Peptide inhibitors of interleukin-23 receptor, and use thereof for treating inflammatory diseases

Abstract

To provide peptide inhibitors of an interleukin-23 receptor, and use thereof for treating inflammatory diseases.SOLUTION: Provided are novel peptide inhibitors of an interleukin-23 receptor, and related composition and method for treating or preventing various diseases and disorders including inflammatory bowel disease by using the peptide inhibitors. An interleukin-23 (IL-23) cytokine plays an important role in a cause of autoimmune inflammation and associated diseases and disorders which are multiple sclerosis, bronchial asthma, articular rheumatism, psoriasis for example, and inflammatory bowel diseases (IBD) which are ulcerative colitis and Crohn's disease for example.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is incorporated herein by reference in its entirety. Priority is claimed to provisional application No. 62 / 447,778.

[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 by reference. The text file containing the sequence listing is named PRTH_027_ The text file is 01WO_ST25.txt. It is 255KB and was created in 2018. Created on January 18, 2017 and submitted electronically via EFS-Web.

[0003] The present invention relates to novel peptide inhibitors of the interleukin-23 receptor, as well as to the treatment of inflammatory bowel disease. for treating or preventing various diseases and disorders, including psoriasis, Crohn's disease, and Concerning their use. [Background technology]

[0004] Interleukin-23 (IL-23) cytokines play a key role in autoimmune inflammation and related Diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease It plays an important role in the pathogenesis of inflammatory bowel disease (IBD), e.g., ulcerative colitis and Crohn's disease. Studies in acute and chronic IBD mouse models have demonstrated the role of IL-1 in pathogenesis. This study revealed the key role of IL-23R and downstream effector cytokines. R is a marker for Th17 cells, γδT cells, and natural killer (NK) cells, which are abundant in the intestine. various adaptive and innate immune cells, including dendritic cells, macrophages, and innate lymphoid cells IL-23R gene expression and protein expression are increased at the intestinal mucosal surface. IL-23 levels have been shown to be elevated in IBD patients. Pathogenic CD4 producing IL-17 and tumor necrosis factor (TNF) + Development of T cell populations It is thought to mediate this effect by promoting life.

[0005] IL-23 production is abundant in the intestine and is associated with T helper 1 (Th1) and Th17 T cell-dependent and T cell-independent pathways of intestinal inflammation through their effects on cytokines to regulate the balance between tolerance and immunity, as well as suppress regulatory T cell responses in the gut. It is believed to play an important role in suppressing inflammation and favoring inflammation. Polymorphisms in the IL-23 receptor (IL-23R) are associated with susceptibility to IBD. This finding further establishes the crucial role of the IL-23 pathway in intestinal homeostasis.

[0006] Psoriasis, a chronic skin disease that affects approximately 2% to 3% of the general population, is a T-cell inflammation of the body. It has been shown that Il-23 is mediated by an interferon-dependent mechanism. Chronic inflammation is mediated by induction of inflammatory cytokines (IL-17), regulation of T memory cells, and activation of macrophages. plays a key role in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation It has one of several interleukins, IL-23 and IL- 23R expression has been shown to be increased in tissues of psoriasis patients, and neutralizing IL-23 The antibody showed IL-23-dependent inhibition of psoriasis pathogenesis in an animal model of psoriasis.

[0007] IL-23 is composed of its own p19 subunit and the p40 subunit of IL-12. It is a heterodimer consisting of interferon-γ (IFN-γ)-producing T helper (T H 1) Both IL-23 and IL-12 are cytokines involved in cell development. Although both contain the p40 subunit, they have different phenotypic properties. Animals lacking IL-12 are prone to inflammatory autoimmune diseases, while those lacking IL-23 Putatively, animals lacking IL-23 have a higher level of IL-6, I in the CNS. L-17 and TNF-producing CD4 + Resistance due to decreased number of T cells. IL-23 binds to IL-23R, which binds to IL-12Rβ1 and IL- It is a heterodimeric receptor consisting of IL-23R subunits. Binding is mediated by the Jak-stat signaling molecules Jak2, Tyk2, and Stat1 , activates Stat3, Stat4, and Stat5, but Stat4 activation is A qualitatively weaker and different DNA-binding Stat complex is involved in IL-23 compared with IL-12. IL-23R is formed in response to Jak2 constitutively and in a ligand-dependent manner. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 acts selectively on memory CD4(+) T cells.

[0008] Therapies that inhibit the IL-23 pathway are being developed for use in treating IL-23-associated diseases and disorders. Efforts have been made to identify therapeutic moieties. IL-23, which is approved for the treatment of psoriasis, including ustekinumab, a humanized antibody that binds to IL-23 or IL-23R Many antibodies have been identified that bind to IL-23R and inhibit IL-23. Polypeptide inhibitors that inhibit the binding of IL-23R to IL-23R have been identified (e.g., US See Patent Application No. US2013 / 0029907. riakinumab (which targets the common p40 subunit), and tildrakizumab, Guselkumab, MEDI2070, and BI-655066 (Il-23's proprietary p1 Clinical trials in Crohn's disease and psoriasis using rheumatoid arthritis drugs (targeting the rheumatoid arthritis subunit 9) have shown promising results. These findings highlight the potential of IL-23 signaling blockade in the treatment of inflammatory diseases. While the results are promising, bowel diseases, including Crohn's disease, ulcerative colitis, and related disorders, A stable anti-inflammatory drug selectively targeting the IL-23 pathway in the intestine that can be used for the treatment of intestinal inflammation Challenges remain with regard to identifying effective and selective agents. Apparently, treating IL-23-associated diseases, including those associated with autoimmune inflammation in the intestinal tract and the need for new therapeutic agents that target the IL-23 pathway that can be used to prevent In addition, the specificity of IL-23R from the luminal side of the intestine is unclear. Compounds and methods for specific targeting may be therapeutic for IBD patients suffering from localized inflammation of intestinal tissue. The present invention may provide benefits by binding IL-23R to mediate IL-23 binding and signaling. By providing novel peptide inhibitors that inhibit signal transduction and are suitable for oral administration. , addressing these needs. [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 relates, inter alia, to novel peptide inhibitors of IL-23R and related methods of use. provide.

[0011] In a first aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor, or The present invention provides a peptide inhibitor having a pharmaceutically acceptable salt or solvate thereof, the peptide inhibitor having the formula (II): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-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)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-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, and 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-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or T rp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen , Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, 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(A c) or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or non-existent; 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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. inhibits.

[0012] In a second aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor, or The present invention provides a peptide inhibitor having 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-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(V) (SEQ ID NO: 238) comprising or consisting of the amino acid sequence of X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-MeTyr, Lys(Ac), Lys(Y1-Ac) or absent, wherein 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, and 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-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), Homo-Lys(Ac), 1-Na l, 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-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, Ala, cyclohexyl Ala, 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(A c) 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, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, 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)Se r, (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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, alpha-MeTyr, alpha-MeAsp, or absent; The peptide inhibitors are cyclized via the bond between X4 and X9, and the peptide inhibitors are intercalated. -Inhibits the binding of leukin-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 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-Me In certain embodiments, (D)Cys, (D)Abu, (D)Pen, or Pen. X4 is Pen(sulfoxide).

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

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

[0017] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyra THP, alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-Me Asn, alpha-MeTyr, Ala, cyclohexyl Ala, Lys, or Aib In certain embodiments, X12 is Ala, cyclohexylAla, or L ys.

[0018] In certain embodiments, X13 is Glu, Cit, Gln, Lys(Ac), Al alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLy s, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap (Ac), homo-Lys(Ac), or Lys. In certain embodiments, X1 3 is Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac), wherein Y2 is an amino acid.

[0019] In certain embodiments, X16 is Glu, Phe, Lys, Asn, Trp, GI y, Thr, Pro, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D )Leu, (D)Gln, alpha-MeArg, alpha-MePhe, alpha-M eLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Al In certain embodiments, X16 is A la, Asp, Tyr, Arg, Leu, Gln, Ser, Ile, 1-Nal, 2-N al, (D)Ala, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D )Ser, or (D)Ile.

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

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

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

[0023] In certain embodiments, any of the peptide inhibitors described herein is In certain embodiments, the conjugated chemical substituent is a lipophilic Substituent or polymer moiety, e.g., Ac, Palm, Gama Glu-Palm (gama Glu-Palm), IsoGlu-Palm, PEG2-Ac, PEG4-IsoGlu- Palm, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid (pyro glutaric acid), benzoic acid, IVA, octanoic acid, 1,4 diaminobutane , isobutyl, Alexa488, Alexa647, or biotin. In this embodiment, the conjugated chemical substituents have a molecular weight of 400 Da to 40,000 Da. In certain embodiments, the peptide is conjugated at X8. In another particular embodiment, the peptide is conjugated at X9. In a typical embodiment, 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. Mi, during the ceremony, R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, and may be used alone or in combination with any of the above. any of which contains a PEGylated form as a spacer; R 2 is a bond, OH, or NH2; X is a peptide comprising any of the amino acid sequences described herein, and has the formula ( I), Formula (II), Formula (IIIa), (IVa), Formula (V), Formula (XII)~(XVII Ih), or any of the peptide acid sequences listed in the tables herein. or a peptide containing

[0025] In a related aspect, the present invention provides peptide dimeric inhibitors of the interleukin-23 receptor. and the peptide dimeric inhibitor comprises two peptides connected via one or more linker moieties. Each peptide monomer subunit comprises a peptide monomer subunit of formula (I), formula (I I), a sequence of formula (V), or any other sequence or structure described herein In certain embodiments, one or both peptide monomer subunits comprise X and X 9. In certain embodiments, one or both of the molecules The intramolecular bond is a disulfide bond or a thioether bond. The linker may be any of the linkers shown in Table 2 or described herein. In certain embodiments, the linker moiety is a diethylene glycol linker, Iminodiacetic acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker In certain embodiments, each peptide monomer subunit is a In certain embodiments, the N-termini of each peptide unit are connected by a linker moiety. The C-termini of the dimeric subunits are connected by a linker moiety. In the present invention, the linker is a peptide monomer subunit having at least one internal amino acid residue. The group is attached to the N-terminus, C-terminus, or internal amino acid residue of another peptide monomer subunit. To be continued.

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

[0027] In another aspect, the present invention provides a method for the preparation of a peptide inhibitor or a peptide dimer inhibitor of the present invention, comprising administering to a subject a drug and a physiologically acceptable carrier, excipient, or diluent. In embodiments, the pharmaceutical composition comprises an enteric coating. The coating protects and releases the pharmaceutical composition within the subject's lower gastrointestinal system.

[0028] Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease ( Non-tropical sprue), seronegative arthropathy associated with enteropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, leukocyte adhesion disorder Colitis associated with innate immune disorders such as those in type 1, chronic granulomatous disease, and glycogen storage disease 1 Type B, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wisco syndrome Watt-Aldrich syndrome, pouchitis after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer , pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis , chronic sinusitis, asthma, psoriasis, or graft-versus-host disease. and methods for treating or preventing diseases associated with IL-23 signaling that are not present in the body. The method comprises providing to a subject a therapeutically effective amount of a peptide inhibitor or pharmaceutical composition of the present invention. In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In embodiments, the peptide inhibitor or peptide dimer inhibitor is interleukin-23 It inhibits the binding of IL-23 to the interleukin-23 receptor (IL-23R). In certain embodiments, the pharmaceutical composition is administered orally, intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, or intrathecally. Intracavitary, inhalation, vapor, spray, sublingual, buccal, parenteral, rectal, ocular, inhalation, vaginal, or topical administration In certain embodiments, the pharmaceutical composition is administered to a subject via an oral route. It is given orally to treat IBD, ulcerative colitis, and Crohn's disease. In embodiments, the pharmaceutical composition is administered topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously to treat psoriasis. or given intravenously. DETAILED DESCRIPTION OF THE INVENTION

[0029] Unless otherwise specified herein, scientific and technical terms used in this application are understood to be of ordinary skill in the art. Generally, the terms used herein shall have the meaning commonly understood by those skilled in the art. Chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein The terminology used in connection with and techniques related to protein and nucleic acid chemistry is understood to be within the skill of the art. is well known and commonly used.

