa) has the following sequence: [Pen]-X5-X6-X7-X8-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] (SEQ ID NO: 266); [Pen]-X5-X6-X7-X8-[Pen]-[Phe[4-(2-aminoethoxy)]-W-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 267); or [Pen]-X5-X6-X7-X8-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 268),

[0178] wherein X5 to X8 are defined as above and further comprise (i) at least one, at least two, or at least three amino acid residues N-terminal to the most N-terminal Pen, or (ii) at least three, at least four, at least five, at least six, or at least seven amino acid residues C-terminal to the C-terminal amino acid residue shown above. In certain embodiments, X5 to X8 are selected from QTWQ (SEQ ID NO: 242), NDWQ (SEQ ID NO: 243), N(Dab)WQ (SEQ ID NO: 244), NT(1-Nal)Q (SEQ ID NO: 245), NT(2-Nal)Q (SEQ ID NO: 246), NTWE (SEQ ID NO: 247), NTWF (SEQ ID NO: 248), NTWQ (SEQ ID NO: 249), and NT[Trp(5-F)]Q (SEQ ID NO: 250).

[0179] In certain embodiments of peptides of Formula (I), (II), IIIa), or (IVa), X7 is (Trp(5-F).

[0180] In certain embodiments of the peptide inhibitor of formula III, the peptide inhibitor has a structure shown in Table 2 or Table 3 or comprises an amino acid sequence set forth in Table 2 or Table 3 (or a pharmaceutically acceptable salt thereof), wherein the two Pen residues can be linked via a disulfide bond. [Table 2-1] [Table 2-2] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0181] Exemplary Peptide Inhibitors Containing Thioether Bonds In certain embodiments, the present invention includes a peptide inhibitor of the interleukin-23 receptor, the peptide inhibitor having Formula IV: R 1 -XR 2 (IV)

[0182] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0183] R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, alkylsulfonate, acid, γ-Glu, or pGlu, and is attached to the N-terminus and includes PEGylated forms (e.g., 200 Da to 60,000 Da) alone or as a spacer for any of the above;

[0184] R 2 is a bond, OH, or NH2;

[0185] X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 amino acids.

[0186] In certain embodiments of the peptide inhibitor of formula IV, X is a group of formula IVa: X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(IVa) (Sequence number 270) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, or Pen; X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Gln; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or Aib; X13 is Glu, Cit, Gln, alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or absent; wherein X4 and X9 are capable of forming a thioether bond.

[0187] In certain embodiments of the peptide of Formula (IVa), the peptide inhibitor is cyclized via a thioether bond between X4 and X9. In one embodiment of the peptide of Formula (IVa), X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain embodiments, the peptide inhibitor inhibits binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0188] In certain embodiments, X7 and X11 are both W, or X7 is Trp, X11 is 2-Nal or Trp(5-F), X10 is Phe[4-(2-acetylaminoethoxy)], Phe[4-(2-aminoethoxy)], Phe(CONH2), or alpha-MeTyr, and X4 and X9 are amino acid residues capable of forming a thioether bond. In certain embodiments, X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond.

[0189] In certain embodiments of a peptide of Formula (IVa), X5-X8 are selected from any of the following tetrapeptide sequences: QTWQ (SEQ ID NO: 242), NDWQ (SEQ ID NO: 243), N(Dab)WQ (SEQ ID NO: 244), NT(1-Nal)Q (SEQ ID NO: 245), NT(2-Nal)Q (SEQ ID NO: 246), NTWE (SEQ ID NO: 247), NTWF (SEQ ID NO: 248), NTWQ (SEQ ID NO: 249), and NT[Trp(5-F)]Q (SEQ ID NO: 250).

[0190] In certain embodiments, peptides of Formula (IVa) contain Asn residues at both X14 and X15. In related embodiments, these peptides further contain at least two, at least three, or at least four amino acid residues carboxyl to X15. In certain embodiments, the carboxy amino acid residues are the same as each other.

[0191] In certain embodiments, the peptide inhibitor of Formula IV is cyclized. In certain embodiments, the peptide inhibitor is cyclized via a thioether bond between X4 and X9. In certain embodiments, the peptide inhibitor of Formula IV is linear and not cyclized.

[0192] In certain embodiments of peptide inhibitors of Formula IV, one or more, two or more, three or more, or all four of X0, X1, X2, and X3 are absent. In certain embodiments, X0 is absent and / or X1 is absent. In certain embodiments, X0, X1, and X2 are absent. In certain embodiments, X0, X1, X2, and X3 are absent. In certain embodiments of peptide inhibitors of Formula IV, one or more, two or more, three or more, or all four of X0, X1, X2, and X3 are present, i.e., not absent. In certain embodiments, X3 is present, in certain embodiments, X3 and X2 are present, in certain embodiments, X3, X2, and X1 are present, and in certain embodiments, X3, X2, X1, and X0 are present, i.e., an amino acid is present at each position.

[0193] In certain embodiments of peptide inhibitors of Formula IV, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or all nine of X15, X16, X17, X18, X19, X20, X21, X22, and X23 are absent. In certain embodiments of peptide inhibitors of Formula IV, one or more, two or more, three or more, or all of X17, X18, X19, and X20 are absent. In certain embodiments, one or more, two or more, or all three of X17, X19, and X20 are absent. In certain embodiments of peptide inhibitors of Formula IV, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or all nine of X15, X16, X17, X18, X19, X20, X21, X22, and X23 are absent. In certain embodiments of peptide inhibitors of Formula IV, one or more, two or more, three or more, four or more, five or more, six or more, or all seven of X17, X18, X19, X20, X21, X22, and X23 are present. In certain embodiments, one or more, two or more, or all three of X18, X19, and X20 are present.

[0194] In certain embodiments of the peptide inhibitor of formula IV, one of X4 or X9 is Abu and the other of X4 or X9 is not Abu. In certain embodiments, X4 is Abu and X9 is Cys.

[0195] In certain embodiments of any of the peptide inhibitors described herein, any of the amino acids of the peptide inhibitor are connected by a linker moiety, eg, PEG.

[0196] In certain embodiments, the N-terminus of the peptide inhibitor comprises an Ac group.

[0197] In certain embodiments, the C-terminus of the peptide inhibitor comprises an NH2 group.

[0198] In certain embodiments of the peptide inhibitor of formula IV, X10 is not Tyr.

[0199] In certain embodiments, the peptide of formula (IVa) has the following sequence: [Abu]-X5-X6-X7-X8-[Cys]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] (SEQ ID NO: 271); [Abu]-X5-X6-X7-X8-[Cys]-[Phe[4-(2-aminoethoxy)]-W-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 272); or [Abu]-X5-X6-X7-X8-[Cys]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 273),

[0200] In the formula, X5 to X8 are defined as above and further include (i) at least one, at least two, or at least three amino acid residues on the N-terminal side of Abu, or (ii) at least three, at least four, at least five, at least six, or at least seven amino acid residues on the C-terminal side of the C-terminal amino acid residue shown above. In certain embodiments, X5 through X8 are selected from any of QTWQ (SEQ ID NO:242), QTWE (SEQ ID NO:251), ETWQ (SEQ ID NO:252), ETWE (SEQ ID NO:253), QTW-(alpha-MeLeu) (SEQ ID NO:254), QTW-(alpha-MeLys) (SEQ ID NO:255), QTW-(alpha-MeLys(Ac)) (SEQ ID NO:256), QTW-((D)Gln) (SEQ ID NO:257), QTW-(B-homoGln) (SEQ ID NO:258), QTWF (SEQ ID NO:259), QTWW (SEQ ID NO:260), QTWAib (SEQ ID NO:261), QTWT (SEQ ID NO:262), QTWV (SEQ ID NO:263), or QT-(Trp(5-F))-Q (SEQ ID NO:264).

[0201] In certain embodiments of peptides of Formula (I), (II), IIIa), or (IVa), X7 is (Trp(5-F).

[0202] In certain embodiments, the present invention includes peptides comprising or consisting of the amino acids set forth in either Table 4 or 5, or peptide inhibitors comprising or consisting of the structures set forth in either Table 4 or 5 (or pharmaceutically acceptable salts thereof). In certain embodiments, the peptide does not include a conjugate moiety but includes an Abu residue. In certain embodiments, the peptide or inhibitor includes a thioether bond between two Abu and Cys residues, or between the two outermost amino acids in parentheses following the term "cyclo" to indicate the presence of a cyclic structure. In certain embodiments, the inhibitor is an acetate salt. Exemplary inhibitor peptide sequences are shown in Tables 4 and 5 from N-terminus to C-terminus, with the conjugate moiety and the N-terminal Ac and / or C-terminal NH groups indicated. The cyclic structure is indicated by "cyclo" as shown in Table 5, indicating the presence of a thioether bond between the bracketed Abu at X4 and the Cys at X9. Exemplary examples of peptide inhibitor structures are shown in Tables 4 and 5 below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0203] In certain embodiments, the peptide or peptide dimer is selected from the peptides listed in Table 6. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10]

[0204] In certain embodiments, the peptide is Alexa488-[PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 71); [Biotin]-[PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 89); Ac-[(D)Arg]-cyclo[[Abu]-QT-[Trp(5-F)]-QC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 105); Ac-cyclo[[Abu]-QT-[Trp(5-F)]-QC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 106); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 107); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 138); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[3-cyclohexyl-Ala]-ENN-NH2 (SEQ ID NO: 147); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-ENN-NH2 (SEQ ID NO: 148); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNY-NH2 (SEQ ID NO: 159); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNR-NH2 (SEQ ID NO: 161); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNQ-NH2 (SEQ ID NO: 164); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNS-NH2 (SEQ ID NO: 165); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 170); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Arg]-NH2 (SEQ ID NO: 174); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 175); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Gln]-NH2 (SEQ ID NO: 177); (Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Lys]-NH2)2-DIG (SEQ ID NO: 184); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNG-NH2 (SEQ ID NO: 195); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[β-Ala]-NH2 (SEQ ID NO: 196); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[Ahx]-NH2 (SEQ ID NO: 197); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[Sar]-NH2 (SEQ ID NO: 198); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Asn)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 218); Ac-[Lys(Ac-Glu)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 223); Ac-[Lys(Ac-Phe)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 224); Ac-[Lys(Ac-Tyr)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 225); Ac-[Lys(Ac-Ser)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 226);[[ID=ll]] Ac-[Lys(Ac-Arg)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 227); Ac-[Lys(Ac-Leu)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 228); Ac-[Lys(Ac-Pro)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 229); Ac-[(D)Lys(Ac-Glu)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 230); Ac-[(D)Lys(Ac-Phe)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 231); Ac-[(D)Lys(Ac-Tyr)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 232); Ac-[(D)Lys(Ac-Ser)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 233); Ac-[(D)Lys(Ac-Arg)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 234); Ac-[(D)Lys(Ac-Leu)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 235); or It comprises or consists of the sequence Ac-[(D)Lys(Ac-Pro)]-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 236).