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

[0031] Throughout this specification, the terms "comprise" or "comprise" are used interchangeably. Variations such as "ses" or "comprising" are used to refer to It means the inclusion of an integer (or component) or a group of integers (or components), but means excluding any other integer (or component) or group of integers (or components). It will be understood that this is not a

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

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

[0034] The terms "patient," "subject," and "individual" may be used interchangeably and refer to a human or These terms refer to any animal, including humans, primates, and domestic animals (e.g., cattle). , pigs), companion animals (e.g., dogs, cats), as well as rodents (e.g., This includes mammals such as mice and rats.

[0035] The term "peptide" as used herein refers to a group of peptides joined together by peptide bonds. The term broadly refers to a sequence of two or more amino acids that is a specific length of amino acids. It does not imply a polymer, nor does it imply that the polypeptide is recombinantly, chemically synthesized, or otherwise refers to whether it is produced using enzymatic synthesis or occurs naturally. It should be understood that the present invention is not intended to

[0036] "Sequence identity," "percent identity," "percent homology," or e.g., As used herein, a recitation of "contains sequences that are 50% identical" means that the sequences are 50% identical over the comparison window. It refers to the degree of identity between nucleotides or amino acids. The "percentage" is calculated by comparing two optimally aligned sequences over a comparison window and determining the percentage of identical nucleobases (e.g., A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Th r, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, Hi s, Asp, Glu, Asn, Gln, Cys, and Met) occur at positions in both sequences. Determine the number of positions, obtain the number of matching positions, and multiply that number by the total number of positions in the comparison window (total Divide by the window size (i.e., the window size) and multiply the result by 100 to get the percentage of sequence identity. It can be calculated by:

[0037] Sequence similarity or sequence identity between sequences (the terms are used interchangeably herein) The calculation of the α (used in the calculation) can be performed as follows: To determine percent identity of a sequence, the sequences may be aligned for optimal comparison purposes (e.g., For example, one or both of the first and second amino acid or nucleic acid sequences may be aligned for optimal alignment. Gaps may be introduced between sequences and non-homologous sequences may be ignored for comparison purposes. In some embodiments, the length of the reference sequence to be aligned for comparison purposes is at least 30% of the length of the reference sequence. , preferably at least 40%, more preferably at least 50%, 60%, and even more preferably Preferably, it is at least 70%, 80%, 90%, or 100%. or nucleotides at corresponding amino acid positions, or nucleotide positions are compared A position in the first sequence has the same amino acid residue as the corresponding position in the second sequence. or nucleotide, then the molecules are identical at that position.

[0038] The percent identity between two sequences must be determined for optimal alignment of the two sequences. the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap. It is a function of the number of positions.

[0039] The comparison of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences can be achieved by Needleman and Wunsch (1970, J. Mol. Biol. 4 8:444-453) algorithm, which is based on Blossum 62 Either matrix or PAM250 matrix, as well as 16, 14, 12, 10 , 8, 6, or 4 gap weights, and 1, 2, 3, 4, 5, or 6 length weights. The weights are incorporated into the GAP program of the GCG software package. In yet another preferred embodiment, the percent identity between two nucleotide sequences is: NWSgapdna.CMP matrix, as well as 40, 50, 60, 70, or 80 G with a gap weight of and a length weight of 1, 2, 3, 4, 5, or 6 The GAP program in the CG software package is used to determine the The parameter set is a gap penalty of 12, a gap extension penalty of 4, and Blossum 62 scoring matrix with a frameshift gap penalty of 5 The percent identity between two amino acid or nucleotide sequences can also be expressed as E .Meyers and W.Miller(1989,Cabios,4:11-17 ) algorithm, which can be determined using the PAM120 weight residue table, ALIGN program with a gap length penalty and a gap penalty of 4 (version 2.0).

[0040] The peptide sequences described herein may be used in combination with other family members or related sequences, for example. A "query sequence" is used to perform a search against public databases to identify sequences. Such a search can be performed using the method described in Altschul, et al. (1990 , J. Mol. Biol., 215:403-10) NBLAST and XBLAST programs BLAST nucleotide searches can be performed using the BLAST program (version 2.0). , the NBLAST program, to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention; BLAST protein searches can be performed using a score of 100 and a word length of 12. To obtain amino acid sequences homologous to the protein molecules of the present invention, use the XBLAST program, This can be done using a score = 50 and word length = 3. Obtain a gapped alignment for comparison purposes. For this purpose, Gapped BLAST was used as a method for identifying nucleotide sequences in a BLAST database. c Used as described in Acids Res. 25:3389-3402, 1997 When using BLAST and Gapped BLAST programs, The default parameters of each program (e.g., XBLAST and NBLAST) ) can be used.

[0041] The term "conservative substitution," as used herein, refers to a substitution in which one or more amino acids are replaced by another. It means that the residue is replaced by a biologically similar residue. Examples include residues with similar characteristics. amino acid residues, e.g., small amino acids, acidic amino acids, polar amino acids, basic amino acids Substitutions of amino acids include, for example, hydrophobic amino acids, and aromatic amino acids. See the table below. In some embodiments of the present invention, one or more Met residues are selected from the group consisting of Met's biological It is substituted with norleucine (Nle), which is an isoform but, in contrast to Met, is not readily oxidized. Conservative substitutions at residues not commonly found in endogenous mammalian peptides and proteins Other examples of substitutions include, for example, ornithine, canavanine, aminoethylcysteine, or another In some embodiments, the basic amino acid of In some embodiments, one or more cysteines of the peptide analogs of the invention are replaced with another residue, such as serine. Further information on non-phenotypic substitutions in peptides and proteins may be obtained. For more information, see, for example, Bowie et al., Science 247, 1306-13 10, 1990. In the following scheme, conservative substitutions of amino acids are They are grouped by their chemical properties: I: neutral, hydrophilic, II: acid and amide, III: : basic, IV: hydrophobic, V: aromatic, large amino acids. [Table A]

[0042] In the scheme below, conservative amino acid substitutions are grouped by physicochemical properties. VI: Neutral or hydrophobic, VII: Acidic, VIII: Basic, IX: Polar, X: Aromatic Xiang tribe. [Table B]

[0043] The term "amino acid" or "any amino acid" as used herein refers to an amino acid. Naturally occurring amino acids (e.g., α-amino acids), unnatural amino acids, modified amino acids, and non- This refers to all amino acids, including naturally occurring amino acids. This includes D-amino acids and L-amino acids. Naturally occurring amino acids include those found in nature, e.g., synthetic amino acids. There are 23 amino acids that combine to form peptide chains, forming the building blocks of a wide variety of proteins. These are primarily L-stereoisomers, although several D-amino acids are also present in bacteria. occur in the outer coat and in some antibiotics. The 20 "standard" naturally occurring amino acids are listed above. The "non-standard" natural amino acids are pyrrolysine (found in methanogenic organisms and and other eukaryotes), selenocysteine ​​(found in most eukaryotes as well as N-formylmethionine (present in many non-eukaryotic organisms), and N-formylmethionine (present in bacteria, mitochondria, etc.) (encoded by the start codon AUG in the chloroplasts and the mitochondrial DNA). "Non-natural" amino acids are non-proteinogenic amino acids that occur naturally or are chemically synthesized. Neoplastic amino acids (i.e., not naturally encoded, i.e., not found in the genetic code) There are over 140 known unnatural amino acids, and thousands of more. Many combinations are possible. Examples of "unnatural" amino acids include β-amino acids (β 3 oh and β 2), homo-amino acids, proline and pyruvic acid derivatives, trisubstituted 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. Amino acids contain a group, groups, or chemical moiety that does not naturally occur on amino acids. Amino acids that have been chemically modified to contain certain amino acids (e.g., naturally occurring amino acids) are also included. According to this embodiment, the peptide inhibitor comprises two amino acid residues present in the peptide inhibitor. The amino acid residues that form the bond are not bonded to each other. It is understood that certain amino acids may vary somewhat when bonded to one another compared to Reference to an acid is intended to encompass an amino acid in both its unbound and bound state. For example, the amino acid residue homoserine (hSer) or homoserine in its unbound form is shown. When involved in the intramolecular bond according to the present invention, 2-aminobutyric acid (Abu) The present invention relates to peptide inhibitors comprising a bridge between X4 and X9, as well as X 4 and X9, e.g., including both the peptide inhibitors prior to crosslink formation. Thus, the names hSer and Abu are intended to refer to the same amino acid, Used interchangeably.

[0044] For the most part, naturally occurring aminoacyl residues and naturally occurring aminoacyl residues used herein The name of the non-existent aminoacyl residue is "Nomenclature of α-Ami no Acids(Recommendations,1974)”Biochemis As presented in IUPAC Commission, 14(2), (1975) on the Nomenclature of Organic Chemis try, and IUPAC-IUB Commission on Biochemistry The nomenclature proposed by the International Nomenclature Committee will be followed. The names of amino acids and aminoacyl residues used in the appended claims are To the extent that the names and abbreviations differ from these suggestions, they will be made clear to the reader. Some abbreviations useful for explanation 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, naturally occurring amino acids are referred to by their full names. Unless (e.g., alanine, arginine, etc.), they are replaced by their conventional three-letter or are indicated by single letter abbreviations (e.g., Ala or A for alanine, arginine, (e.g., Arg or R for α-amino acids). Unless otherwise specified, the amino acid's three-letter or single-letter The abbreviation refers to the L-isomer form of the amino acid in question. When used in the specification, references to peptides in their "L" isomeric form are used, and conversely, "D-amino acids" are used. The term refers to peptides in their "D" isomeric form (e.g., Dasp, (D)Asp). , or D-Asp; DPhe, (D)Phe, or D-Phe). Depending on the peptide The D-isomer form of an amino acid residue can be substituted for any L-amino acid residue, so long as the desired function is retained. When D-amino acids are referred to using one-letter abbreviations, they are conventionally It can be denoted in lower case by

[0046] In the case of less common or non-naturally occurring amino acids, Unless referred to by its full name (e.g., sarcosine, ornithine, etc.), The available three- or four-letter code is used for the residue, Sar or Sarc ( Sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropionic acid), γ-Gl u (γ-glutamic acid), GABA (γ-aminobutanoic acid), β-Pro (pyrrolidine- 3-carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Ab u (2-aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenyl (β,β-diphenylalanine) and Bip (β,β-diphenylalanine), and Ida (iminodiacetic acid) acid).

[0047] As will be apparent to those skilled in the art, the peptide sequences disclosed herein are read from left to right. The left end of the sequence is the N-terminus of the peptide and the right end of the sequence is the The C-terminus of the sequence. Some of the sequences disclosed herein include the amino terminus (N-terminus) of the sequence. the "Hy-" moiety at the carboxyl end (C-terminus) of the sequence, and the "-OH" moiety at the carboxyl end (C-terminus) of the sequence. In such cases, and as otherwise noted, Unless otherwise stated, the "Hy-" moiety at the N-terminus of the sequence refers to a free primary amino acid at the N-terminus. or hydrogen atoms corresponding to the presence of a secondary amino group, while " The "-OH" or "-NH2" moiety corresponds to the presence of an amide (CONH2) group at the C-terminus. In each of the sequences of the present invention, the C-terminal The "-OH" moiety at the C-terminus may be substituted for the "-NH2" moiety at the C-terminus, and vice versa. do.

[0048] Those skilled in the art will appreciate that certain amino acids and other chemical moieties, when attached to another molecule, For example, an amino acid side chain may be modified with another amino acid side chain. The crosslinks may be modified upon formation, e.g., one or more hydrogens may be removed by bonding. Therefore, as used herein, the present invention The amino acid or modified amino acid present in the peptide dimer (e.g., position X4 or position X 9) is present in the peptide both before and after formation of the intramolecular bond. Any such amino acid or modified amino acid form is intended to be included.

[0049] The term "dimer" as used herein broadly refers to a group of two or more monomeric subunits. Certain dimers are peptides comprising the dimers of formula (I) or described herein. The dimers of the present invention include homodimers and heterodimers. The monomeric subunits of the dimer are linked at their C- or N-termini. or it can be linked via an internal amino acid residue. The subunits can be linked through the same site, or each can be linked through a different site (e.g. , C-terminal, N-terminal, or internal site).

[0050] The term "NH2," as used herein, refers to the amino acid at the amino terminus of a polypeptide. The term "OH" as used herein may refer to a free amino group present in the In this case, it can refer to the free carboxy group present at the carboxy terminus of the peptide. The term "Ac" as used herein refers to the C- or N-terminus of a polypeptide. In certain peptides shown herein, In this context, NH2 located at the C-terminus of the peptide refers to the amino group.

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

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

[0053] The term "cyclization" as used herein refers to the process by which a portion of a polypeptide molecule is cyclized. to another part of the peptide molecule to form a disulfide bridge or a thioether bond. This refers to the formation of a closed loop by, for example,

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

[0055] The term "linker moiety" as used herein broadly refers to a linker moiety that connects two peptides. Chemical compounds capable of linking or bonding together monomeric subunits to form dimers. Refers to the structure.

[0056] The term "pharmaceutically acceptable salt" as used herein means a water-soluble or Oil-soluble or dispersible to treat disease without excessive toxicity, irritation, or allergic response are suitable for the intended purpose, are commensurate with a reasonable benefit / risk ratio, and are

[0023] Figures 1A and 1B show salt or zwitterionic forms of the peptides or compounds of the invention that are effective for use. Salts can be obtained during the final isolation and purification of the compounds or by reacting the amino group with a suitable acid. Representative acid addition salts include acetate, adipate, and acetone. Sulfate, citrate, aspartate, benzoate, benzenesulfonate, bisulfite Acid salt, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemiphosphate Sulfate (hemisulfate), heptanoate, hexanoate, formate, fumarate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (Isetin nitrate, lactate, maleate, mesitylenesulfonate, methanesulfonate, sodium Phthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate acid salts, pectinates, persulfates, 3-phenylproprionates oprionate), picrate, pivalate, propionate, succinate, tartar Acid salts, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates , para-toluenesulfonate, and undecanoate. The amino groups in the compound are methyl, ethyl, propyl, and butyl chlorides, bromides, and iodide; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decitronellol chlorides, bromides, and iodides of benzoyl, lauryl, myristyl, and steryl; and benzyl bromide and phenethyl bromide. Examples of acids that can be used to form salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and inorganic acids such as malonic and phosphoric acids, as well as oxalic, maleic, succinic, and citric acids Pharmaceutically acceptable salts include, for example, acid addition salts and salts. The salt may be selected from basic salts. Examples of acid addition salts include chloride salts, citrate salts, and the like. Examples of base salts include salts of alkali metal cations, e.g., For example, sodium or potassium ions, alkaline earth metal cations, for example, calcium or magnesium ions, as well as substituted ammonium ions, such as N(R)(R 2) Ions of the type (R3)(R4)+ (where R1, R2, R3, and R4 are independently and is typically hydrogen, optionally substituted C1-6-alkyl, or optionally substituted Examples of such salts include those in which the cation is selected from the group consisting of C2-6 alkenyl. Examples of 1-6-alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl. Examples of potentially relevant C2-6-alkenyl groups include ethenyl, 1 Other examples of pharmaceutically acceptable salts include: “Encyclopaedia of Pharmaceutical Technol ogy”, 3rd edition, James Swarbrick (Ed.) Remington's Pharmaceutical Sciences”,17t h edition, Alfonso R. Gennaro(Ed.), Mark Pu Blishing Company, Easton, PA, USA, 1985 (and others) (more recent editions), Informa Healthcare USA (Inc.), NY , USA, 2007, and J. Pharm. Sci. 66:2 (1977) For a review of suitable salts, see the Handbook of Pharmaceuticals. Maceutical Salts:Properties,Selection,an d Use by Stahl and Wermuth(Wiley-VCH,200 2). Other suitable base salts are formed from bases which form non-toxic salts. Typical examples include aluminum, arginine, benzathine, calcium, choline, and dietary fiber. Thiolamine, diolamine, glycine, lysine, magnesium, meglumine, olamine , potassium, sodium, tromethamine, and zinc salts. Hemisalts, such as hemisulfate and hemicalcium salts, may also be formed.

[0057] The term "N(alpha) methylation" as used herein generally refers to N- Describes the methylation of the alpha amine of an amino acid, also called methylation.

[0058] The terms "control methylation" or "Arg-Me-sym" are used herein. In this case, the symmetric methylation of the two nitrogens of the guanidine group of arginine is described. , "asym methylation" or "Arg-Me-a The term "sym" describes the methylation of the single nitrogen of the guanidine group of arginine.

[0059] The term "acylated organic compound" as used herein refers to an acylated organic compound that forms a C-terminal dimer. Before synthesis, amino acids or monomers or dimers, e.g., the N-terminus of a monomeric subunit Refers to a variety of compounds with carboxylic acid functionality that are used to acylate the ends. Non-limiting examples of silylating organic compounds include cyclopropylacetic acid, 4-fluorobenzoic acid, , 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclohexyl 3,3,3-trifluoropropionic acid ropeonic acid, 3-fluoromethylbutyric acid, tetrahedro edro)-2H-pyran-4-carboxylic acid.

[0060] The term "alkyl" refers to straight or branched, non-cyclic alkyl chains containing 1 to 24 carbon atoms. or cyclic, saturated aliphatic hydrocarbons. Representative saturated linear alkyls include methyl, Examples include ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. While saturated branched alkyl includes, but is not limited to, isopropyl, sec-butyl Examples include, but are not limited to, butyl, isobutyl, tert-butyl, isopentyl, etc. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, Examples include, but are not limited to, butyl, cyclohexyl, and the like, while unsaturated cyclic alkyl groups include, but are not limited to, butyl, cyclohexyl, and the like. Examples of alkyl include cyclopentenyl and cyclohexenyl. Not limited.

[0061] The term "mammal" includes humans, mice, rats, dogs, cats, hamsters, guinea pigs, and the like. This refers to any mammal species, such as rats, rabbits, or livestock.

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

[0063] "Analogs" of amino acids, e.g., "Phe analogs" or "Tyr analogs," are referred to. Various amino acid analogs, including Phe and Tyr analogs, are used. In certain embodiments, the amino acid An analogue, for example, a Phe analogue or a Tyr analogue, is a Phe or Tyr analogue, respectively. In comparison, it contains 1, 2, 3, 4, or 5 substitutions. In certain embodiments, the substitution is in the side chain of the amino acid. Phe(R) 2 ), wherein R 2 are Hy, OH, CH3, CO2H, CONH2, CONH2OCH2CH2NH2, t-Bu, OCH2CH2NH2, Phenoxy, OC H3, OAllyl, Br, Cl, F, NH2, N3, or guanadino. In certain embodiments, R 2 is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3, or CO2H. Examples of Phe analogs include hPhe, Phe(4- OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH 2), Phe(4-phenoxy), Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH 2), BhPhe(4-F), Phe(4-F), Phe(3,5 DiF), Phe( CH2CO2H), Phe(penta-F), Phe(3,4-Cl2), Phe(3,4 -F2), Phe(4-CF3), ββ-diPheAla, Phe(4-N3), Phe [4-(2-aminoethoxy)], 4-phenylbenzylalanine, Phe(4-CON H2), Phe(3,4-dimethoxy), Phe(4-CF3), Phe(2,3-Cl 2), and Phe(2,3-F2). Examples of analogues include hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4- N3), and βhTyr.

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

[0065] The present invention generally relates to IL-23R peptides, including both peptide monomers and peptide dimers. In certain embodiments, the present invention relates to peptides having antagonist activity. Oral delivery of L-23 antagonists for the treatment of IBD and other diseases and disorders This study demonstrates a new paradigm for IBD. IBD represents local inflammation of the intestinal tissue and therefore Advantageous therapeutic agents act from the luminal side of the intestine, providing greater efficacy in affected tissues compared to systemic approaches. Providing high drug concentrations, minimizing systemic availability, and improved efficacy Oral administration of the compounds of the present invention results in improved drug levels in affected intestinal tissues. It maximizes the efficacy of steroids while limiting the drug concentration in the blood circulation, thereby improving the efficacy of steroids in IBD and provide effective, safe, and sustained delivery for lifelong treatment of other diseases and disorders It is expected that this will happen.

[0066] In certain embodiments, the present invention provides cyclized structures through disulfide bonds or other bonds. The peptides may contain various peptides or hetero- or homo-monomeric subunits that form a structure In certain embodiments, the peptide dimers include those having a disulfide bond or other bond. is an intramolecular bond. The monomeric subunits of peptide monomeric inhibitors and peptide dimeric inhibitors Cyclization of the unit has been shown to increase the potency and selectivity of peptide inhibitors. In certain embodiments, the peptide dimer inhibitor comprises two dimers within the peptide dimer inhibitor. One or more intermolecular bonds linking two monomeric peptide subunits, e.g., two Pe may contain intermolecular bridges between n residues (one in each peptide monomer subunit) .

[0067] The present invention provides peptide inhibitors that bind to IL-23R, which may be monomeric or dimeric. In certain embodiments, the peptide inhibitor inhibits the binding of IL-23 to IL-23R. In certain embodiments, the IL-23R is human IL-23R and inhibits IL -23 is human IL-23. In certain embodiments, the peptide inhibitors of the present invention are , inhibits the binding of IL-23 to IL-23R by at least 20% compared to a negative control peptide , at least 30%, at least 40%, at least 50%, at least 60%, less The binding is reduced by at least 70%, at least 80%, or at least 90%. are known in the art and can be used in ELISA, as described in the accompanying Examples. Assays included.

[0068] In certain embodiments, peptide inhibitors of the invention are useful for inhibiting IL-2, e.g., IL-23. To inhibit binding to IL-3R (e.g., human IL-23 and human IL-23R), Less than mM, less than 1 mM, 500 nM to 1000 nM, less than 500 nM, less than 250 nM, Less than 100nM, less than 50nM, less than 25nM, less than 10nM, less than 5nM, less than 2nM , less than 1 nM, or less than 5 mM. Methods for determining activity are known in the art. The present invention also encompasses any of those known in the art and those described in the accompanying examples.

[0069] In certain embodiments, the peptide inhibitors of the present invention exhibit increased activity compared to a control peptide. Enhanced stability, increased gastrointestinal stability, simulated intestinal fluid (SIF) or simulated gastric fluid (S GF) and / or under redox conditions (DTT). In certain embodiments, the control peptide is an unrelated peptide having the same or similar length. In certain embodiments, the control peptide is identical to or highly related to the peptide inhibitor. A peptide having a similar amino acid sequence (e.g., greater than 90% sequence identity). In embodiments, the control peptide is an amino acid sequence identical to or highly related to the peptide inhibitor. have a sequence identity (e.g., greater than 90%), but e.g., two sequences in the reference peptide It does not have a cyclized structure through an intramolecular bond between amino acid residues or is dimerized. In certain embodiments, the peptide is free of or does not contain a stabilizing conjugate. The only difference between the peptide inhibitor and the control peptide inhibitor is that the peptide inhibitor one or more amino acid substitutions that introduce one or more amino acid residues into the peptide inhibitor, The amino acid residue(s) bound to the peptide inhibitor form an intrasulfide bond with another amino acid residue in the peptide inhibitor. The key feature is the formation of sulfide or thioether bonds. An example of a control for this is one of the monomeric subunits present in a peptide dimeric inhibitor. An example of a control for a peptide inhibitor containing a conjugate is A peptide having the same sequence but without the conjugated moiety. The reference peptide is a peptide corresponding to the region of IL-23 that binds to IL-23R (e.g., It is a peptide that does not occur in nature.

[0070] Methods for determining peptide stability are known in the art. In embodiments, the stability of peptide inhibitors is determined using SIF as described, for example, in Example 3. In certain embodiments, the stability of a peptide inhibitor is determined using an assay such as: For example, as determined using an SGF assay, as described in Example 3. In embodiments, the peptide inhibitors are capable of producing SIF or When exposed to SGF or DTT, the Half-lives of more than 1, 90, 120, 3, or 4 hours (e.g., SIF In certain embodiments, the temperature is about 25 °C, about 4 °C, or about 37 °C, and the pH is physiological pH, i.e., about 7.4. do.

[0071] In some embodiments, the half-life can be determined using any suitable method known in the art. For example, in some embodiments, the stability of the peptides of the invention is measured in vitro using The peptides were incubated with pre-warmed human serum (Sigma) at 37°C. Typically, samples are taken at various time points for up to 24 hours and the peptides are analyzed. The peptide or peptide dimer is separated from the serum protein and then LC-MS is used to identify the corresponding The stability of the samples was analyzed by analyzing the presence of peptides or peptide dimers. can be.