[0205] In another particular embodiment, the peptide is Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 1); Ac-[Pen]-N-[Dab]-WQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 3); Ac-[Pen]-NT-[2-Nal]-Q-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 5); Ac-[Pen]-NTWE-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 6); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-W-[4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 8); Ac-[Pen]-NT-[Trp(5-F)]-Q-[Pen]-[Phe[4-(2-aminoethoxy)]-W-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 9); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-END-NH (SEQ ID NO: 73) Ac-[(D)Arg]-cyclo[[Abu]-QTWEC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 75); Ac-[(D)Arg]-cyclo[[Abu]-ETWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 76); Ac-[(D)Arg]-cyclo[[Abu]-QTWEC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-END-NH2 (SEQ ID NO: 78); Ac-[(D)Arg]-cyclo[[Abu]-ETWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-END-NH2 (SEQ ID NO: 79); Ac-[(D)Arg]-cyclo[[Abu]-ETWEC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 82); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-OH (SEQ ID NO: 83); Ac-[(D)Arg]-cyclo[[Abu]-QTWEC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-OH (SEQ ID NO: 86); [Ac-[(D)Arg]-cyclo[[Abu]-ETWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-OH (SEQ ID NO: 87); [NH2-PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 88); [NH2-PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)-(PEG4-NH2)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 90); [NH2-PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)-(PEG4)-(biotin)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 91); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[a-MeLeu]-C]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 93); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[α-MeLys(Ac)]-C]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 95); Ac-[(D)Arg]-cyclo[[Abu]-QTWWC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 100); Ac-[(D)Arg]-cyclo[[Abu]-QT-[Trp(5-F)]-QC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 104); Ac-cyclo[[(D)Abu]-NTWQ-[Pen]]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 136); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[2-Nal]-C]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 139); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[1-Nal]-C]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 140); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[5-fluoro-Trp]-C]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 141); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-OH (SEQ ID NO: 142); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-ND-NH2 (SEQ ID NO: 143); Ac-[Pen]-NTWE-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 145); Ac-[Pen]-DTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 146); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[Lys(PEG)]-C]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH (SEQ ID NO: 154); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys(PEG)]-NN-NH (SEQ ID NO: 156); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NND-NH2 (SEQ ID NO: 158); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNW-NH2 (SEQ ID NO: 160); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNL-NH2 (SEQ ID NO: 162); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNG-NH2 (SEQ ID NO: 163); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-N-[Lys(Ac)]-NH2 (SEQ ID NO: 166); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 168); Ac-[Pen]-[Lys(Ac)]-TWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 169); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Asp]-NH2 (SEQ ID NO: 171); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Tyr]-NH2 (SEQ ID NO: 172); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[2-Nal]-NH2 (SEQ ID NO: 173); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Ala]-NH2 (SEQ ID NO: 176); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Ser]-NH2 (SEQ ID NO: 178); Ac-[Lys(Ac)]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 179); Ac-[Lys(Ac)]-[Pen]-NTWQ-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 180); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[Lys(Ac)]-NH2 (SEQ ID NO: 181); Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[Lys(Ac)]-NH2 (SEQ ID NO: 182); Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Lys]-NH2 (SEQ ID NO: 183); Ac-[Pen]-NT-[5-Fluoro-Trp]-Q-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 185); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[β-homo-Glu]-NN-NH2 (SEQ ID NO: 186); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-[Cit]-N-NH2 (SEQ ID NO: 188); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-N-[Cit]-NH2 (SEQ ID NO: 189); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 190); Ac-[Pen]-NTW-[Cit]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 191); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-N-[Sarc]-NH2 (SEQ ID NO: 192); Ac-[Pen]-[Cit]-TW-[Cit]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 193); Ac-[Pen]-NTWQ[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Deg]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 194); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Arg]-NH2 (SEQ ID NO: 199); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 200); Ac-[Pen]-NT-[Trp(5-F)]-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 202); Ac-[Pen]-NT-[Trp(5-F)]-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNG-NH2 (SEQ ID NO: 203); (Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2)2-DIG (SEQ ID NO: 204); (Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2)2-PEG4 (SEQ ID NO: 207); (Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2)2-PEG13 (SEQ ID NO: 208); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Arg)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 209); Ac-[Pen]-NTW[-Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Tyr)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 210); Ac-[Pen]-NTW[-Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Asn)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 211); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Thr)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 212); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Asp)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 213); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Leu)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 214); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-Phe)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 215); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Arg)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 216); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Tyr)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 217); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Thr)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 219); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Asp)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 220); or It comprises or consists of the sequence Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Phe)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 222).

[0206] Further characteristics of peptide inhibitors Any of the peptide inhibitors of the present invention may be further defined, for example, as described below. It is understood that each of the additional defining characteristics described herein may apply to any peptide inhibitor, and that the amino acid specified at a particular position allows for the presence of the additional defining characteristic. In certain embodiments, these characteristics may be present in any of the peptides of formula (I), (II), (III), (IV), (V), or (XII)-(XVIIIh).

[0207] In various embodiments, R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, or C1-C20 alkanoyl, and includes PEGylated forms alone or as a spacer, e.g., acetyl, of any of the above. 1 It is understood that R can replace or be present in addition to the typical amino group located at the amino terminus of a peptide. 1 It is further understood that R may be absent. In certain embodiments, the peptide inhibitor comprises an N-terminus selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, or C1-C20 alkanoyl, and includes a PEGylated form, either alone or as a spacer, e.g., acetyl, of any of the above. In certain embodiments of any of the peptide inhibitors described herein, R 1 Or the N-terminal moiety is hydrogen. In certain embodiments, R 1 is a bond, e.g., a covalent bond.

[0208] In certain embodiments of any of the peptide inhibitors having any of the various formulas described herein, R 1 or the N-terminal moiety is selected from methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid. 1 Or the N-terminal portion is pGlu. 1 is hydrogen. In certain embodiments, R 1 is acetyl, whereby a peptide inhibitor is acylated at its N-terminus, for example, to cap or protect the N-terminal amino acid residue, e.g., an N-terminal Pen or Abu residue.

[0209] In certain embodiments of any of the peptide inhibitors described herein, R 1 Or the N-terminal moiety is an acid. In certain embodiments, R 1 Alternatively, the N-terminal moiety is an acid selected from acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, octanoic acid, lauric acid, hexadecanoic acid, 4-biphenylacetic acid, 4-fluorophenylacetic acid, gallic acid, pyroglutamic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, 4-methylbicyclo(2.2.2)-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, alkylsulfonic acids, and arylsulfonic acids.

[0210] In certain embodiments, R 1Or the N-terminal moiety is an alkylsulfonic acid selected from methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, and 2-hydroxyethanesulfonic acid.

[0211] In certain embodiments, R 1 Or the N-terminal moiety is an arylsulfonic acid selected from benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonic acid.

[0212] In some embodiments, when a peptide of the invention includes a conjugate to an acidic compound, such as isovaleric acid, isobutyric acid, or valeric acid, the presence of such a conjugate is referred to in its acidic form. Thus, for example, and in no way as a limitation, in some embodiments, instead of referring to the conjugation of isovaleric acid to a peptide by reference to isovaleryl (e.g., isovaleryl-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 307), the present application refers to a conjugate such as isovaleric acid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 307). Reference to the acidic form of the conjugate is intended to encompass the form present in a peptide inhibitor.

[0213] In certain embodiments, the peptide inhibitor has a C-terminus (e.g., R 2 or C-terminal portion). In certain embodiments, R 2 is a bond. In various embodiments of any of the peptide inhibitors having any of the various formulas described herein, R 2 Or the C-terminal moiety is OH or NH2. 2 Alternatively, it is understood that the C-terminal moiety can replace or be in addition to the carboxyl group typically located at the carboxy terminus of a peptide. 2It is further understood that may not be present.

[0214] Peptide dimers In certain embodiments, the present invention includes dimers of the monomeric peptide inhibitors described herein, including dimers of any of the monomeric peptide inhibitors described herein or in the accompanying tables. These dimers fall within the general term "peptide inhibitor" as used herein. Exemplary dimers of the present invention are also shown in the accompanying tables, which show dimerized monomer subunits in parentheses followed by a linker. Unless otherwise noted, the subunits are linked via their C-termini. The term "dimer," as in peptide dimer, refers to a compound in which two peptide monomer subunits are linked. The peptide dimer inhibitors of the present invention may contain two identical monomer subunits, resulting in a homodimer, or two non-identical monomer subunits, resulting in a heterodimer. A cysteine ​​dimer contains two peptide monomer subunits linked through a disulfide bond between a cysteine ​​residue of one monomer subunit and a cysteine ​​residue of the other monomer subunit.

[0215] In some embodiments, the peptide inhibitors of the present invention can be active in a dimeric conformation, especially when a free cysteine ​​residue is present in the peptide.In certain embodiments, this occurs either as a synthetic dimer, or especially when a free cysteine ​​monomer peptide is present and dimerizes under oxidizing conditions.In some embodiments, the dimer is a homodimer.In other embodiments, the dimer is a heterodimer.

[0216] In certain embodiments, the monomer subunits of the present invention can be dimerized by a suitable linking moiety, such as a disulfide bridge between two cysteine ​​residues, one in each peptide monomer subunit, or another suitable linker moiety, including, but not limited to, those defined herein. Some of the monomer subunits are shown with C- and N-termini, both of which contain free amines. Thus, to generate peptide dimeric inhibitors, the monomer subunits can be modified to eliminate the free amine at either the C- or N-terminus, thereby allowing dimerization at the remaining free amine. Furthermore, optionally, the termini of one or more of the monomer subunits are acylated with an acylating organic compound selected from the group consisting of trifluoropentyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4carboxylic acid, succinic acid, and glutaric acid. In some cases, the monomeric subunits contain both a free carboxyl terminus and a free amino terminus, allowing the user to selectively modify the subunits to achieve dimerization at the desired terminus. Thus, one of skill in the art will understand that the monomeric subunits of the present invention can be selectively modified to obtain a single specific amine for the desired dimerization.

[0217] It is further understood that the C-terminal residue of the monomer subunit disclosed herein is optionally an amide. Furthermore, it is understood that in certain embodiments, dimerization at the C-terminus is promoted by using a suitable amino acid with a side chain having an amine functionality, as is generally understood in the art. With respect to the N-terminal residue, it is generally understood that dimerization can be achieved through the free amine of the terminal residue, or by using a suitable amino acid side chain with a free amine, as is generally understood in the art.