[0072] In some embodiments, the peptide inhibitors of the present invention exhibit improved activity compared to a control peptide. The solubility may be determined by any suitable method known in the art. In some embodiments, the techniques for determining solubility may be Suitable methods known in the art include the use of various buffers (acetate pH 4.0, acetate pH 5.0, , Phosphate / Citrate (Phos / Citrate) pH 5.0, Citrate Phosphate (P hos Citrate) pH 6.0, Phosphate pH 6.0, Phosphate pH 7.0, Phosphate p H7.5, Strong PBS pH7.5, Tris pH7.5, Tris pH8.0, Glycine pH 9.0, water, acetic acid (pH 5.0 and others known in the art). This involves incubating the sample and testing for aggregation or solubility using standard techniques. These include, for example, visible precipitation, dynamic light scattering, circular dichroism, and measuring surface hydrophobicity. Examples of suitable dyes include, but are not limited to, fluorescent dyes for detecting globulin, agglutination, or fibrillation. In some embodiments, improved solubility is achieved by determining whether the peptide is more soluble in a given liquid than a control peptide. In some embodiments, improved solubility means that the A peptide aggregates less than a control peptide in a given liquid under a given set of conditions. It means to have.

[0073] Certain compounds are advantageous for achieving high compound concentrations in intestinal tissue when delivered orally. In embodiments, the peptide inhibitors of the present invention are stable in the gastrointestinal (GI) environment. Intraductal proteolytic metabolism involves the production of enzymes secreted from the pancreas into the lumen or produced as brush border enzymes. Enzymes produced (pepsin, trypsin, chymotrypsin, elastase, aminopeptides) Proteases (including carboxypeptidases A / B) typically cleaves peptides and proteins in an extended conformation. Within the cell wall, disulfide bonds are broken, resulting in linear peptides and rapid proteolysis. This luminal redox environment is mainly driven by the Cys / CySS redox cycle. In the intestinal cells, the relevant activities are CYP450 and UDP-glucuronidation. It contains many digestive enzymes, including α-transferases. 10 ~10 12 CF Bacteria present in the large intestine at concentrations in the range of U / mL constitute another metabolic barrier. In embodiments, the peptide inhibitors are soluble in water, ranging from highly acidic (pH 1.5-1.9) in the stomach to soluble in water in the small intestine. It appears to be in the basic range (pH 6-7.5) and then in the colon, where it is in the slightly acidic range (pH 5-7). Such peptide inhibitors are stable in the intestine for 3-4 hours and It is transported through various GI compartments, a process that is estimated to take 6 to 48 hours in the colon. It is stable during the passage of peptide inhibitors.

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

[0075] In certain embodiments, the peptide inhibitors of the present invention inhibit or inhibit IL-23 mediated inflammation. In related embodiments, the peptide inhibitors of the invention inhibit or reduce, for example, I on the cell surface. by binding to IL-23R and thus inhibiting IL-23 binding to cells. In certain embodiments, the IL-23-mediated secretion of the above cytokines is inhibited or reduced. The peptide inhibitors of the present invention are capable of inhibiting Jak2, Tyk2, Stat1, Stat3, Stat Inhibit or reduce IL-23-mediated activation of Stat5 or Stat6. Methods for determining inhibition of secretion and inhibition of signaling molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling is described, for example, in PCT Publication No. As described in WO2016 / 011208, phospho-Stat3 levels in cell lysates The activity can be determined by measuring the inhibition of bell activity.

[0076] In certain embodiments, the peptide inhibitors may inhibit increased oxidation relative to a control peptide. Various assays that can be used to determine redox stability are available. Any of these peptides of the present invention may be used in combination with other peptides. It can be used to determine the redox stability of inhibitors.

[0077] In certain embodiments, the present invention provides a method for detecting IL-23R binding in vitro or in vivo. or various peptides that associate with and disrupt or block the binding between IL-23 and IL-23R. In certain embodiments, the peptide inhibitor is a peptide inhibitor of human IL-23. In certain embodiments, the peptide inhibitor binds to and / or inhibits human I R. IL-23R and rodent IL-23R. In embodiments, the peptide inhibitor is an inhibitor of both human IL-23R and rat IL-23R. In certain embodiments, the peptide inhibitor binds to and / or inhibits the At least 50%, at least 6%, as determined by the assay described in the specification 0%, at least 70%, at least 80%, at least 90%, or at least 95% % rat IL-23R and they bind and / or inhibit human IL-23R In certain embodiments, the peptide inhibitor inhibits the expression of IL-23R relative to murine IL-23R. selectively binds to and / or inhibits human IL-23R and / or rat IL-23R In certain embodiments, the peptide inhibitor inhibits Rat IL-23R compared to murine IL-23R. In certain embodiments, the peptide inhibitor selectively binds to mouse IL-23R. In certain embodiments, the antibody selectively binds to human IL-23R compared to human IL-23R. Binding of peptide inhibitors to mouse IL-23R was confirmed by the binding of peptide inhibitors to human IL-23R and / or human IL-23R. Less than 75%, less than 50%, and less than 40% of the binding of the same peptide inhibitor to the rat IL-23R , less than 30%, less than 20%, or 10%. Selectively binds and / or inhibits IL-23R and / or rat IL-23R In certain embodiments of the peptide inhibitor, the peptide inhibitor is human IL-23R or The presence of additional amino acids present in mouse IL-23R but not in rat IL-23 In one embodiment, the IL-23R binds to a region of the IL-23R that is disrupted by the IL-23R. The additional amino acids present are from about amino acid residue 315 to about amino acid residue 316 of the mouse IL23R protein. The region corresponding to amino acid residue 340, e.g., the amino acid region NWQPWSSPFVHQTS QETGKR (SEQ ID NO: 239). In certain embodiments, the peptide inhibitor is within about It binds to the region of human IL-23R from amino acid 230 to approximately amino acid residue 370.

[0078] In certain embodiments, the peptide inhibitors exhibit GI-restricted localization following oral administration. In certain embodiments, greater than 50%, greater than 60%, or greater than 70% of orally administered peptide inhibitors , greater than 80%, or greater than 90% are localized to gastrointestinal organs and tissues. In this study, plasma levels of orally administered peptide inhibitors were measured in the small intestinal mucosa, colonic mucosa, or proximal Less than 20%, less than 10%, less than 5%, and less than 2% of the levels of peptide inhibitors found in the colon less than, less than 1%, or less than 0.5%.

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

[0080] In certain embodiments, the peptide inhibitors of the present invention comprise one or more modified or non-naturally occurring amino acids. In some embodiments of the invention, the peptide inhibitor comprises a hydroxyamino acid as shown in Table 1A. In certain embodiments, the peptide inhibitors of the present invention comprise one or more unnatural amino acids. is an amino acid sequence or peptide inhibitor structure shown in any one of the tables herein. Any of the structures described herein, including, but not limited to, This includes any of the following:

[0081] The present invention also provides the peptide inhibitors described herein, either in free or salt form. Thus, among the peptide inhibitors described herein, Embodiments of any of the above (and related methods of use thereof) may include pharmaceutically acceptable carriers of the peptide inhibitor. Contains acceptable salts.

[0082] The present invention also relates to a method for the preparation of a medicament ... The peptide inhibitors described herein include, but are not limited to, and any variant thereof, wherein one or more L-amino acid residues are replaced by the D-isomer of the amino acid residue. For example, L-Ala is replaced with D-Ala.

[0083] The peptide inhibitors described herein include isotopically labeled peptide inhibitors. In certain embodiments, the present disclosure provides methods for determining whether one or more atoms have an atomic mass or an atomic mass that is normally found in nature. or mass number of an atom that has a different atomic mass or mass number from that of the atom that has the same atomic mass or mass number. Without the benefit of any particular fact, the various formulas and structures presented herein may be used or may be combined with other compounds. The present compounds incorporate the same peptide inhibitors as any of those listed. Examples of rare isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine; For example, each 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 include: ,for example, 3 H and 14 Radioisotopes such as C are incorporated into drugs and / or or substrate tissue distribution assays. 2 H and others Substitution at the hydroxyl group may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased This may result in an increased in vivo half-life or reduced dosage requirements.

[0084] The present invention also provides a method for the preparation of a linker comprising any of the specific linker moieties described herein. any of the peptide monomeric inhibitors described herein linked to a carrier moiety In certain embodiments, the linker is attached to the N-terminal or C-terminal amino acid, and in other embodiments, the linker is attached to an internal amino acid. The linker may be a linker between two internal amino acids, e.g., two monomeric subunits that form a dimer. In some embodiments of the invention, the peptide blocker is attached to each of the internal amino acids of the peptide. The inhibitor is attached to one or more linker moieties as shown.

[0085] The present invention also provides at least one peptide sequence for the peptide inhibitors described herein. at least 90%, at least 95%, at least 98%, or at least 99% sequence identity In certain embodiments, the present invention includes peptides having the formula: The peptide inhibitors of the invention comprise a core peptide sequence and one or more N-terminal and / or may contain C-terminal modifications (e.g., Ac and NH2), and / or one or more conjugated phosphorus As used herein, a core peptide includes a core moiety and / or a half-life extending moiety. A peptide sequence is the amino acid sequence of a peptide without such modifications and conjugations. For example, 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 (sequence number 240).

[0086] In certain embodiments, the peptide inhibitors or monomeric subunits of the peptide inhibitors of the present invention The units are composed of 7 to 35 amino acid residues, 8 to 35 amino acid residues, and 9 to 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 acid residues, or 10 to 18 amino acid residues, and optionally a conjugated chemical moiety, e.g. For example, the amino acid sequence may contain or be free of one or more additional non-amino acid moieties, such as PEG or a linker moiety. In certain embodiments, any embodiment of Formula I The peptide inhibitors of the present invention (or a single one thereof) include, but are not limited to, (multimeric subunits) is greater than 10, greater than 12, greater than 15, greater than 20, greater than 25, greater than 30, or greater than 35 In certain embodiments, the peptide is a peptide of more than 30 amino acids, for example, 35-50 amino acids. The inhibitor (or its monomeric subunit) 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 this study, the monomeric subunit of a peptide inhibitor (or peptide monomeric inhibitor) was , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and comprises or consists of 35 amino acid residues. The monomeric subunits of the peptide inhibitors contain 10 to 23 amino acid residues, and optionally , one or more additional non-antigenic molecules, such as conjugated chemical moieties, e.g., PEG or linker moieties. In various embodiments, the monomeric subunits comprise or consist of amino acid moieties. 7-35 amino acid residues, 7-20 amino acid residues, 8-20 amino acid residues , 9 to 20 amino acid residues, 10 to 20 amino acid residues, 8 to 18 amino acid residues , 8 to 19 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues, or comprises or consists of 10 to 18 amino acid residues. In certain embodiments of any of the various formulas provided herein, X is a group consisting 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, containing 9 to 18 amino acid residues, or 10 to 18 amino acid residues, or It consists of:

[0087] Certain exemplary peptide inhibitors described herein are those consisting of 12 or more amino acid residues. However, the present invention also provides for 7, 8, 9, 10, or 11 amino acid residues. Any of the peptide sequences described herein, including peptide inhibitors having a group For example, the peptide inhibitors of the present invention include peptide inhibitors containing fragments of X4 to X9, X4~X10, X4~X11, X4~X12, X4~X13, X4~X14, X4~X1 5, or a peptide comprising or consisting of X4 to X16. In this embodiment, the present invention is or any of the formulae described herein, wherein one or more of X23 is absent. or those shown in any of the tables provided herein. A peptide having any of the sequences described herein, including but not limited to: Contains inhibitors.

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

[0089] Peptide inhibitors The peptide inhibitors of the present invention have any of the amino acid sequences described herein. and compounds comprising any of the peptide sequences described herein. and compounds having any of the structures described herein, as well as peptides such as The peptide inhibitors of the present invention include dimers of any of the following compounds: For example, the bond between X4 and X9 can be determined before and after a crosslink is introduced between X4 and X9. Exemplary peptides of the present invention include peptides both without and with an attached peptide. It includes an amino acid sequence or structure set forth in any of the accompanying tables.