[0218] The linker moiety connecting the monomeric subunits can have any structure, length, and / or size compatible with the teachings herein. In at least one embodiment, the linker moiety is selected from the non-limiting group consisting of cysteine, lysine, DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, glutaric acid, isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, triazine, Boc-triazine, IDA-biotin, PEG4-biotin, AADA, suitable aliphatic, aromatic, heteroaromatic, and polyethylene glycol-based linkers having a molecular weight of approximately 400 Da to approximately 40,000 Da. In certain embodiments, PEG2 is HO2CCH2CHOCH2CH2OCH2CH2CO2H. Non-limiting examples of suitable linker moieties are provided in Table 7. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0219] In some embodiments, the peptide dimeric inhibitor is dimerized via a linker moiety. In some embodiments, the peptide dimeric inhibitor is dimerized via an intermolecular disulfide bond formed between two cysteine ​​residues, one in each monomer subunit. In some embodiments, the peptide dimeric inhibitor is dimerized via both the linker moiety and the intermolecular disulfide bond formed between the two cysteine ​​residues. In some embodiments, the intramolecular bond is a thioether, lactam, triazole, selenoether, diselenide, or olefin instead of a disulfide bond.

[0220] Those skilled in the art will understand that the linker moieties (e.g., C- and N-terminal linkers) disclosed herein are non-limiting examples of suitable linkers, and that the present invention may include any suitable linker moiety. Accordingly, some embodiments of the present invention include homo- or heterodimeric peptide inhibitors consisting of two monomeric subunits selected from peptides set forth in any of the tables herein, or comprising or consisting of a sequence set forth in any of the tables herein, wherein the C- or N-termini of each monomeric subunit (or internal amino acid residues) are linked by any suitable linker moiety to provide a dimeric peptide inhibitor having IL-23R inhibitory activity. In certain embodiments, the linker is attached to the N- or C-terminus of one monomeric subunit and to an internal amino acid residue of the other monomeric subunit, forming a dimer. In certain embodiments, the linker is attached to an internal amino acid residue of one monomeric subunit and to an internal amino acid residue of the other monomeric subunit, forming a dimer. In further embodiments, the linker is attached to the N- or C-termini of both subunits.

[0221] In certain embodiments, one or both of the monomeric subunits comprises the sequence or structure of any one of Formulas I, II, III, IV, V, XII-XVIIIh, or any of the peptides described herein, e.g., in Tables 2-6.

[0222] In certain embodiments, the peptide dimeric inhibitor has formula VI: (R 1 -XR 2 )2-L(VI)

[0223] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0224] Each R 1 is independently absent, a bond (e.g., a covalent bond), or R1 is selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, C1-C20 alkanoyl, and includes a PEGylated form alone or as a spacer in any of the above;

[0225] Each R 2 is independently absent, a bond (e.g., a covalent bond), or selected from OH or NH; L is a linker moiety; and each X is an independently selected peptide monomer subunit comprising a sequence of Formula (I), (II), (V), (III), (IV), or (XII)-(XVIIIh), as described herein. In certain embodiments, one or both peptide monomer subunits of the peptide dimeric inhibitor are cyclized, e.g., via an intramolecular bond between X and X. In certain embodiments, one or both peptide monomer subunits are linear and not cyclized.

[0226] In certain embodiments of peptide dimeric inhibitors, each X7 and each X11 are both W. In certain embodiments of peptide dimeric inhibitors, one or both peptide monomer subunits have a structure shown herein, e.g., in Tables 2, 3, 4, 5, or 6.

[0227] In certain embodiments, each R 1are independently a bond (e.g., a covalent bond) or selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, C1-C20 alkanoyl, and include a PEGylated moiety either alone or as any of the above spacers. In certain embodiments, the N-terminus of each subunit includes a moiety selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, C1-C20 alkanoyl, and include a PEGylated moiety either alone or as any of the above spacers, e.g., acetyl.

[0228] In certain embodiments of any of the peptide inhibitors having any of the various formulas described herein, each R 1 (or the N-terminal moiety) is selected from methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and the conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

[0229] In certain embodiments, each R 2 (or the C-terminal portion) is independently a bond (eg, a covalent bond) or selected from OH or NH2.

[0230] In certain embodiments of any of the peptide dimeric inhibitors described herein, one or both R 1 is hydrogen.

[0231] In certain embodiments of any of the peptide dimeric inhibitors of the invention, the linker moiety (L) is any of the linkers described herein or shown in Tables 1 or 7. In certain embodiments, L is a lysine linker, a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker.

[0232] In various embodiments of any of the peptide dimeric inhibitors, each of the peptide monomer subunits is attached to a linker moiety via its N-terminus, C-terminus, or internal amino acid residue. In certain embodiments of any of the peptide dimeric inhibitors, the N-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments of any of the peptide dimeric inhibitors, the C-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments of any of the peptide dimeric inhibitors, each peptide monomer subunit is connected by a linker moiety attached to an internal amino acid.

[0233] Peptide inhibitor conjugates and biopolymers In certain embodiments, the peptide inhibitor of the present invention, including both monomer and dimer, comprises one or more conjugated chemical substituents, such as lipophilic substituents and polymer moieties, which can be referred to herein as half-life extending moieties.Without wishing to be bound by any particular theory, it is believed that lipophilic substituents bind to albumin in bloodstream, thereby protecting peptide inhibitors from enzymatic degradation, and thus enhancing their half-life.In addition, it is believed that polymer moieties enhance half-life and reduce clearance in bloodstream.

[0234] In additional embodiments, the peptide inhibitor, e.g., any of the peptides of Formula (I), (II), (V), (III), (IV), or (XI), further comprises a linker moiety attached to an amino acid residue present in the inhibitor, e.g., the linker moiety can be attached to the side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[0235] In additional embodiments, the peptide inhibitor, e.g., any of the peptides of Formula (I)-(VI) or (XI), further comprises a half-life extending moiety attached to an amino acid residue present in the inhibitor, e.g., the half-life extending moiety can be attached to the side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[0236] In additional embodiments, the peptide inhibitor, e.g., any of the peptides of Formula (I)-(VI) or (XI), further comprises a half-life extending moiety attached to a linker moiety attached to an amino acid residue present in the inhibitor, e.g., the half-life extending moiety can be attached to the side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to a linker moiety attached to the C-terminal amino acid of the peptide inhibitor.

[0237] In certain embodiments, the peptide inhibitor comprises a half-life extending moiety having the structure shown below, where n=0-24 or n=14-24. [ka]

[0238] In certain embodiments, the peptide inhibitors of the invention comprise a half-life extending moiety shown in Table 8. [Table 8-1] [Table 8-2] [Table 8-3]

[0239] In certain embodiments, the half-life extending moiety is directly attached to the peptide inhibitor, while in other embodiments, the half-life extending moiety is attached to the peptide inhibitor via a linker moiety, such as any of those shown in Tables 1, 7, or 9. [Table 9-1] [Table 9-2] [Table 9-3]

[0240] In certain embodiments, the peptide inhibitors of the invention comprise any of the linker moieties shown in Tables 7 or 9, including any of the following combinations shown in Table 10, and any of the half-life extending moieties shown in Table 8. [Table 10-1] [Table 10-2]

[0241] In some embodiments, there can be multiple linkers between the peptide and the conjugate moiety, e.g., half-life extending moiety, as shown, for example, in Table 11. [Table 11-1] [Table 11-2]

[0242] In certain embodiments, the half-life of a peptide inhibitor of the invention comprising a conjugated chemical substituent, i.e., a half-life extending moiety, is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the half-life of the same peptide inhibitor but without the conjugated chemical substituent. In certain embodiments, the lipophilic substituent and / or polymer moiety enhances the permeability of the peptide inhibitor across epithelia and / or its retention in the lamina propria. In certain embodiments, the permeability of a peptide inhibitor of the invention comprising a conjugated chemical substituent across epithelia and / or retention in the lamina propria is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the half-life of the same peptide inhibitor but without the conjugated chemical substituent.

[0243] In one embodiment, the side chain of one or more amino acid residues (e.g., Lys residues) in the peptide inhibitors of the present invention is conjugated (e.g., covalently attached) to a lipophilic substituent. The lipophilic substituent may be covalently bonded to an atom in the amino acid side chain or may be conjugated to the amino acid side chain via one or more spacers. The spacer, if present, may provide spacing between the peptide analog and the lipophilic substituent. In certain embodiments, the peptide inhibitor comprises any of the conjugated moieties shown in the peptides disclosed in Tables 2-6.

[0244] In certain embodiments, the lipophilic substituent may comprise a hydrocarbon chain having 4 to 30 carbon atoms, e.g., at least 8 to 12 carbon atoms, preferably 24 or fewer carbon atoms, or 20 or fewer carbon atoms. The hydrocarbon chain may be linear or branched, saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a moiety that forms the amino acid side chain or the attachment portion to the spacer, such as an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom. In some embodiments, the hydrocarbon chain is substituted with an acyl group, and thus the hydrocarbon chain may form part of an alkanoyl group, e.g., palmitoyl, caproyl, lauroyl, myristoyl, or stearoyl.

[0245] Lipophilic substituents may be conjugated to any amino acid side chain in the peptide inhibitors of the present invention.In certain embodiments, the amino acid side chain comprises a carboxy, hydroxy, thiol, amide, or amine group to form an ester, sulfonyl ester, thioester, amide, or sulfonamide with a spacer or lipophilic substituent.For example, lipophilic substituents may be conjugated to Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys, or Dbu, Dpr, or Orn.In certain embodiments, lipophilic substituents may be conjugated to Lys.The amino acid shown as Lys in any of the formulas provided herein may be replaced by, for example, Dbu, Dpr, or Orn, where a lipophilic substituent is added.

[0246] In certain embodiments, the peptide inhibitors of the present invention can be modified to enhance stability, increase permeability, or enhance drug-like properties, for example, through the conjugation of chemical moieties to one or more amino acid side chains within the peptide. For example, the N of lysine N (epsilon), the β-carboxyl of aspartic acid, or the γ-carboxyl of glutamic acid can be appropriately functionalized. Thus, to produce modified peptides, amino acids within the peptide can be appropriately modified. Furthermore, in some cases, the side chains are acylated with an acylating organic compound selected from the group consisting of trifluoropentyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4 carboxylic acid, succinic acid, glutaric acid, and bile acid. Those skilled in the art will understand that a variety of conjugates, such as PEG4, isoglu, and combinations thereof, can be attached. Those skilled in the art will understand that amino acids having a peptide may be isosterically replaced, for example, Lys may be replaced with Dap, Dab, α-MeLys, or Orn. ​​Examples of modified residues within peptides are shown in Table 12. [Table 12-1] [Table 12-2] [Table 12-3]

[0247] In further embodiments of the present invention, alternatively or in addition, the side chains of one or more amino acid residues in the peptide inhibitors of the present invention are conjugated to a polymer moiety, e.g., to increase in vivo (e.g., plasma) solubility and / or half-life and / or bioavailability. Such modifications are also known to reduce clearance (e.g., renal clearance) of therapeutic proteins and peptides.