[0090] In certain embodiments, the present invention provides peptide inhibitors of the interleukin-23 receptor. or a pharmaceutically acceptable salt or solvate thereof, and the peptide inhibitor is represented by the formula (I ): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(I) (SEQ ID NO: 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, Ab u, 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, Ab u, or (D) Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, 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(A c) 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 related embodiments, the present invention provides peptide inhibitors of the interleukin-23 receptor, includes pharmaceutically acceptable salts or solvates thereof, and the peptide inhibitor is of formula (II): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(II) (SEQ ID NO: 237) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-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, and 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-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or T rp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen , Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, 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(A c) or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or non-existent; 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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 peptide inhibitors of the interleukin-23 receptor, or wherein the peptide inhibitor is of formula (V): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(V) (SEQ ID NO: 238) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-MeTyr, Lys(Ac), Lys(Y1-Ac) or absent, wherein 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, and 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-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), Homo-Lys(Ac), 1-Na l, 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-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, Ala, cyclohexyl Ala, 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(A c) 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, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, 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)Se r, (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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, alpha-MeTyr, alpha-MeAsp, or absent; The peptide inhibitors are cyclized via the bond between X4 and X9, and the peptide inhibitors are intercalated. -Inhibits the binding of leukin-23 (IL-23) to the IL-23 receptor.

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

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

[0096] Certain embodiments of peptide inhibitors of formula (V) or any other formula disclosed herein In terms of structure, X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-Me Gln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys (Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-L In certain embodiments, X5 is Asp or C ys.

[0097] Certain embodiments of peptide inhibitors of formula (V) or any other formula disclosed herein In morphology, 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), A Rufa-MeLys(Ac), Dab(Ac), Dap(Ac), Homo-Lys(Ac) In certain embodiments, X8 is 1-Nal or 2-Nal is.

[0098] Certain embodiments of peptide inhibitors of formula (V) or any other formula disclosed herein In the form, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Alpha-MeLys, Alpha-MeLeu, Alpha-MeArg, Alpha-MeP he, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha -MeTyr, Ala, cyclohexyl Ala, Lys, or Aib. In this embodiment, X12 is Ala, cyclohexyl Ala, or Lys.

[0099] Certain embodiments of peptide inhibitors of formula (V) or any other formula disclosed herein In the form, X13 is Glu, Cit, Gln, Lys(Ac), alpha-MeArg , alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-M e-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo- In certain embodiments, X13 is Lys, P EG-Lys, β-homoGlu, or Lys(Y2-Ac), wherein Y2 is It is an amino acid.

[0100] Certain embodiments of peptide inhibitors of formula (V) or any other formula disclosed herein In the form, X16 is Glu, Phe, Lys, Asn, Trp, Gly, Thr, Pr o, (D)Arg, (D)Phe, (D)Glu, (D)Thr, (D)Leu, (D) Gln, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha alpha-MeLys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp In certain embodiments, X16 is Ala, Asp, T yr, Arg, Leu, Gln, Ser, Ile, 1-Nal, 2-Nal, (D)Al a, (D)Asp, (D)Tyr, (D)Arg, (D)Leu, (D)Ser, or (D)Ile.

[0101] A peptide of formula (I), formula (II), or formula (V), or any of the peptides disclosed herein. Any other peptide inhibitor, or one of the peptide dimers disclosed herein In certain embodiments of either or both monomeric subunits, the peptide inhibitor comprises X4 and X9 and In certain embodiments, the bond is a disulfide bond or In certain embodiments, the peptide inhibitor is an interleukin- It inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0102] In some embodiments, the peptides of formula (I), (II), and (V) (or the present invention) Any other peptide inhibitor disclosed herein, or a peptide inhibitor disclosed herein X4 and X9 of one or both monomer subunits of the dimer are Cys, Ar 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] Peptides of formula (I), (II), and (V), or any of the peptides disclosed herein Other peptide inhibitors, or one or both of the peptide dimers disclosed herein In one embodiment of one monomeric subunit, X4 is selected from the group consisting of Abu, Cys, Pen, D-Pe n, or D-Abu, and X9 is Abu, Cys, Pen, D-Pen, or D -Abu, and the intramolecular bond is a thioether bond. 4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu or D-Abu and X9 is Cys. The intramolecular bond is a thioether bond, and the S of Cys is attached to the γ-C of Abu. In certain embodiments, X4 is Abu or D-Abu and X9 is , Cys, the intramolecular bond is a thioether bond, and the intermolecular bond is -X3-N( H)—C(H)(CHCH—S*—)C(O)—X—, where “S*” is , S in Cys.

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

[0105] A peptide of formula (I), formula (II), (V), (IIIa), or (IVa), or any other peptide inhibitor disclosed herein, or and those having one or both monomer subunits of a dimer of tide. Certain embodiments of any of the peptide inhibitors or monomeric subunits described in In an embodiment, X7 and X11 are both W. In certain embodiments of any of the sets, X7 and X11 are both Trp In certain embodiments, X7 is Trp and X11 is not Trp. In certain embodiments, X7 is Trp and X11 is 2-Nal or Trp(5-F In certain embodiments, X7 and X11 are both W and X10 is P he[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)] , Phe(4-OMe), or alpha-MeTyr. X7 and X11 are both W, and X10 is Phe[4-(2-aminoethoxy) ], Phe[4-(2-acetylaminoethoxy)], Phe(4-OMe), or X11 is 2-Nal or Trp(5-F). In certain embodiments, X7 is Trp and 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 and X10 is Phe[4-(2- aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe( 4-OMe), or alpha-Me-Tyr, and X11 is 2-Nal or Tr p(5-F).

[0106] In certain embodiments, X7 and X11 are both W, or X7 is Tr p, X11 is 2-Nal or Trp(5-F), and X10 is Phe[4 -(2-acetylaminoethoxy)], Phe[4-(2-aminoethoxy)], Phe (CONH2), or alpha-Me-Tyr, and X4 and X9 are thioethers. These are amino acid residues that can form sulfonyl bonds or disulfide bonds. In an embodiment, 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 molecule The internal bond is a thioether bond.

[0107] A peptide of formula (I), formula (II), formula (V), formula (IIIa), or formula (IVa) or any other peptide inhibitor disclosed herein, or In certain embodiments, one or both monomeric subunits of a peptide dimer are X5 to X8 are 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) Sequence number 245), NT(2-Nal)Q (sequence number 246), NTWE (sequence number 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 (V), formula (IIIa), or formula (IVa), X X5 to X8 are the following tetrapeptide sequences: QTWQ (SEQ ID NO: 242), QTWE (SEQ ID NO: 243), 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), 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), 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 compound of formula (I), (II), (V), (IIIa), or (I Va) or any other peptide inhibitor disclosed herein, or One or both monomeric subunits of the peptide dimers disclosed herein may be X It contains Asn residues at both X14 and X15.

[0109] In certain embodiments, a compound of formula (I), (II), (V), (IIIa), or (I A peptide of Va, or any other peptide inhibitor disclosed herein, or One or both monomeric subunits of the peptide dimers disclosed herein may be X4 at least one, at least two, at least three, or at least In certain embodiments, the amino acid N-terminal to X4 also contains four amino acid residues. At least one, at least two, at least three, or at least four of the acid residues are the same amino acid residues as each other. In certain embodiments, they are all the same as each other. In certain embodiments, the amino acid residues N-terminal to X4 are the same. At least one, at least two, at least three, or at least four of the , F, E, Q, T, and (D)-Arg). In certain embodiments, X0 to X3 are any of the corresponding residues shown in any of the peptides in Tables 2 to 5. The same as shown in either

[0110] In certain embodiments, a compound of formula (I), (II), (V), (IIIa), or (I Va) or any other peptide inhibitor disclosed herein, or One or both monomeric subunits of the peptide dimers disclosed herein may be X At least two, at least three, at least four, or at least four carboxyl groups on the 14 In certain embodiments, X1 and X2 each contain 5 or at least 6 amino acid residues. At least two, at least three, or at least four of the amino acid residues on the carboxy side of at least four, at least five, or at least six amino acid residues are the same as each other In certain embodiments, they are all the same residue as each other. In certain embodiments, X14 and X15 are both N. At least two, at least three, or at least two of the amino acid residues on the carboxy side At least four are selected from N, E, F, K, W, G, T, P, K, F, or Q. In certain embodiments, X14-X23 are shown in any of the peptides in Tables 2-5. The corresponding residues are the same as those shown.

[0111] In certain embodiments, a compound of formula (I), (II), (V), (IIIa), or (I Va) or any other peptide inhibitor disclosed herein, or One or both monomeric subunits of the peptide dimers disclosed herein may be N In certain embodiments, the aryl group represented by formula (I), (II), (V), (IIIa) ), or (IVa) peptides and any peptide inhibitors disclosed herein, Contains a C-terminal NH2 group.

[0112] In certain embodiments, the peptide inhibitors of the invention are those described herein, e.g., in Tables 2-6. In certain embodiments, the present invention comprises or consists of the amino acid sequence shown. Suitable peptide inhibitors have the structures shown herein, for example, in Tables 2-6. In some embodiments, the Phe[4-(2- Any of the residues of Phe[4-(2-acetylaminoethoxy)] is It may be replaced by ).

[0113] In additional embodiments, the present invention provides isosteric substitutions of one or more amino acid residues X0 to X23. of formula (I), (II), (V), (IIIa), or (IVa), or of table Peptide inhibitors, including peptides containing variants of any of the sequences shown in 2 to 6. In certain embodiments, isosteric substitutions are conservative amino acid substitutions, and certain embodiments In embodiments, an isosteric substitution is a substitution of an amino acid with an analogue.

[0114] In a further embodiment, the present invention provides a method for the preparation of a nucleotide sequence comprising one or both of amino acid residues X4 and X9. contains different amino acid residues (or chemicals) at X4 and X9, The acid residue may be, for example, to form an intramolecular bond or a triazole ring within the peptide. Formula (I), (II), (V), (IIIa), or or a peptide containing a variant of any of the sequences shown in Tables 2 to 6. In certain embodiments, the bond is a disulfide bond. , thioether bond, lactam bond, triazole ring, selenoether bond, diselenide bond, or an olefinic bond.

[0115] For example, in certain embodiments, X4 is selected from the group consisting of Abu, 2-chloromethylbenzoic acid, methyl Capto-propionic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propionic acid acid (3-choro-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 thiol. In certain embodiments, X4 forms a thioether bond with X9. X9 is a 2-methylbenzoyl moiety that can be selected from Cys, N-Me-Cys, D In certain embodiments, the amino acid sequence is selected from -Cys, hCys, Pen, and D-Pen. X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain cases, a peptide monomer of any of the formulas and peptides described herein X4 may be a modified Ser, a modified hSer (e.g., H omo-Ser-Cl), suitable isosteres, and the corresponding D-amino acids. In other cases, X4 has 1 to 4 carbon atoms and forms a thioether bond with X9. Optionally, X4 is a modified 2-amino group that forms a thioether bond with X9. In some embodiments, X4 is a 5- or 6-membered alicyclic acid having a -methyl group. In certain embodiments, X4 is a 2-methylbenzoyl moiety. , Pen, and a 2-methylbenzoyl moiety. X4 consists of modified Ser, modified hSer, the appropriate isostere, and the corresponding D-amino acid. In one embodiment, X4 is selected from the group consisting of hSerCl (a thioether bond) and X9. and thus Cl is removed), or hSer precursors (e.g., homoS In other cases, X4 has 1 to 4 carbons and is thiolated with X9. An aliphatic acid that forms an ether bond. In some cases, X4 can form a thioether with X9. It is a 5- or 6-membered alicyclic acid with a modified 2-methyl group that forms a bond. In the example, X4 is a 2-methylbenzoyl moiety. X4 is not an amino acid, but is bound to X9. In certain embodiments, X1, X2, and X3 are absent. In some embodiments, X4 is conjugated or bonded to X5. In certain embodiments, X4 is an aromatic amino acid. In other embodiments, X4 is a carboxylic acid, while in other embodiments, X4 is a carboxylic acid, for example, to form a thioether bond. In certain embodiments, X4 is another chemical moiety that can be attached to X9. , for X4, selected from any of the non-amino acid moieties described herein In certain embodiments where X4 is a different chemical moiety, X1, X2, and X3 is absent and another chemical moiety is bonded or conjugated to X5. In this embodiment, X4 is, for example, 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3- 3-Chloropropanoic acid, 4-Chlorobutyric acid , 3-chloroisobutyric acid, etc., are defined as chemical moieties containing groups such as chloride. However, those skilled in the art will appreciate that once the peptide has undergone cyclization, a thioether bond is formed between X4 and X9. It will be appreciated that upon forming the chloride bond, the chloride group is no longer present. The description of the chemical moiety in X4 containing a reactive group such as chloride is intended to include the group with chloride, and The present invention means both groups having no chloride, i.e., groups after forming the bond with X9. Also, compounds having the same structure as shown in any of the other formulas or tables described herein. However, the present invention also includes peptides in which the thioether bond is in the reverse orientation. In general, the amino acid residue or other chemical moiety shown at X4 is instead shown at X9. and the amino acid residue shown at X9 is instead present at X4, i.e., The amino acid residue containing the sulfur of the thioether bond is located at X4 instead of X9, and X4 and thioether bond are An amino acid residue or other moiety having a carbon side chain capable of forming an ether bond , X9. However, in this reverse orientation, The amino acid or chemical moiety in this context is one that contains a free amine. For example, in certain embodiments In this embodiment, the amino acid at X9 is a protected homoserine, such as homoserine (OTBDMS). Serine. Thus, a peptide inhibitor of any of the formulas described herein In certain reverse orientation embodiments, X9 has a side chain with one or two carbons, and X4 X4 is an amino acid residue that forms a thioether bond with Cys, N-Me-Cys , D-Cys, HCys, Pen, and D-Pen. and specific examples of amino acid residues and other chemical moieties present at the corresponding positions in the table are: As described herein.