[0248] As used herein, "polyethylene glycol" or "PEG" is a polyether compound of the general formula H-(O-CH2-CH2)n-OH. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE) depending on their molecular weight, with PEO, PEE, or POG referring to oligomers or polymers of ethylene oxide as used herein. While the three names are chemically synonymous, PEG tends to refer to oligomers and polymers with molecular weights less than 20,000 Da, PEO to polymers with molecular weights greater than 20,000 Da, and POE to polymers of any molecular weight. PEG and PEO are liquids or low-melting solids depending on their molecular weight. Throughout this disclosure, the three names are used interchangeably. PEG is prepared by polymerization of ethylene oxide and is commercially available over a wide range of molecular weights, from 300 Da to 10,000,000 Da. While PEG and PEO of different molecular weights are used for different applications and have different physical properties (e.g., viscosity) due to the chain length effect, their chemical properties are nearly identical. The polymer moiety is preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymer moieties include polyethylene glycol (PEG), PEG homo- or copolymers, monomethyl-substituted polymers 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 included are PEGs prepared for the purpose of half-life extension, such as monoactivated, alkoxy-terminated polyalkylene oxides (POA), e.g., mono-methoxy-terminated polyethylene glycol (mPEG); bis-activated polyethylene oxide (glycol), or other PEG derivatives. Suitable polymers vary substantially in weight ranging from about 200 Da to about 40,000 Da, with about 200 Da to about 60,000 Da typically being selected for purposes of the present invention.Certain embodiments use PEG with a molecular weight of 200 to 2,000 or 200 to 500. Depending on the initiator used for the polymerization process, different forms of PEG can also be used, with common initiators being monofunctional methyl ether PEG or methoxypoly(ethylene glycol), abbreviated as mPEG.

[0249] Low molecular weight PEGs are also available as pure oligomers, referred to as monodisperse, uniform, or discrete, which are used in certain embodiments of the present invention.

[0250] PEGs are also available in different forms: branched PEGs have 3-10 PEG chains emanating from a central core group, star PEGs have 10-100 PEG chains emanating from a central core group, and comb PEGs have multiple PEG chains typically grafted to a polymer backbone. PEGs can also be linear. A number often included in the name of PEGs indicates their average molecular weight (e.g., a PEG with n=9 has an average molecular weight of approximately 400 daltons and is classified as PEG400).

[0251] As used herein, "PEGylation" refers to the act of covalently attaching a PEG structure to a peptide inhibitor of the present invention, which is then referred to as a "PEGylated peptide inhibitor." In certain embodiments, the PEG of the PEGylated side chain is a PEG having a molecular weight of about 200 to about 40,000. In some embodiments, the spacer of a peptide of Formula I, Formula I', or Formula I'' is PEGylated. In certain embodiments, the PEG of the PEGylated spacer is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of the PEGylated spacer is PEG3 or PEG8.

[0252] Other suitable polymer moieties are poly-amino acids, such as poly-lysine, poly-aspartic acid, and poly-glutamic acid (see, e.g., Gombotz, et al. (1995), Bioconjugate Chem., vol. 6:332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57, and Tsukada, et al. (1984), J. Natl. Cancer Inst., vol. 73, :721-729). The polymer moiety may be linear or branched. In some embodiments, the polymer moiety has a molecular weight of 500 to 40,000 Da, e.g., 500 to 10,000 Da, 1000 to 5000 Da, 10,000 to 20,000 Da, or 20,000 to 40,000 Da.

[0253] In some embodiments, the peptide inhibitors of the present invention may comprise two or more such polymer moieties, in which case the total molecular weight of all such moieties will generally fall within the ranges provided above.

[0254] In some embodiments, the polymer moiety is attached (covalently) to the amino, carboxyl, or thiol group of an amino acid side chain. Particular examples are the thiol group of Cys residues and the epsilon amino group of Lys residues, although the carboxyl groups of Asp and Glu residues may also be involved.

[0255] Those skilled in the art will recognize suitable techniques for carrying out coupling reactions. For example, a PEG moiety bearing a methoxy group can be linked to a Cys thiol group via a maleimide linkage using a commercially available reagent from Nektar Therapeutics AL. For details of suitable chemistries, see also WO2008 / 101017 and the references listed above. Maleimide-functionalized PEG can also be conjugated to the side chain sulfhydryl group of a Cys residue.

[0256] As used herein, disulfide bond oxidation can occur in a single step or a two-step process. As used herein, for a single oxidation step, a trityl protecting group is often used during construction, allowing for deprotection during cleavage, followed by solution oxidation. If a second disulfide bond is required, there are options for natural oxidation or selective oxidation. For selective oxidation, which requires orthogonal protecting groups, Acm and trityl are used as protecting groups for cysteines. Cleavage results in the removal of one protecting pair of cysteines, allowing oxidation of this pair. A second oxidative deprotection step of the cysteine-protecting Acm group is then performed. For natural oxidation, trityl protecting groups are used on all cysteines, allowing the peptide to fold natively. Those skilled in the art will recognize the appropriate technique to use to perform the oxidation step.

[0257] Some chemical moieties, including poly(ethylene) glycol, react with functional groups present in the 20 naturally occurring amino acids, such as the epsilon amino group in lysine amino acid residues, the thiol present in cysteine ​​amino acid residues, or other nucleophilic amino acid side chains. When multiple naturally occurring amino acids react in a peptide inhibitor, these non-specific chemical reactions result in a final peptide inhibitor containing many isomers of the peptide conjugated to one or more poly(ethylene) glycol chains at different positions within the peptide inhibitor.

[0258] One advantage of certain embodiments of the present invention includes the ability to attach one or more chemical moieties (such as PEG) by incorporating one or more unnatural amino acid(s) with a unique functional group that reacts with activated PEG as a chemical that does not react with naturally occurring amino acids present in peptide inhibitors. For example, azide and alkyne groups do not react with all naturally occurring functional groups in proteins. Therefore, unnatural amino acids can be incorporated into one or more specific sites in peptide inhibitors, making PEG or other modifications without undesired nonspecific reactions desirable. In certain embodiments, the specific chemicals involved in the reaction result in a stable covalent bond between the PEG chain and the peptide inhibitor. In addition, such reactions can be performed under mild aqueous conditions that are not damaging to most peptides. In certain embodiments, the unnatural amino acid residue is AHA.

[0259] Chemical moieties attached to natural amino acids are limited in number and range. In contrast, chemical moieties attached to unnatural amino acids can utilize a significantly larger spectrum of useful chemistries for attaching chemical moieties to target molecules. Essentially any target molecule can serve as a substrate for attaching a chemical moiety, including any protein that contains an unnatural amino acid, e.g., an unnatural amino acid that contains a reactive site or side chain to which a chemical moiety can be attached, e.g., an aldehyde- or keto-derivatized amino acid.

[0260] Many chemical moieties can be bound or linked to a particular molecule through various methods known in the art. Various such methods are described in U.S. Patent No. 8,568,706. As an illustrative example, azide moieties can be useful for conjugating chemical moieties such as PEG or others described herein. The azide moiety serves as a reactive functional group and is absent in most naturally occurring compounds (and therefore does not react with the natural amino acids of naturally occurring compounds). Azides also undergo selective ligation with a limited number of reaction partners, and azides are small and can be introduced into biological samples without significantly altering their molecular weight. One reaction that allows the incorporation or introduction of azides into molecules is the copper-mediated Huisgen [3+2] cycloaddition of azides. This reaction can be used for selective PEGylation of peptide inhibitors. (Tornoe et al.,J.Org.Chem.67:3057,2002;Rostovtsev et al.,Angew.Chem.,Int.Ed.41:596,2002;andWang et al.,J.Am.Chem.Soc.125:3192,2003,Speers et al. al., J. Am. Chem. Soc., 2003, 125, 4686).

[0261] Synthesis of peptide inhibitors The peptide inhibitors of the present invention can be synthesized by many techniques known to those of skill in the art. In certain embodiments, the monomeric subunits are synthesized, purified, and dimerized using the techniques described in the accompanying Examples. In certain embodiments, the present invention provides methods for producing the peptide inhibitors of the present invention (or their monomeric subunits), comprising chemically synthesizing a peptide comprising, consisting of, or consisting essentially of a peptide having an amino acid sequence described herein, including, but not limited to, any of the amino acid sequences set forth in Formula I, II, or any of the tables herein. In other embodiments, the peptide is synthesized recombinantly instead of chemically. In certain embodiments, the peptide inhibitor is a dimer, and the method comprises synthesizing both monomeric subunits of the peptide dimeric inhibitor and then dimerizing the two monomeric subunits to produce the peptide dimeric inhibitor. In various embodiments, dimerization is achieved via any of the various methods described herein. In certain embodiments, the method of producing a peptide inhibitor (or a monomeric subunit thereof) further comprises cyclizing the peptide inhibitor (or a monomeric subunit thereof) after its synthesis. In certain embodiments, cyclization is achieved via any of the various methods described herein. In certain embodiments, the present invention provides a method of producing a peptide inhibitor (or a monomeric subunit thereof) of the present invention, comprising introducing an intramolecular bond, e.g., a disulfide, amide, or thioether bond, between two amino acid residues in a peptide comprising, consisting of, or consisting essentially of a peptide having an amino acid sequence described herein, including, but not limited to, any of the amino acid sequences set forth in Formulas (I), (II), (III), (IV), or any of the accompanying Examples or Tables.

[0262] In related embodiments, the invention includes polynucleotides that encode polypeptides having a sequence as set forth in any one of Formulas (I)-(IV) or the accompanying Examples or Tables.

[0263] In addition, the present invention includes vectors, eg, expression vectors, which comprise the polynucleotides of the present invention.

[0264] Treatment method In certain embodiments, the present invention includes a method for inhibiting IL-23 binding to IL-23R on a cell, comprising contacting IL-23 with a peptide inhibitor of the present invention. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the method is performed in vitro or in vivo. Inhibition of binding can be determined by a variety of routine experimental methods and assays known in the art.

[0265] In certain embodiments, the present invention includes a method for inhibiting IL-23 signaling by a cell, comprising contacting IL-23 with a peptide inhibitor of the present invention. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the method is performed in vitro or in vivo. In certain embodiments, inhibition of IL-23 signaling can be determined by measuring changes in phospho-STAT3 levels in the cell.

[0266] In some embodiments, the present invention provides methods for treating a subject afflicted with a condition or indication associated with IL-21 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), the method comprising administering to the subject a peptide inhibitor of the present invention. In one embodiment, a method is provided for treating a subject afflicted with a condition or indication characterized by inappropriate, unregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the individual a peptide inhibitor of the present invention in an amount sufficient to inhibit (partially or completely) binding of IL-23 to IL-23R in the subject. In certain embodiments, inhibition of IL-23 binding to IL-23R occurs in an organ or tissue of the subject, e.g., the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[0267] In some embodiments, the methods of the present invention comprise providing a peptide inhibitor of the present invention to a subject in need thereof. In certain embodiments, the subject in need thereof has been diagnosed with or has been determined to be at risk for developing a disease or disorder associated with IL-23 / IL-23R. In certain embodiments, the subject is a mammal.

[0268] In certain embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In certain embodiments, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, ectopic acne, psoriasis related to psoriasis (e.g., psoriasis purpurea, psoriasis erythroderma, psoriasis purpurea ... ectopica), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as in leukocyte adhesion deficiency type 1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[0269] In certain related embodiments, the present invention provides methods for selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject in need thereof, comprising providing a peptide inhibitor of the present invention to the subject. In certain related embodiments, the present invention includes methods for selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in the gastrointestinal tract in a subject in need thereof, comprising providing a peptide inhibitor of the present invention to the subject by oral administration. In certain embodiments, the exposure of the administered peptide inhibitor in gastrointestinal tissues (e.g., small intestine or colon) is at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold higher than the exposure in the blood. In certain embodiments, the present invention includes a method of selectively inhibiting IL23 or IL23R signaling (or binding of IL23 to IL23R) in the gastrointestinal tract in a subject in need thereof, comprising providing a peptide inhibitor to the subject, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In further related embodiments, the present invention includes a method of inhibiting gastrointestinal inflammation and / or neutrophil infiltration into the gastrointestinal tract, comprising providing a peptide inhibitor of the present invention to a subject in need thereof. In some embodiments, the method of the present invention comprises providing a peptide inhibitor of the present invention (i.e., a first therapeutic agent) in combination with a second therapeutic agent to a subject in need thereof. In certain embodiments, the second therapeutic agent is provided to the subject before, simultaneously with, and / or after the peptide inhibitor is administered to the subject. In certain embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In another embodiment, the method comprises administering a third therapeutic agent to the subject. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

[0270] In certain embodiments, the peptide inhibitor or pharmaceutical composition comprising the peptide inhibitor is suspended in a sustained-release matrix.The sustained-release matrix used herein is a matrix made of a material (usually a polymer) that can be degraded by enzymatic hydrolysis or acid-base hydrolysis, or by dissolution.When inserted into the body, enzymes and body fluids act on this matrix.The sustained-release matrix is ​​preferably selected from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolides (polymers of glycolic acid), polylactide-co-glycolides (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicone. One embodiment of a preferred biodegradable matrix is ​​a matrix of any one of polylactide, polyglycolide, or polylactide-co-glycolide (a copolymer of lactic acid and glycolic acid).

[0271] In certain embodiments, the present invention comprises pharmaceutical compositions comprising one or more peptide inhibitors of the present invention and pharmaceutically acceptable carriers, diluents or excipients.Pharmaceutically acceptable carriers, diluents or excipients refer to any kind of non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary.Prevention of microbial activity can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc.It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc.

[0272] In certain embodiments, the composition is administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (such as by powder, ointment, drop, suppository, or transdermal patch), by inhalation (such as intranasal spray), ocularly (intraocularly), or bucally. As used herein, the term "parenteral" refers to administration modes including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injection and infusion. Thus, in certain embodiments, the composition is formulated for delivery by any of these administration routes.

[0273] In certain embodiments, pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of injectable pharmaceutical forms can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0274] Injectable depot forms include those made by forming microencapsulated matrices of peptide inhibitors in one or more biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG. Depending on the ratio of peptide to polymer and the nature of the particular polymer used, the release rate of the peptide inhibitor can be controlled. Injectable depot formulations can also be prepared by entrapping the peptide inhibitor in liposomes or microemulsions that are compatible with body tissues.

[0275] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0276] Local administration includes administration to the skin or mucous membrane, including the surface of the lungs or eyes.Compositions for local pulmonary administration can include solutions and suspensions in aqueous and non-aqueous formulations, including those for inhalation and intranasal administration, and can be prepared as dry powders, either pressurized or non-pressurized.In non-pressurized powder compositions, the active ingredient can be in micronized form, or can be used in a mixture with larger-sized pharmaceutically acceptable inert carriers, including particles with a diameter of up to 100 micrometers.Suitable inert carriers include sugars such as lactose.

[0277] Alternatively, the composition may be pressurized and contain compressed gas such as nitrogen or liquefied gas propellant. The liquefied propellant medium, and indeed the entire composition, may be such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may contain a surfactant, such as a liquid or solid nonionic surfactant, or may be a solid anionic surfactant. It is preferred to use a solid anionic surfactant in the form of a sodium salt.

[0278] Another form of local administration is to the eye.The peptide inhibitor of the present invention can be delivered in a pharmaceutically acceptable ophthalmic vehicle, so that the peptide inhibitor can be maintained in contact with the surface of the eye for a sufficient period of time, allowing the peptide inhibitor to penetrate the cornea and internal regions of the eye, such as the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina and sclera.The pharmaceutically acceptable ophthalmic vehicle can be, for example, ointment, vegetable oil or encapsulating material.Alternatively, the peptide inhibitor of the present invention can be directly injected into the vitreous humor and aqueous humor.

[0279] Compositions for rectal or vaginal administration include suppositories, which may be prepared by mixing the peptide inhibitors of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0280] The peptide inhibitors of the present invention can also be administered in liposomes or other lipid-based carriers. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes may be used. The composition in liposomal form may contain stabilizers, preservatives, excipients, etc. in addition to the peptide inhibitors of the present invention. In certain embodiments, the lipid comprises a phospholipid, including both natural and synthetic phosphatidylcholine (lecithin) and serine. Methods for forming liposomes are known in the art.

[0281] Pharmaceutical compositions used in the present invention suitable for parenteral administration may comprise sterile aqueous solutions and / or suspensions of the peptide inhibitors made isotonic with the blood of the recipient, generally using sodium chloride, glycerin, glucose, mannitol, sorbitol, or the like.

[0282] In some embodiments, the present invention provides pharmaceutical compositions for oral delivery.The compositions and peptide inhibitors of the present invention can be prepared for oral administration according to any of the methods, techniques and / or delivery vehicles described herein.In addition, those skilled in the art will understand that the peptide inhibitors of the present invention can be modified or integrated into systems or delivery vehicles that are not disclosed herein but are known in the art and are suitable for use in oral delivery of peptides.

[0283] In certain embodiments, formulations for oral administration may include adjuvants (e.g., resorcinol and / or nonionic surfactants, such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of the apical wall, and / or enzyme inhibitors (e.g., pancreatic trypsin inhibitor, diisopropyl fluorophosphate (DFF), or trasylol) to inhibit enzymatic degradation. In certain embodiments, the peptide inhibitor in a solid dosage form for oral administration may be mixed with at least one additive such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextrin, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer, or glyceride. These dosage forms may also contain other type(s) of additives, such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavorings, or perfuming agents.

[0284] In certain embodiments, oral dosage forms or unit doses suitable for use with the peptide inhibitors of the present invention may include a mixture of the peptide inhibitor with non-drug ingredients or excipients, as well as other non-recyclable materials that may be considered either ingredients or packaging. Oral compositions may include at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, oral dosage forms are provided that contain an effective amount of the peptide inhibitor, and the dosage form includes at least one of pills, tablets, capsules, gels, pastes, beverages, syrups, ointments, and suppositories. In some cases, oral dosage forms are provided that are designed and configured to achieve delayed release of the peptide inhibitor in the small intestine and / or colon of a subject.

[0285] In one embodiment, oral pharmaceutical compositions comprising a peptide inhibitor of the present invention include an enteric coating designed to delay release of the peptide inhibitor in the small intestine. In at least some embodiments, pharmaceutical compositions are provided that include a peptide inhibitor of the present invention and a protease inhibitor, such as aprotinin, in a delayed-release pharmaceutical formulation. In some cases, the pharmaceutical compositions of the present invention include an enteric coating that is soluble in gastric fluid at a pH of about 5.0 or higher. In at least one embodiment, pharmaceutical compositions are provided that include an enteric coating comprising a polymer with a dissociable carboxylic acid group, such as derivatives of cellulose, including hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, and similar derivatives of cellulose and other carbohydrate polymers.

[0286] In one embodiment, pharmaceutical compositions comprising the peptide inhibitors of the present invention are provided in an enteric coating, which is designed to protect and release the pharmaceutical composition in a controlled manner in the subject's lower gastrointestinal system and to avoid systemic side effects.In addition to enteric coatings, the peptide inhibitors of the present invention can be encapsulated, coated, engaged, or otherwise associated with any suitable oral drug delivery system or component.For example, in some embodiments, the peptide inhibitors of the present invention are provided in a lipid carrier system, including at least one of polymer hydrogels, nanoparticles, microparticles, micelles, and other lipid systems.

[0287] To overcome peptide degradation in the small intestine, some embodiments of the present invention include a hydrogel polymer carrier system in which the peptide inhibitors of the present invention are contained, whereby the hydrogel polymer protects the peptide inhibitors from proteolytic degradation in the small intestine and / or colon. The peptide inhibitors of the present invention can further be formulated for compatible use with carrier systems designed to increase the dissolution kinetics of the peptide and enhance intestinal absorption. These methods include the use of liposomes, micelles, and nanoparticles to increase the gastrointestinal penetration of peptides.

[0288] Various bioresponsive systems may also be combined with one or more peptide inhibitors of the present invention to provide pharmaceuticals for oral delivery. In some embodiments, the peptide inhibitors of the present invention are used in combination with bioresponsive systems, such as hydrogels and mucoadhesive polymers with hydrogen-bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan, alginate), to provide therapeutic agents for oral administration. Other embodiments include methods for optimizing or extending the drug residence time of the peptide inhibitors disclosed herein, in which the surface of the peptide inhibitor is modified to contain mucoadhesive properties through hydrogen bonding, polymers with linked mucin, or / and hydrophobic interactions. These modified peptide molecules may demonstrate increased drug residence time within a subject, in accordance with a desired feature of the present invention. Furthermore, targeted mucoadhesive systems may specifically bind to receptors on the surface of enterocytes and M-cells, thereby further enhancing the uptake of particles containing the peptide inhibitor.