[0116] In certain peptides that form a thioether bond between X4 and X9, X4 is , an amino acid having a carbon side chain capable of forming a thioether bond with X9, an aliphatic acid , alicyclic acid, or modified 2-methyl aromatic acid, and X9 forms a thioether bond with X4. In certain embodiments, X4 is a sulfur-containing amino acid capable of forming Cy s, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, As p, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Gl u, D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propionic acid, mer Captobutyric acid, 2-chloroacetic acid, 3-chloropropionic acid (3-choro-pro panoic acid), 4-chlorobutyric acid, 3-chloroisobutyric acid, Abu, β- Dihydro-Ala-OH, Propargylglycine, 2-(3'-butenyl)glycine, 2-Ala 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine, 2-(5'-hexenyl)glycine, X9 is Cys, Pen, hCys , D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Va l, Phe, Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine 2-allylglycine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine In certain embodiments, the glycine is 2-(5'-hexenyl)glycine, or 2-(5'-hexenyl)glycine. X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propionic acid, mercapto 4-chlorobutyric acid, 2-chloroacetic acid, 3-chloropropionic acid, 4-chlorobutyric acid, 3-chloro rho-isobutyric acid, and X9 is Abu, Cys, Pen, hCys, D-Pen, DC ys, 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; The intramolecular bond is a lactam bond.

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

[0119] In certain embodiments, X4 and X9 are each 2-allylglycine, 2-(3'- 2-(4'-pentenyl)glycine, or 2-(5'-hexenyl)glycine It is a peptide inhibitor, 2-(5´-hexenyl)glycinem. The inhibitor (or monomeric subunit) undergoes ring closing metathesis. cyclization via thasis) to give the corresponding olefin / "staple peptide" Drop.

[0120] In certain embodiments, X4 is 2-chloromethylbenzoic acid, mercapto-propio carboxylic acid, mercaptobutyric acid, 2-chloroacetic acid, 3-chloropropionic acid (3-chloro o-propanoic acid), 4-chlorobutyric acid, 3-chloroisobutyric acid, is hSer(Cl), and 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(C l), 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. do.

[0121] In certain embodiments, X4 is 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3 -chloro-propionic acid (3-choro-propanoic acid), 4-chloro rho-butyric acid, 3-chloro-isobutyric acid, Abu, or Sec, and 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, for any of the formulas described herein, X3 is , (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-MePhe , alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-M In other embodiments, X3 is Lys(Ac) or is Lys(Y1-Ac), where Y1 is an amino acid. is a natural amino acid. In another embodiment, Y is a (D) amino acid. In this embodiment, Y is Glu, Phe, Tyr, Ser, Arg, Leu, or P It is ro.

[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(A c), beta-homo Gln, Cit, Glu, Phe, Asn, Thr, Val, Aib , alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLy s(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Trp In other embodiments, X8 is 1-Nal or 2-Nal.

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

[0127] In some embodiments, for any of the formulae described herein, X are Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-Me Glu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, Al Fa-MeLys(Ac), Dab(Ac), Dap(Ac), Homo-Lys(Ac), or Lys. In other embodiments, X13 is Lys, PEGylated Lys, b-homo Glu, or Lys(Y2-Ac), wherein Y2 is an amino acid. In another embodiment, Y2 is a (D) amino acid. In certain embodiments, Y2 is Glu, Phe, Asn, Thr, Asp, Tyr, S 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, for any of the formulae described herein, X are 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 In another embodiment, X 16 are 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 provides peptide inhibitors of the interleukin-23 receptor. and the peptide inhibitor comprises a compound of 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, alkyl sulfonate, acid, γ- Glu or pGlu, added to the N-terminus, and either alone or in combination with any of the above PEGylated forms (e.g., 200 Da to 60,000 Da) as spacers; 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. In embodiments, R 1 is a bond, hydrogen, or Ac. In certain embodiments, R 1 teeth, 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-X 14-X15-X16(XII) (SEQ ID NO: 275) wherein: X2 is Arg, (D)Arg, Gln, or absent; X3 is (D)Arg, Phe, (D)Phe, Lys, (D)Lys, Lys(Y1- (D) Lys(Y1-Ac), or absent, wherein Y1 is an amino acid. is an acid or Y1 is absent; X4 is Cys, (D)Cys), alpha-MeCys, Abu, (D)Pen, Pe n, (D) Pen sulfoxide, or Pen sulfoxide; X5 is Cit, Lys, Asn, Asp, Glu, Lys(Ac), or Gln the law of nature; X7 is Trp, substituted Trp, or 1-Nal; X8 is Gln, Lys, Lys(Ac), a-MeLeu, Cit, Glu, 1-Na l, 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, tetrahydro Lopiran Ala, or Lys(Peg12); X13 can be Glu, β-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or or (D) Lys(Y2-Ac); wherein Y2 is an amino acid or Y2 is non-existent; X14 is Asn, Asp, Cit, or Lys(Ac); X15 is Asn, Lys, Lys(Ac), Cit, Asp, Gly, Ala, bA la, or Sarc; X16 is an amino acid or is absent; the substituted Trp is a halo- or aza-Trp. is a substituted Trp; In the formula, X4 and X9 can form a disulfide bond or a thioether bond. Alternatively, they may be linked via disulfide or thioether bonds.

[0133] In one embodiment, the substituted Trp is fluoro-substituted Trp. Trp is azaTrp. In certain embodiments, 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 an embodiment, X2 is absent.

[0135] In one embodiment, X7 is Trp or Trp(5-F). , 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: 27 6) 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. and X4 and X9 are linked together to form a thioether bond. In this configuration, X4 is Pen, and X4 and X9 are linked together by a disulfide bond. Form a union.

[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: 2 77); or X3-Pen-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)] -(2-Nal)-X12-X13-X14-Asn-X16(XIVb) (SEQ ID NO: 2 78); wherein X3, X5, X8, X9, X12, X13 , X14, or X16 are 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 the group consisting of formula XVa, XVb, XVc, and XV d: X3-Abu-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy) ]-(2-Nal)-X12-X13-X14-Asn-X16(XVa) (SEQ ID NO: 2 79); X3-Pen-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy) ]-(2-Nal)-X12-X13-X14-Asn-X16(XVb) (SEQ ID NO: 2 80); X3-Abu-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy) ]-(2-Nal)-X12-X13-X14-Asn-X16(XVc) (SEQ ID NO: 2 81); 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, X1 4, 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. Forms an ether bond.

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

[0147] In certain embodiments, with respect to formula XI, X is selected from the group consisting of formulas XVIa, XVIb, XVIc, XV Id, 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: No. 283); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIb)(SEQ ID NO: No. 284); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIc)(SEQ ID NO: No. 285); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVId)(SEQ ID NO: No. 286); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIe)(SEQ ID NO: No. 287); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIf)(Sequence No. No. 288); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIg)(SEQ ID NO: No. 289); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIh)(Sequence No. No. 290); wherein X3, X8, X12, X13, X14, or 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 disulfides. It forms a thioether bond or a thioimide 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 the group consisting of formulas 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(XVI Ia) (SEQ ID NO: 291); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ib) (SEQ ID NO: 292); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ic) (SEQ ID NO: 293); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Id) (SEQ ID NO: 294); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ie) (SEQ ID NO: 295); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI If)(SEQ ID NO:296); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ig) (SEQ ID NO: 297); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ih) (SEQ ID NO: 298); wherein X3, X8, X12, X13, or X1 6 is as described for formula XII.

[0152] In certain embodiments, with respect to formula XI, X is selected from the group consisting of formulas XVIIIa, XVIIIb, XVI IIc, XVIIId, XVIIIe, XVIIIf, XVIIIg, or XVIII h: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIa) (SEQ ID NO: 299); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIb) (SEQ ID NO: 300); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIc) (SEQ ID NO: 301); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IId) (SEQ ID NO: 302); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIe) (SEQ ID NO: 303); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIf)(SEQ ID NO:304); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIg) (SEQ ID NO: 305); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIh) (SEQ ID NO: 306); wherein X3, X8, X13, or X16 is a sequence of the formula As described for XII.

[0153] In certain embodiments, with respect to Formulae XI-XVIIIh, X3 is (D)Arg, P he, (D)Phe, Lys, (D)Lys, Lys(Y1-Ac), (D)Lys(Y 1-Ac) or absent, and Y1 is an amino acid or absent. In one embodiment, Y is a natural amino acid. In another embodiment, Y is a (D)amino acid. In certain embodiments, Y is Glu, Phe, Tyr, Ser, Ar In certain embodiments, X3 is g, Leu, or Pro. In certain embodiments, X3 is absent. In certain embodiments, X3 is (D)Arg. In more specific embodiments, X3 is L In one embodiment, Y is (D)Lys(Y-Ac) or (D)Lys(Y-Ac). In another embodiment, Y is Glu. In another embodiment, Y is In another embodiment, Y is Tyr. In another embodiment, Y is In another embodiment, Y is Ser. In another embodiment, Y is , Arg.

[0154] In certain embodiments, with respect to Formulas XI-XVIIIh, X8 is selected from the group consisting of Gln, Lys, , Lys(Ac), a-MeLeu, Cit, or Glu. , X8 is Gln, Glu, Lys(Ac), or a-MeLeu. In embodiments, X8 is Gln or Lys(Ac). , X8 is Gln.

[0155] In certain embodiments, with respect to formulae XI-XVIIIh, X13 is Glu, b-hydroxybenzoate. MonoGlu, Lys, (D)Lys, Lys(Y2-Ac), or (D)Lys(Y2- Ac); and Y2 is an amino acid or Y2 is absent. In the formula (I), X13 is Glu, Cit, Lys, or Lys(Ac). In an embodiment, X13 is Glu or Lys(Ac).

[0156] In certain embodiments, with respect to Formulae XI-XVIIIh, X16 is absent or or an amino acid. In certain embodiments, X16 is absent. In one embodiment, 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] A variant of any of formulas (I), (II), (V), (IIIa), or (IVa) In certain embodiments of peptide inhibitors, including variants, when X4 is not an amino acid, X1, X2 and X3 are absent. In certain embodiments, X1 is a D-amino acid. 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 embodiments, X19 is a D-amino acid or is absent. In this embodiment, X20 is a D-amino acid or is absent.

[0158] In certain embodiments, a compound of formula (I), (II), (V), (IIIa), or (IVa) The peptides are conjugated to one or more chemical substituents, such as lipophilic substituents and polymer moieties. and these may be referred to herein as half-life extending moieties. In certain embodiments, The peptide of formula (I), (II), (V), (IIIa), or (IVa) may comprise one or more is conjugated to a detectable marker or dye.

[0159] In some embodiments, the peptides of the present invention may be, for example, isovaleric acid, isobutyric acid, valeric acid, When conjugated to an acidic compound such as an acid, the presence of such conjugation is referred to as the acidic form. Thus, for example, but in no way limiting, in some embodiments, isovaler Isovaleryl (e.g., isovaleryl-[Pen]-QTWQ[Pen]-[Phe(4-OMe )]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NG-NH2(sequence Instead of indicating the conjugation of isovaleric acid to a peptide by referring to (number 307), The present application discloses isovaleric acid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[ 2-Nal]-[a-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 30 7) refers to conjugations such as

[0160] In certain embodiments, the peptide inhibitor is described in PCT Application No. PCT / US2014 / 0 30352, PCT Application No. PCT / US2015 / 038370, PCT Application No. PC T / US2015 / 040658, or PCT Application No. PCT / US2016 / 042 680.

[0161] Exemplary Peptide Inhibitors Containing a Pen-Pen Disulfide Bond In certain embodiments, the present invention provides peptide inhibitors of the interleukin-23 receptor. and the peptide inhibitor comprises a compound of 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, alkyl sulfonate, acid, γ- Glu or pGlu, added to the N-terminus, and either alone or in combination with any of the above PEGylated forms (e.g., 200 Da to 60,000 Da) as spacers;

[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-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(IIIa) (SEQ ID NO: 265) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-MeTyr or absent; X4 is Cys, (D)Cys), alpha-MeCys, (D)Pen, or Pen and; X5 is Cit, Glu, Gly, Lys, Asn, Pro, alpha-MeGln, and 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-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or T rp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Pen, or Pen and; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, 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(A c) or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or non-existent; 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, alpha-MeTyr, alpha-MeAsp, or absent; wherein X4 and X9 are capable of forming a disulfide bond.

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

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

[0168] In certain embodiments, X7 and X11 are both W, or X7 is Tr p, X11 is 2-Nal or Trp(5-F), and X10 is Phe[4 -(2-acetylaminoethoxy)], Phe[4-(2-aminoethoxy)], Phe (CONH2), or alpha-MeTyr, and X4 and X9 are disulfides. In certain embodiments, X4 and X5 are amino acid residues capable of forming a bond. Both of the X9 residues are Pen, and the intramolecular bond is a disulfide bond.

[0169] In certain embodiments of peptides of formula (IIIa), X5-X8 are selected from the group consisting of the following tetrapeptides: Peptide 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) is selected from either one of them.

[0170] In certain embodiments, the peptide of formula (IIIa) has at both X14 and X15 In a related embodiment, these peptides contain an Asn residue in X15. At least two, at least three, or at least four amino acid residues on the carboxy side are In certain embodiments, the carboxy amino acid residues are the same as each other. It is the base.

[0171] In certain embodiments of the peptide inhibitors of formula (III), X0, X1, X2, and X3 One or more, two or more, three or more, or all four of the above may not exist. In an embodiment, X0 is absent and / or X1 is absent. In certain embodiments, X0, X1, and X2 are absent. X2 and X3 are absent. In certain embodiments of the peptide inhibitor of Formula III , one or more, two or more, three or more, or all four of X0, X1, X2, and X3 In certain embodiments, X3 is present, i.e., not absent. In certain embodiments, X3 and X2 are present, and in certain implementations In some embodiments, X, X, and X are present, and in certain embodiments, X, X2, X1, and X0 are present, i.e., there is no amino acid at each position. are.

[0172] In certain embodiments of the peptide inhibitors of Formula III, X15, X16, X17, X18, One or more, two or more, three or more of X19, X20, X21, X22, and X23 , 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or all 9 are not present In certain embodiments of the peptide inhibitors of Formula III, X17, X18, X19, and X One or more, two or more, three or more, or all of the 20 may not exist. In an embodiment, one or more, two or more, or all three of X17, X19, and X20 In certain embodiments of the peptide inhibitors of Formula III, X15, X16, One or more of X17, X18, X19, X20, X21, X22, and X23, 2 1 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or all 9 In certain embodiments of the peptide inhibitors of Formula III, X17, X18, One or more, two or more, three or more of X19, X20, X21, X22, and X23 , 4 or more, 5 or more, 6 or more, or all 7 are present. In this state, one or more, two or more, or all three of X18, X19, and X20 , exists.

[0173] In certain embodiments of any of the peptide inhibitors described herein, Any of the amino acids of the peptide inhibitors may be attached by a linker moiety, e.g., PEG. To be continued.

[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) ci)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] (sequence No. 266); [Pen]-X5-X6-X7-X8-[Pen]-[Phe[4-(2-aminoethoxy) ci)]-W-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 267); or [Pen]-X5-X6-X7-X8-[Pen]-[Phe[4-(2-aminoethoxy) ci)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 268) and

[0178] In the formula, X5 to X8 are defined as above, and (i) the N-terminal side of the most N-terminal Pen at least one, at least two, or at least three amino acid residues, or (i i) at least three, at least four, C-terminal amino acid residues of the C-terminal amino acid residue shown above; It further comprises at least 5, at least 6, or at least 7 amino acid residues. In certain embodiments, X5 to X8 are selected from the group consisting of QTWQ (SEQ ID NO: 242), NDWQ (SEQ ID NO: 243), and the like. 243), N(Dab)WQ (SEQ ID NO: 244), NT(1-Nal)Q (SEQ ID NO: 24 5), NT(2-Nal)Q (SEQ ID NO: 246), NTWE (SEQ ID NO: 247), NTW F (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 is selected from the group consisting of those listed in Table 2 or Table III. 3, or the amino acid sequence set forth in Table 2 or Table 3 (if or a pharmaceutically acceptable salt thereof), wherein two Pen residues are linked by a disulfide bond. can be connected via [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 provides peptide inhibitors of the interleukin-23 receptor. and the peptide inhibitor comprises a compound of 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 Alkyl, C1-C6 alkyl, C1-C20 alkanoyl, alkyl sulfonate, acid, gamma -Glu or pGlu, added to the N-terminus, and either alone or in any of the above PEGylated forms (e.g., 200 Da to 60,000 Da) as any spacer;

[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-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(IVa) (SEQ ID NO: 270) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-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, and 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-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or T rp; X9 is Cys, (D)Cys), alpha-MeCys, (D)Abu, (D)Pen , Pen, or Abu; X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, 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(A c) or Lys; X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15 is Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, alpha-MeAsn, alpha-MeTyr, alpha-MeAsp, or non-existent; 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, alpha-MeTyr, alpha-MeAsp, or absent; In the formula, X4 and X9 can form a thioether bond.

[0187] In certain embodiments of the peptide of formula (IVa), the peptide inhibitor is In one embodiment of the peptide of formula (IVa), X 4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain embodiments, the peptide inhibitor is Inhibits binding to the IL-23 receptor.

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

[0189] In certain embodiments of peptides of formula (IVa), X5-X8 are selected from the group consisting of the following tetrapeptides: Tide sequences: QTWQ (SEQ ID NO: 242), NDWQ (SEQ ID NO: 243), N(Dab)W Q (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), N TWQ (SEQ ID NO: 249), and NT[Trp(5-F)]Q (SEQ ID NO: 250) One of these is selected.

[0190] In certain embodiments, the peptide of formula (IVa) has at both X14 and X15 In a related embodiment, these peptides contain a carboxyl group at X15. and at least two, at least three, or at least four amino acid residues on the hydroxyl side. In certain embodiments, the carboxy amino acid residues are the same amino acid residues as each other. is.

[0191] In certain embodiments, the peptide inhibitor of Formula IV is cyclized. In this case, 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 the peptide inhibitor of Formula IV, among X0, X1, X2, and X3, One or more, two or more, three or more, or all four of are not present. In one particular embodiment, X is absent and / or X is absent. X, X, and X are absent. In certain embodiments, X, X, X, and X3 is absent. In certain embodiments of the peptide inhibitor of Formula IV, X0, One or more, two or more, three or more, or all four of X1, X2, and X3 exist. In certain embodiments, X3 is present, i.e., not absent. In certain embodiments, X3 and X2 are present, and in certain embodiments, , X3, X2, and X1 are present, and in certain embodiments, X3, X2, X 1, and X0 are present, ie, an amino acid is present at each position.

[0193] In certain embodiments of the peptide inhibitor of Formula IV, X15, X16, X17, X18, X One or more, two or more, three or more of 19, X20, X21, X22, and X23; There are no four or more, five or more, six or more, seven or more, eight or more, or all nine. In certain embodiments of the peptide inhibitor of Formula IV, X17, X18, X19, and X20 One or more, two or more, three or more, or all of are absent. In this state, one or more, two or more, or all three of X17, X19, and X20 are In certain embodiments of the peptide inhibitor of Formula IV, X15, X16, X17 are absent. , one or more, two or more of X18, X19, X20, X21, X22, and X23 , 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or all 9 In certain embodiments of the peptide inhibitor of Formula IV, X17, X18, X19, One or more, two or more, three or more, four or more of X20, X21, X22, and X23 In certain embodiments, the above, five or more, six or more, or all seven are present. One or more, two or more, or all three of X18, X19, and X20 are present are.

[0194] In certain embodiments of the peptide inhibitor of formula IV, one of X4 or X9 is selected from Ab u, and the other of X4 or X9 is not Abu. In the present invention, 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 inhibitors may be attached by a linker moiety, e.g., PEG. To be continued.

[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)- ci)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] (sequence No. 271); [Abu]-X5-X6-X7-X8-[Cys]-[Phe[4-(2-aminoethoxy)- ci)]-W-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 272); or [Abu]-X5-X6-X7-X8-[Cys]-[Phe[4-(2-aminoethoxy)- ci)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)] (SEQ ID NO: 273) and

[0200] In the formula, X5 to X8 are defined as above, and (i) at least one amino acid sequence on the N-terminal side of Abu (ii) at least two, or at least three amino acid residues; or at least 3, at least 4, at least 5 amino acid residues C-terminal to the C-terminal amino acid residue The amino acid sequence further comprises at least 6, or at least 7 amino acid residues. In this state, X5 to X8 are QTWQ (SEQ ID NO: 242), QTWE (SEQ ID NO: 251), E TWQ (SEQ ID NO: 252), ETWE (SEQ ID NO: 253), QTW-(alpha-MeL eu) (SEQ ID NO: 254), QTW-(alpha-MeLys) (SEQ ID NO: 255), Q TW-(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: Sequence number 259), QTWW (sequence number 260), QTWAib (sequence number 261), QT WT (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 provides an amino acid sequence as shown in either Table 4 or 5. a peptide comprising or consisting of an amino acid, or any of Tables 4 or 5 A peptide inhibitor (or a pharmaceutically acceptable salt thereof) comprising or consisting of the structure shown in In certain embodiments, the peptide does not include a conjugate moiety, but includes an Ab In certain embodiments, the peptide or inhibitor contains two Abu residues and a Cy residue. between the s residue or in parentheses following the term "cyclo" to indicate the presence of a cyclic structure In certain embodiments, the inhibitor comprises a thioether bond between the outermost amino acids of The peptide sequences of exemplary inhibitors are shown in Tables 4 and 5 from N-terminus to C-terminus. The conjugated portion and the N-terminal Ac and / or C-terminal NH groups are shown. , indicated by "cyclo" as shown in Table 5, and bracketed Abu in X4 and X9 The structure of an exemplary peptide inhibitor shows the presence of a thioether bond between Cys and β-Cys. Examples 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 a peptide listed in Table 6. is selected from the [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-carboxylate carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 71); [Biotin]-[PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]- [Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carbo oxy-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]-EN N-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: No. 106); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2- methylethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 1 07); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2- methylethoxy)]-[2-Nal]-[α-MeLeu]-ENN-NH2 (SEQ ID NO: 1 38); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2- methylethoxy)]-[2-Nal]-[3-cyclohexyl-Ala]-ENN-NH2 (SEQ ID NO: 147); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2- minoethoxy)]-[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-A [[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-N al]-[α-MeLeu]-[Lys(Ac)]-NN-[(D)Lys]-NH2) 2-DIG (SEQ ID NO: 184); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-a minoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NNG -NH2 (SEQ ID NO: 195); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-a minoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN- [β-Ala]-NH2 (SEQ ID NO: 196); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-a minoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN- It should be noted that some of the chemical names and sequences might need further verification and adjustment according to the specific context and chemical knowledge to ensure the most accurate translation.[Ahx]-NH2 (SEQ ID NO: 197); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-amino ethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN- [Sar]-NH2 (SEQ ID NO: 198); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-amino ethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)As n)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 218); Ac-[Lys(Ac-Glu)]-[Pen]-NTW-[Lys(Ac)]-[Pe n]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu] -[Lys(Ac)]-NN-NH2 (SEQ ID NO: 223); Ac-[Lys(Ac-Phe)]-[Pen]-NTW-[Lys(Ac)]-[Pe n]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu] -[Lys(Ac)]-NN-NH2 (SEQ ID NO: 224); Ac-[Lys(Ac-Tyr)]-[Pen]-NTW-[Lys(Ac)]-[Pe n]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu] -[Lys(Ac)]-NN-NH2 (SEQ ID NO: 225); Ac-[Lys(Ac-Ser)]-[Pen]-NTW-[Lys(Ac)]-[Pe n]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu] -[Lys(Ac)]-NN-NH2 (SEQ ID NO: 226); ​​​ -[Lys(Ac)]-NN-NH2 (SEQ ID NO: 227); Ac-[Lys(Ac-Leu)]-[Pen]-NTW-[Lys(Ac)]-[Pe n]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu] -[Lys(Ac)]-NN-NH2 (SEQ ID NO: 228); Ac-[Lys(Ac-Pro)]-[Pen]-NTW-[Lys(Ac)]-[Pe n]-[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-MeL eu]-[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-MeL eu]-[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-MeL eu]-[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-MeL eu]-[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-MeL eu]-[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-MeL eu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 235); or Ac-[(D)Lys(Ac-Pro)]-[Pen]-NTW-[Lys(Ac)]- [Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeL eu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 236), or It consists of that.