[0289] Other embodiments include methods for oral delivery of the peptide inhibitors of the present invention, wherein the peptide inhibitor is provided to a subject in combination with a permeation enhancer that promotes transport of the peptide across the intestinal mucosa by increasing paracellular or transcellular permeation. Various permeation enhancers and methods for oral delivery of therapeutic agents are described in Brayden, DJ, Mrsny, RJ, 2011. Oral peptide delivery: prioritizing The leading technologies. Ther. Delivery 2(12), 1567-1573.

[0290] In certain embodiments, the pharmaceutical compositions and formulations of the present invention comprise the peptide inhibitors of the present invention and one or more permeation enhancers. Examples of absorption enhancers may include, for example, bile salts, fatty acids, surfactants (anionic, cationic, and non-anionic), chelating agents, Zonular OT, esters, cyclodextrins, dextran sulfate, azone, crown ethers, EDTA, sucrose esters, and phosphotidylcholine. Although absorption enhancers are typically not carriers themselves, they are also widely associated with other carriers to improve oral bioavailability by transporting peptides and proteins across the intestinal mucosa. Such substances can be added to the formulation as excipients or incorporated to form nonspecific interactions with the target peptide inhibitors.

[0291] Dietary components and / or other naturally occurring substances that have been identified as promoting tight junction permeation and as generally recognized as safe (GRAS) include, for example, asglycerides, acylcarnitines, bile salts, and medium-chain fatty acids. Sodium salts of medium-chain fatty acids (MCFAS) have also been suggested to be permeation enhancers. The most widely studied MCFAS is sodium caprate, a salt of capric acid, which contains 2-3% fatty acids in the milk fat fraction. To date, sodium caprate has been primarily used as an excipient in suppository formulations (Doktacillin™) to improve rectal ampicillin absorption. Another dietary MCFAS, sodium caprylate (8 carbons), has been shown in vitro to have lower permeation properties compared to sodium caprate. Sodium caprylate and peptide drugs were formulated in a mixture with other excipients in oil to produce an oil suspension (OS) with enhanced permeability (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014)).

[0292] For example, in one embodiment, a permeation enhancer is combined with a peptide inhibitor, the permeation enhancer comprising at least one of a medium-chain fatty acid, a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In certain embodiments, the medium-chain fatty acid salt enhances absorption by increasing the paracellular permeability of the intestinal epithelium. In one embodiment, a permeation enhancer comprising sodium N-(hydroxybenzoyl)amino)caprylate is used to form a weak non-covalent association with the peptide inhibitor of the present invention, which favors membrane transport and further dissociation once it reaches the blood circulation. In another embodiment, the peptide inhibitor of the present invention is conjugated to oligoarginine, thereby increasing the cellular penetration of the peptide into various cell types. Furthermore, in at least one embodiment, a non-covalent bond is provided between the peptide inhibitor of the present invention and a permeation enhancer selected from the group consisting of cyclodextrins (CDs) and dendrimers, which reduces peptide aggregation and increases the stability and solubility of the peptide inhibitor molecule.

[0293] In certain embodiments, a pharmaceutical composition or formulation comprises a peptide inhibitor of the present invention and a transient permeation enhancer (TPE). The permeation enhancer and TPE can be used to increase the oral bioavailability of the peptide inhibitor. One example of a TPE that can be used is an oil suspension formulation that disperses a powder containing sodium caprylate and a therapeutic agent (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014)).

[0294] In certain embodiments, pharmaceutical compositions and formulations may comprise a peptide inhibitor of the invention and one or more absorption enhancers, enzyme inhibitors, or mucoadhesive polymers.

[0295] In certain embodiments, the peptide inhibitors of the present invention are formulated in a formulation vehicle such as, for example, an emulsion, liposome, microsphere, or nanoparticle.

[0296] One embodiment of the present invention provides a method for treating a subject with a peptide inhibitor of the invention having an increased half-life. In one aspect, the present invention provides peptide inhibitors having a half-life of at least several hours to a day in vitro or in vivo (e.g., when administered to a human subject) sufficient for once-daily (qd) or twice-daily (bid) therapeutically effective dosing. In another embodiment, the peptide inhibitor has a half-life of 3 days or more, sufficient for once-weekly (qw) therapeutically effective dosing. In yet another embodiment, the peptide inhibitor has a half-life of 8 days or more, sufficient for biweekly (biw) or monthly therapeutically effective dosing. In another embodiment, the peptide inhibitor is derivatized or modified so that it has a longer half-life compared to the underivatized or unmodified peptide inhibitor. In another embodiment, the peptide inhibitor contains one or more chemical modifications to increase serum half-life.

[0297] When used in at least one of the treatment or delivery systems described herein, the peptide inhibitors of the present invention may be used in pure form or, if such forms exist, in the form of a pharmaceutically acceptable salt.

[0298] The total daily use amount of the peptide inhibitors and compositions of the present invention can be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject depends on various factors, including: a) the disease to be treated and the severity of the disease, b) the activity of the specific compound used, c) the specific composition used, the patient's age, weight, general health, sex and diet, d) the administration time, administration route and excretion rate of the specific peptide inhibitor used, e) the duration of treatment, f) the drugs used in combination with or simultaneously with the specific peptide inhibitor used, and similar factors well known in the medical field.

[0299] In certain embodiments, the total daily dose of the peptide inhibitors of the invention to be administered to a human or other mammalian host in single or divided doses can be, for example, in amounts of 0.0001 to 300 mg / kg body weight, or 1 to 300 mg / kg body weight per day.

[0300] Non-invasive detection of intestinal inflammation The peptide inhibitors of the present invention may be used as part of a non-invasive diagnostic procedure to detect, evaluate, and diagnose enteritis by microPET imaging, where the peptide inhibitor is labeled with a chelating group or detectable label. In one embodiment, the peptide inhibitor is conjugated to a bifunctional chelator. In another embodiment, the peptide inhibitor is radiolabeled. The labeled peptide inhibitor is then administered orally or rectally to the subject. In one embodiment, the labeled peptide inhibitor is included in drinking water. Following uptake of the peptide inhibitor, microPET imaging can be used to visualize inflammation throughout the subject's intestines and digestive tract. [Example]

[0301] Example 1 Synthesis of peptide inhibitors The peptide monomers of the present invention were synthesized using Merrifield solid-phase synthesis technology on a Protein Technology Symphony multichannel synthesizer. Peptides were graft-assembled using HBTU (O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate) and diisopropylethylamine (DIEA) coupling conditions. For some amino acid couplings, PyAOP (7-azabenzotriazol-1-yloxy) tripyrrolidinophosponium hexafluorophosphate) and DIEA conditions were used. For peptides with C-terminal amides, Rink Amide MBHA resin (100-200 mesh, 0.57 mmol / g) was used, and for peptides with C-terminal acids, pre-loaded Wang resin with N-α-Fmoc-protected amino acids was used. The coupling reagents (HBTU and DIEA premix) were prepared at 100 mmol concentrations. Similarly, amino acid solutions were prepared at 100 mmol concentrations. The peptide inhibitors of the present invention were identified based on medicinal chemistry optimization and / or phage display and screened to identify those with superior binding and / or inhibitory properties.

[0302] construction Peptides were constructed using standard Symphony protocols. The peptide sequence was constructed as follows: Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4 mL of DMF, followed by treatment with 2.5 mL of 20% 4-methylpiperidine (Fmoc deprotection) for 10 minutes. The resin was then filtered, washed twice with 4 mL of DMF, and re-treated with N-methylpiperidine for another 30 minutes. The resin was washed again and three times with 4 mL of DMF, followed by the addition of 2.5 mL of amino acid and 2.5 mL of HBTU-DIEA mixture. After 45 minutes of frequent stirring, the resin was filtered and washed three times with 4 mL of DMF. For a typical peptide of the present invention, double couplings were performed. After completion of the coupling reaction, the resin was washed three times with 4 mL of DMF before proceeding to the next amino acid coupling.

[0303] Ring-closing metathesis to form olefins The resin (100 μmol) was washed with 2 mL of DCM (3 × 1 min) and then with 2 mL of DCE (3 × 1 min), before being treated with 2 mL of a 6 mM solution of Grubbs' first-generation catalyst in DCE (4.94 mg mL; 20 mol% in terms of resin substitution). The solution was refluxed under nitrogen overnight (12 h) and then drained. The resin was washed three times with DMF (4 mL each) and DCM (4 mL), then dried and cleaved.

[0304] Disconnect Following completion of peptide assembly, the peptide was cleaved from the resin by treatment with a cleavage reagent such as Reagent K (82.5% trifluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol), which successfully cleaved the peptide as well as any remaining side chain protecting groups from the resin.

[0305] The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in acetonitrile:water (7:3 with 1% TFA) and filtered. Electrospray ionization mass spectrometry (ESI-MS) (Micromass / Waters ZQ) was then used to verify the quality of the linear peptide, which was then purified.

[0306] Disulfide bond formation by oxidation Peptides containing a free thiol (e.g., diPen) were assembled onto Rink Amide-MBHA resin according to the general Fmoc-SPPS procedure. The peptide was cleaved from the resin by treatment with a cleavage reagent (90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in acetonitrile:water solution (7:3 with 1% TFA) and filtered to yield the desired unoxidized crude peptide.

[0307] Crude cleaved peptides bearing X4 and X9 with either Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys were dissolved in 20 mL of water:acetonitrile. Saturated iodine in acetic acid was then added dropwise with stirring until a yellow color persisted. The solution was stirred for 15 minutes, and the reaction was monitored by analytical HPLC and LCMS. Upon completion, solid ascorbic acid was added until the solution became clear. The solvent mixture was then purified by first diluting with water and then loading onto a reverse-phase HPLC machine (Luna C18 support, 10 μl, 100 A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B and changing to 50% B over 60 minutes at a flow rate of 15 mL / min). The fractions containing pure product were then lyophilized on a lyophilizer.

[0308] Thioether bond formation Peptides containing free thiols (e.g., Cys) and hSer(OTBDMS) were assembled on Rink Amide-MBHA resin according to the general Fmoc-SPPS procedure. Chlorination was carried out by treating the resin with PPh3 (10 equivalents) and Cl3CCN (10 equivalents) in DCM for 2 hours. The peptide was cleaved from the resin by treatment with cleavage reagent (90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in acetonitrile:water solution (7:3 with 1% TFA) and filtered to give the desired uncyclized crude peptide.