[0205] In another particular embodiment, the peptide is Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-[Phe[4-(2-A aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NN]-ENN-NH2 (SEQ ID NO: 1); Ac-[Pen]-N-[Dab]-WQ-[Pen]-[Phe[4-(2-aminoethyl) thoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]- ENN-NH2 (SEQ ID NO: 3); Ac-[Pen]-NT-[2-Nal]-Q-[Pen]-[Phe[4-(2-amino Noethoxy)]-[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(A c)]-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-tetrahydropyridine NH]-END-NH2 (SEQ ID NO: 73) Ac-[(D)Arg]-cyclo[[Abu]-QTWEC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NN]-ENN-NH2 (SEQ ID NO: 75); Ac-[(D)Arg]-cyclo[[Abu]-ETWQC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NN]-ENN-NH2 (SEQ ID NO: 76); Ac-[(D)Arg]-cyclo[[Abu]-QTWEC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NH]-END-NH2 (SEQ ID NO: 78); Ac-[(D)Arg]-cyclo[[Abu]-ETWQC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NH]-END-NH2 (SEQ ID NO: 79); Ac-[(D)Arg]-cyclo[[Abu]-ETWEC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NN]-ENN-NH2 (SEQ ID NO: 82); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NN]-ENN-OH (SEQ ID NO: 83); Ac-[(D)Arg]-cyclo[[Abu]-QTWEC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine NN]-ENN-OH (SEQ ID NO: 86); [Ac-[(D)Arg]-cyclo[[Abu]-ETWQC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine Ran]-ENN-OH (SEQ ID NO: 87); [NH2-PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Ph e[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy- tetrahydropyran]-ENN-NH2 (SEQ ID NO: 88); [NH2-PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Ph e[4-(2-aminoethoxy)-(PEG4-NH2)]-[2-Nal]-[4-aminoethoxy] amino-4-carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 90); [NH2-PEG4]-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Ph e[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-carboxylate ci-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 93); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[a-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-tetrahydropyridine NN]-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-carbo oxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 104); Ac-cyclo[[(D)Abu]-NTWQ-[Pen]]-[Phe[4-(2-amino Noethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-N H2 (SEQ ID NO: 136); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[2-Nal]-C]-[Ph e[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]-[Ph e[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-carboxylate 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: 14 2); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]- [2-Nal]-[α-MeLeu]-[Lys(Ac)]-ND-NH2 (SEQ ID NO: 1) 43); Ac-[Pen]-NTWE-[Pen]-[Phe[4-(2-aminoethoxy)]- [2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 1) 45); Ac-[Pen]-DTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]- [2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH2 (SEQ ID NO: 1) 46); Ac-[(D)Arg]-cyclo[[Abu]-QTW-[Lys(PEG12)]-C ]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxylate carboxy-tetrahydropyran]-ENN-NH2 (SEQ ID NO: 154); Ac-[(D)Arg]-cyclo[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyridine 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-A methylethoxy)]-[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]-N H2 (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-CON H2)]-[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-Na l]-[α-MeLeu]-[Lys(Ac)]-NN-[Lys(Ac)]-NH2( SEQ ID NO: 182); Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH2)]-[2-Na l]-[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: 1,89); Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-Aminoethoxy)]- [2-Nal]-[α-MeLeu]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 1 90); Ac-[Pen]-NTW-[Cit]-[Pen]-[Phe[4-(2-Aminoeth oxy)]-[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-A methylethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN- [(D)Arg]-NH2 (SEQ ID NO: 199); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-A methylethoxy)]-[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]-[Ly s(Ac)]-NN-NH2 (SEQ ID NO: 202); Ac-[Pen]-NT-[Trp(5-F)]-[Lys(Ac)]-[Pen]-[ Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Ly s(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-A (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-A (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-A (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-A (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-A [(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 - a [(2 - aminoethoxy)]-[2 - Nal]-[α - MeLeu]-[Lys(Ac - Leu)] -NN-[(D)Ile]-NH2 (SEQ ID NO: 214);<000314[6]] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2 - a [(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 - a [(2 - aminoethoxy)]-[2 - Nal]-[α - MeLeu]-[Lys(Ac - (D)Ar g)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 216); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2 - a [(2 - aminoethoxy)]-[2 - Nal]-[α - MeLeu]-[Lys(Ac - (D)Ty r)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 217); Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2 - a [(2 - aminoethoxy)]-[2 - Nal]-[α - MeLeu]-[Lys(Ac - (D)Th r)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 219);6]] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2 - a [(2 - aminoethoxy)]-[2 - Nal]-[α - MeLeu]-[Lys(Ac - (D)As p)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 220); or Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-[Phe[4-(2-A methylethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac-(D)Ph e)]-NN-[(D)Ile]-NH2 (SEQ ID NO: 222). It consists of:

[0206] Further characteristics of peptide inhibitors Any of the peptide inhibitors of the present invention may further comprise, for example, Each of the additional defining characteristics described herein may be defined as any peptide inhibitor. The amino acid specified at a particular position can be applied to a specific inhibitor, and the amino acid specified at a specific position can be used to determine the additional critical characteristics of the inhibitor. In certain embodiments, these characteristics are understood to enable the presence of a compound of formula (I): (II), (III), (IV), (V), or (XII) to (XVIIIh) peptides It may be present in any of the nucleotide sequences.

[0207] In various embodiments, R 1 is a bond, hydrogen, C1-C6 alkyl, C6-C12 arylate C6-C12 aryl, C1-C6 alkyl, or C1-C20 alkanoyl and PEG alone or as any of the above spacers, e.g., acetyl Includes phenotypes. 1 replaces the typical amino group located at the amino terminus of a peptide. It is understood that R can be present in addition to R. 1 Even if there is no It is further understood that in certain embodiments, the peptide inhibitor may be selected from the group consisting of hydrogen, C 1 to C6 alkyl, C6 to C12 aryl, C6 to C12 aryl C1 to C6 alkyl, or C1 to C20 alkanoyl, and The spacer may be any of the above, for example, acetyl, and may be PEGylated. In certain embodiments of any of the peptide inhibitors described, R 1 or N-terminal part In certain embodiments, R 1 is a bond, e.g., a covalent bond.

[0208] Any of the peptide inhibitors having any of the various formulas described herein. In certain embodiments, R 1 or the N-terminal moiety is methyl, acetyl, or formyl , benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and the conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid. In one embodiment, R 1 Alternatively, the N-terminal portion is pGlu. In the embodiment, R 1 is hydrogen. In certain embodiments, R 1 is acetyl, and Thus, peptide inhibitors may be, for example, N-terminal amino acid residues, e.g., N-terminal Pen or is acylated at its N-terminus to cap or protect the 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 Or the N-terminal part , acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, octanoic acid, lauric acid Phosphoric 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, Luminous acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid acid, 4-methylbicyclo(2.2.2)-oct-2-ene-1-carboxylic acid, Heptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfur Acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, The acid is selected from sulphonic acid, alkylsulphonic acid and arylsulphonic acid.

[0210] In certain embodiments, R 1 Or the N-terminal moiety is methanesulfonic acid, ethanesulfonic acid , 1,2-ethanedisulfonic acid, and 2-hydroxyethanesulfonic acid It is an alkyl sulfonic acid.

[0211] In certain embodiments, R 1 Or the N-terminal part is benzenesulfonic acid, 4-chlorobenzaldehyde 2-Naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphor The arylsulfonic acid is selected from the group consisting of arylsulfonic acids.

[0212] In some embodiments, the peptides of the present invention may be, for example, isovaleric acid, isobutyric acid, valeric acid, When conjugation to an acidic compound, such as an acid, occurs, the presence of such conjugation is referred to as the acidic form. Thus, for example, but in no way limiting, in some embodiments, isovaler Isovaleryl (e.g., isovaleryl-[Pen]-QTWQ[Pen]-[Phe(4-OMe )]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NG-NH2(sequence Instead of indicating the conjugation of isovaleric acid to a peptide by referring to (number 307), The present application discloses isovaleric acid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[ 2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2 (SEQ ID NO: 30 7) and other conjugates. Reference to the acidic form of the conjugate is made to the peptide inhibitors. It is intended to encompass types.

[0213] In certain embodiments, the peptide inhibitor is selected from a bond, OH, or NH. C-terminus (e.g., R 2 or C-terminal portion). In certain embodiments, R 2 teeth, The peptide inhibitors having any of the various formulas described herein are In various embodiments of any of the above, R 2 Or the C-terminal moiety is OH or NH2 R 2 or the C-terminal portion is a carboxyl group typically located at the carboxy terminus of a peptide. It is understood that R may be substituted for or present in addition to R 2 It is further understood that may not be present.

[0214] Peptide dimers In certain embodiments, the present invention provides a compound according to any of the compounds described herein or in the accompanying tables. The monomeric peptide inhibitors described herein, including dimers of any of the monomeric peptide inhibitors, These dimers are referred to as "peptide inhibitors" as used herein. Exemplary dimers of the present invention are also shown in the accompanying tables. which shows the dimerized monomeric subunits in parentheses followed by a linker. Unless otherwise stated, the subunits are linked via their C-termini. The term "dimer" as in dimer refers to the linkage of two peptide monomer subunits. The peptide dimer inhibitors of the present invention refer to compounds that are capable of forming two homodimers. identical monomeric subunits of, or two non-identical monomers resulting in a heterodimer The cysteine ​​dimer may comprise a cysteine ​​dimer of one of the monomer subunits. A disulfide bond is formed between the cysteine ​​residue of one monomer subunit and the cysteine ​​residue of the other monomer subunit. It comprises two peptide monomer subunits linked through one another.

[0215] In some embodiments, the peptide inhibitors of the present invention are those in which the free cysteine ​​residue is When present in a dimeric form, it may be active in a dimeric conformation. This can be done as a synthetic dimer or as a peptide with free cysteine ​​monomers, and In some embodiments, the dimer is formed by: In other embodiments, the dimer is a heterodimer.

[0216] In certain embodiments, the monomeric subunits of the invention may be linked to a suitable linking moiety, e.g., Each peptide monomer subunit is bound by a disulfide bridge between two cysteine ​​residues. Other suitable compounds include, but are not limited to, those described herein or defined herein. Some of the monomeric subunits can be dimerized by a suitable linker moiety. The peptide dimer is shown with the