[0309] Crude peptides bearing a free thiol (e.g., Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys) and an alkyl halide (hSer(Cl)) at either the X4 and X9 positions or the X9 and X4 positions were dissolved in 0.1 M TRIS buffer, pH 8.5. Cyclization was allowed to occur overnight at room temperature. The solvent mixture was then purified by first diluting it two-fold with water and then loading it onto a reverse-phase HPLC machine (Luna C18 support, 10 μl, 100 A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B and changing to 50% B over 60 min at a flow rate of 15 mL / min). The fractions containing the pure product were then lyophilized on a lyophilizer.

[0310] purification Analytical reversed-phase high-performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm × 250 mm) (Phenomenex). Semi-preparative reversed-phase HPLC was performed on a Gemini 10 μm C18 column (22 mm × 250 mm) (Phenomenex) or a Jupiter 10 μm, 300 Å C18 column (21.2 mm × 250 mm) (Phenomenex). Separation was achieved using a linear gradient of buffer B in A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 15 mL / min (preparative). Separation was achieved using a linear gradient of buffer B in A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 15 mL / min (preparative).

[0311] Example 2 Peptide inhibition of interleukin-23 binding to the interleukin-23 receptor Peptide optimization was performed to identify peptide inhibitors of IL-23 signaling that were active at low concentrations (e.g., IC50 less than 10 nM). Peptides were tested to identify peptides that inhibit IL-23 binding to human IL-23R and inhibit IL-23 / IL-23R functional activity, as described below.

[0312] Assays to determine peptide activity were performed as described below, and the results of these assays are provided in Tables E1 and E2. Human ELISA refers to the IL23-IL23R competitive binding assay described below, Rat ELISA refers to the rat IL-23R competitive binding ELISA assay described below, and pStat3HTRF refers to the DB cell IL-23R pSTAT3 cell assay described below. The peptides shown in Table E1 are cyclized via a disulfide bridge formed between two Pen residues in these peptides. The peptides shown in Table E2 are cyclized via a thioether bond between the indicated amino acid residues. Table E2 provides exemplary structures showing thioether cyclization, which is indicated in the table by the term "cyclo," with the cyclic region in parentheses immediately following the term "cyclo." While for certain peptides, residues Abu are present where indicated, in other embodiments, e.g., embodiments related to non-cyclized forms, Abu may be referred to as hSer(Cl) or homoSer residues.

[0313] IL23-IL23R competitive binding ELISA Immulon® 4HBX plates were coated with 50 ng / well of IL23R_huFC and incubated overnight at 4°C. The wells were washed four times with PBST, blocked with PBS containing 3% skim milk at room temperature for 1 hour, and washed four times again with PBST. A serial dilution of test peptide and IL-23 diluted in assay buffer (PBS containing 1% skim milk) to a final concentration of 2 nM was added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected by incubating with 50 ng / well of goat anti-p40 polyclonal antibody (R&D Systems #AF309) diluted in assay buffer for 1 hour at room temperature. The wells were washed four times again with PBST. The secondary antibody, HRP-conjugated donkey anti-goat IgG (Jackson ImmunoResearch Laboratories #705-035-147), diluted 1:5000 in assay buffer, was then added and incubated for 30 minutes at room temperature. Finally, the plates were washed as above. Signals were visualized with Component HRP Membrane Substrate, quenched with 2 M sulfuric acid, and read spectrophotometrically at 450 nm. IC50 values ​​for various test peptides determined from these data are shown in Tables E1 and E2.

[0314] Rat IL-23R competitive binding ELISA Assay plates were coated with 300 ng / well of rat IL-23R_huFC and incubated overnight at 4°C. Wells were washed, blocked, and washed again. Serial dilutions of test peptide and IL-23 at a final concentration of 7 nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected with a goat anti-p40 polyclonal antibody followed by HRP-conjugated donkey anti-goat IgG. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2 M sulfuric acid. IC50 values ​​for the various test peptides determined from these data are shown in Tables E1 and E2.

[0315] DB cell IL23R pSTAT3 cell assay IL-23 plays a central role in supporting and maintaining Th17 differentiation in vivo. This process is thought to be primarily mediated through signal transducer and activator of transcription 3 (STAT3), whose phosphorylation (to obtain pSTAT3) leads to the upregulation of RORC and proinflammatory IL-17. This cellular assay examines the levels of pSTAT3 in IL-23R-expressing DB cells upon stimulation with IL-23 in the presence of test compounds. DB cells (ATCC #CRL-2289) cultured in RPMI-1640 medium (ATCC #30-2001) supplemented with 10% FBS and 1% glutamine were seeded at 5 x 10E5 cells / well in 96-well tissue culture plates. Serial dilutions of test peptide and IL-23 at a final concentration of 0.5 nM were added to each well and incubated at 37°C in a 5% CO2 humidified incubator for 30 minutes. Changes in phospho-STAT3 levels in cell lysates were detected using the Cisbio HTRF pSTAT3 Cellular Assay Kit according to the manufacturer's Two Plate Assay protocol. IC50 values ​​determined from these data are shown in Tables E1, E2, and E3. * = ≤ 1 nM; ** = 1 nM to 10 nM; *** = 10 nM to 100 nM; **** = > 100 nM. Data were not determined unless indicated. [Table E1-1] [Table E1-2] [Table E2-1] [Table E2-2] [Table E2-3] [Table E2-4] [Table E2-5] [Table E2-6] [Table E3-1] [Table E3-2] [Table E3-3] [Table E3-4] [Table E3-5] [Table E3-6] [Table E3-7] [Table E3-8] [Table E3-9] [Table E3-10] [Table E3-11]

[0316] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature referenced herein and / or listed in the Application Data Sheet are hereby incorporated by reference in their entirety.

[0317] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. The present invention provides, for example, the following items. (Item 1) 1. A peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein said peptide inhibitor has the formula (V): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23(V) (Sequence number 238) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Lys(Ac), Lys(Y1-Ac), or absent, where Y1 is an amino acid; X4 is Abu, Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, or Cys; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is Trp, Trp(5-F), 1-Nal, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4-dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen, Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], alpha-MeTyr, or Phe(4-CONH2); X11 is 2-Nal, Trp, Trp(5-F), Trp(7-Aza), Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent; X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, Ala, Asp, Tyr, Arg, Leu, Gln, Ser, Ile, 1-Nal, 2-Nal, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, (D)Ile, or absent; X17 is Lys, Gly, Pro, The, Phe, Trp, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X18 is Gly, Lys, Glu, Phe, Thr, Arg, Gln, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X19 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X20 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X21 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X22 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or absent; X23 is Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp or is absent; A peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is cyclized via the bond between X4 and X9, and wherein the peptide inhibitor inhibits binding of interleukin-23 (IL-23) to the IL-23 receptor. (Item 2) 2. The peptide inhibitor according to item 1, wherein the bond between X4 and X9 is a disulfide bond or a thioether bond. (Item 3) 2. The peptide inhibitor of item 1, wherein X4 is Pen, X9 is Pen, and the bond is a disulfide bond. (Item 4) 4. The peptide inhibitor of claim 3, wherein the peptide inhibitor has the structure of formula (III): (Item 5) 4. The peptide inhibitor according to item 3, wherein the peptide inhibitor comprises an amino acid sequence according to formula (IIIa) or set forth in Table E1. (Item 6) 2. The peptide inhibitor according to item 1, wherein X4 is Abu, X9 is Cys, and the bond is a thioether bond. (Item 7) 7. The peptide inhibitor of claim 6, wherein the peptide inhibitor has the structure of formula (IV): (Item 8) 7. The peptide inhibitor according to item 6, wherein the peptide inhibitor comprises an amino acid sequence according to formula (IVa) or set forth in Table E2. (Item 9) 9. The peptide inhibitor according to any one of items 1 to 8, further comprising one or more half-life extending moieties and / or one or more linker moieties conjugated to said peptide inhibitor. (Item 10) 10. The peptide inhibitor of item 9, wherein the half-life extending moiety is conjugated to the peptide inhibitor via one or more linker moieties. (Item 11) The peptide inhibitor has the formula (Z): R 1 -XR 2 (Z) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, and includes a pegylated form alone or as any of the above spacers; X is an amino acid sequence of Formula (I), Formula (II), Formula (IIIa), Formula (IVa), Formula (V), Formula (XII)-(XVIIIh), or an amino acid sequence set forth in any of Tables E1, E2, or E3; R 2 is OH or NH2. (Item 12) A peptide dimeric inhibitor of the interleukin-23 receptor, wherein the peptide dimeric inhibitor comprises two peptide monomer subunits connected via one or more linker moieties, and each peptide monomer subunit comprises an amino acid sequence or structure of Formula (I), (II), (IIIa), (IVa), Formula (V), Formulas (XII)-(XVIIIh), or an amino acid sequence set forth in any of Tables E1, E2, or E3. (Item 13) 13. The peptide dimeric inhibitor of claim 12, wherein the one or more linker moieties are a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker. (Item 14) 14. The peptide dimer inhibitor of claim 12 or 13, wherein the N-terminus of each peptide monomer subunit is connected by the linker moiety, or the C-terminus of each peptide monomer subunit is connected by the linker moiety. (Item 15) X is a group of formula XII: X2-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(XII) (Sequence number 275) wherein: X2 is Arg, (D)Arg, Gln, or absent; X3 is (D) Arg, Phe, (D) Phe, Lys, (D) Lys, Lys(Y1-Ac), (D) Lys(Y1-Ac), or absent, wherein Y1 is an amino acid or Y1 is absent; X4 is Cys, (D)Cys), alpha-MeCys, Abu, (D)Pen, Pen, (D)Pen sulfoxide, or Pen sulfoxide; X5 is Cit, Lys, Asn, Asp, Glu, Lys(Ac), or Gln; X7 is Trp, substituted Trp, or 1-Nal, wherein the substituted Trp is Trp substituted with halo or azaTrp; X8 is Gln, Lys, Lys(Ac), a-MeLeu, Cit, Glu, 1-Nal, 2-Nal, Trp, substituted Trp, or Lys(Peg12); X9 is Cys, Abu, or Pen; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe(Cmd), or Phe[4-(2-acetylaminoethoxy)]; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal; X12 is alpha-MeLeu, Aib, Lys, cyclohexyl Ala, tetrahydropyran Ala, Lys(Peg12), or Deg; X13 is Glu, b-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or (D)Lys(Y2-Ac); wherein Y2 is an amino acid or Y2 is absent; X14 is Asn, Asp, Cit, or Lys(Ac); X15 is Asn, Lys, Lys(Ac), Cit, Asp, Gly, Ala, b-Ala, or Sarc; X16 is an amino acid or is absent; 13. The peptide inhibitor according to claim 11 or the peptide dimer inhibitor according to claim 12, wherein X4 and X9 are capable of forming a disulfide bond or a thioether bond. (Item 16) X is a group of formula XIII: 16. The peptide or peptide dimer inhibitor according to item 15, wherein the peptide or peptide dimer inhibitor is according to X3-X4-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XIII) (SEQ ID NO: 276). (Item 17) 16. The peptide or peptide dimer inhibitor according to item 15, wherein X4 and X9 are linked together to form a disulfide bond or a thioether bond. (Item 18) X is a group of formula XIVa or XIVb: X3-Abu-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XIVa) (SEQ ID NO: 277); or 16. The peptide inhibitor or peptide dimer inhibitor according to item 15, wherein the peptide or dimer inhibitor is in accordance with X3-Pen-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XIVb) (SEQ ID NO: 278). (Item 19) X is of formula XVa, XVb, XVc, or XVd: X3-Abu-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVa) (SEQ ID NO: 279); X3-Pen-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVb) (SEQ ID NO: 280); X3-Abu-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVc) (SEQ ID NO: 281); or 16. The peptide inhibitor or peptide dimer inhibitor according to item 15, wherein the peptide or dimer inhibitor is in accordance with X3-Pen-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVd) (SEQ ID NO: 282). (Item 20) X is the formula XVIa, XVIb, XVIc, XVId, XVIe, XVIf, XVIg, or XVIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIa) (SEQ ID NO: 283); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIb) (SEQ ID NO: 284); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIc) (SEQ ID NO: 285); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVId) (SEQ ID NO: 286); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIe) (SEQ ID NO: 287); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIf) (SEQ ID NO: 288); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIg) (SEQ ID NO: 289); or 16. The peptide inhibitor or peptide dimer inhibitor according to item 15, wherein the peptide or dimeric peptide inhibitor is in accordance with X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16(XVIh) (SEQ ID NO: 290). (Item 21) X is of formula XVIIa, XVIIb, XVIIc, XVIId, XVIIe, XVIIf, XVIIg, or XVIIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIa) (SEQ ID NO: 291); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIb) (SEQ ID NO: 292); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIc) (SEQ ID NO: 293); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIId) (SEQ ID NO: 294); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIe) (SEQ ID NO: 295); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIf) (SEQ ID NO: 296); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIg) (SEQ ID NO: 297); or 16. The peptide inhibitor or peptide dimer inhibitor according to item 15, wherein the peptide or peptide dimer inhibitor is in accordance with X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVIIh) (SEQ ID NO: 298). (Item 22) X is of formula XVIIIa, XVIIIb, XVIIIc, XVIIId, XVIIIe, XVIIIf, XVIIIg, or XVIIIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIa) (SEQ ID NO: 299); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIb) (SEQ ID NO: 300); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16 (XVIIIc) (SEQ ID NO: 301); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16 (XVIIId) (SEQ ID NO: 302); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVIIIe) (SEQ ID NO: 303); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIf) (SEQ ID NO: 304); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16 (XVIIIg) (SEQ ID NO: 305); or 16. The peptide inhibitor or peptide dimer inhibitor according to item 15, wherein the peptide or dimeric peptide inhibitor is according to the formula: X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIh) (SEQ ID NO: 306). (Item 23) 23. The peptide inhibitor or peptide dimer inhibitor according to any one of items 15 to 22, wherein X3 is Gln, Glu, Lys(Ac), or a-MeLeu. (Item 24) 24. The peptide inhibitor or peptide dimer inhibitor according to any one of items 15 to 23, wherein X8 is Lys(Y1-Ac) or (D)Lys(Y1-Ac) and Y1 is Glu, Phe, Trp, Pro, or Arg. (Item 25) 25. The peptide or peptide dimer inhibitor according to any one of items 15 to 24, wherein X13 is Glu, b-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or (D)Lys(Y2-Ac), and Y2 is an amino acid or is absent. (Item 26) 26. The peptide inhibitor or peptide dimer inhibitor of any one of items 15 to 25, wherein X16 is Sar, Lys, (D)Lys, Ahx, b-Ala, Gly, Arg, (D)Arg, Ile, Gln, (D)Gln, Tyr, Ser, (D)Ser, (D)Tyr, Ala, Trp, Asp, or (D)Asp. (Item 27) 27. The peptide or peptide dimer inhibitor according to any one of items 15 to 26, wherein abu and Pen; abu and Cys; Pen and Pen; or Pen and Cys are linked together to form a disulfide bond. (Item 28) 15. The peptide inhibitor according to any one of items 1 to 11 or the peptide dimer inhibitor according to any one of items 12 to 14, further comprising a conjugated chemical substituent. (Item 29) 16. The peptide inhibitor or peptide dimer according to item 15, wherein the conjugated chemical substituent is a lipophilic substituent or a polymer moiety. (Item 30) 16. The peptide inhibitor or peptide dimer according to item 15, wherein the conjugated chemical substituent is Ac, Palm, GamaGlu-Palm (gamaGlu-Palm), IsoGlu-Palm, PEG2-Ac, PEG4-IsoGlu-Palm, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin. (Item 31) 16. The peptide inhibitor or peptide dimer according to item 15, wherein the conjugated chemical substituent is polyethylene glycol having a molecular weight of 400 Da to 40,000 Da. (Item 32) A polynucleotide comprising a sequence encoding one or both peptide monomer subunits of the peptide inhibitor according to any one of items 1 to 11 or the peptide dimeric inhibitor according to any one of items 12 to 14. (Item 33) 33. A vector comprising the polynucleotide according to Item 32. (Item 34) 34. A pharmaceutical composition comprising the peptide inhibitor or peptide dimer inhibitor according to any one of items 1 to 33 and a pharmaceutically acceptable carrier, excipient, or diluent. (Item 35) 35. The pharmaceutical composition according to item 34, further comprising an enteric coating. (Item 36) 36. The pharmaceutical composition of claim 35, wherein the enteric coating protects and releases the pharmaceutical composition in the lower gastrointestinal system of a subject. (Item 37) In subjects with inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as in leukocyte adhesion deficiency type 1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome 36. A method for treating psoriasis, psoriatic arthritis, or graft-versus-host disease, including rheumatoid arthritis, ... (Item 38) 38. The method of item 37, wherein the pharmaceutical composition is provided to the subject by oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vapor, spray, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, vaginal, or local administration route. (Item 39) 38. The method according to item 37 for treating inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease, wherein the pharmaceutical composition is orally administered to the subject. (Item 40) 38. The method of item 37 for treating psoriasis, wherein the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously.

Claims

1. 1. A peptide inhibitor of the interleukin-23 receptor, the peptide inhibitor having the formula (Z): １ -X-R ２ (Z) or a pharmaceutically acceptable salt or solvate thereof; In the formula, R １ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, and includes pegylated forms alone or as a spacer in any of the above; R ２ is OH or NH ２ and X is an amino acid sequence of formula XII: Formula XII: X2-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (XII) (SEQ ID NO: 275) [In the formula, X2 is absent; X3 is absent; X4 is Pen; X5 is Asn or Gln; X7 is Trp or a substituted Trp, wherein the substituted Trp is a Trp substituted with halo or aza Trp; X8 is Lys(Ac); X9 is Pen; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe(Cmd), or Phe[4-(2-acetylaminoethoxy)]; X11 is 2-Nal or 1-Nal; X12 is alpha-MeLeu; X13 is Lys(Y2-Ac); wherein Y2 is an amino acid or Y2 is absent; X14 is Asn; X15 is Asn; X16 is an amino acid or is absent; and wherein X4 and X9 are capable of forming a disulfide bond. A peptide inhibitor of the interleukin-23 receptor, wherein the peptide inhibitor is cyclized via the bond between X4 and X9, and wherein the peptide inhibitor inhibits binding of interleukin-23 (IL-23) to the IL-23 receptor.

2. 2. The peptide inhibitor of claim 1, wherein X is according to formula XIII: X3-X4-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XIII) (SEQ ID NO: 276).

3. X is a group represented by formula XIVb: X3-Pen-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XIVb) (SEQ ID NO: 278) 2. The peptide inhibitor of claim 1, wherein the peptide inhibitor is in accordance with

4. X is a group of formula XVb or XVd: X3-Pen-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVb) (SEQ ID NO: 280); or X3-Pen-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVd) (SEQ ID NO: 282) 2. The peptide inhibitor of claim 1, wherein the peptide inhibitor is in accordance with

5. X is of formula XVIf or XVIh: X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIf) (SEQ ID NO: 288); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-X12-X13-X14-Asn-X16 (XVIh) (SEQ ID NO: 290) 2. The peptide inhibitor of claim 1, wherein the peptide inhibitor is in accordance with

6. X is of formula XVIIIf or XVIIIh: X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIf) (SEQ ID NO: 304); or 2. The peptide inhibitor of claim 1, according to the sequence X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy)]-(2-Nal)-[α-MeLeu]-X13-Asn-Asn-X16(XVIIIh) (SEQ ID NO: 306).

7. The peptide inhibitor of any one of claims 1 to 6, wherein X16 is absent.

8. 10. The peptide inhibitor of claim 1, further comprising a conjugated chemical substituent that is a lipophilic substituent or a polymer moiety.

9. The conjugated chemical substituents may be Ac, Palm, GamaGlu-Palm (gamaGlu-Palm), IsoGlu-Palm, PEG2-Ac, PEG4-IsoGlu-Palm, (PEG) ５ 9. The peptide inhibitor of claim 8, which is Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin.

10. 9. The peptide inhibitor of claim 8, wherein the conjugated chemical substituent is polyethylene glycol having a molecular weight of 400 Da to 40,000 Da.

11. A pharmaceutical composition comprising a peptide inhibitor according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier, excipient, or diluent.

12. 12. The pharmaceutical composition of claim 11, further comprising an enteric coating.

13. 13. The pharmaceutical composition of claim 12, wherein the enteric coating protects and releases the pharmaceutical composition within the lower gastrointestinal system of a subject.

14. 14. The pharmaceutical composition of any one of claims 11 to 13 for treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as in leukocyte adhesion deficiency type 1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft-versus-host disease in a subject.

15. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is provided to the subject by oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vapor, spray, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, vaginal, or local administration route.

16. 15. The pharmaceutical composition of claim 14 for treating inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease, wherein the pharmaceutical composition is provided orally to the subject.

17. 15. The pharmaceutical composition of claim 14 for treating psoriasis, wherein the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously.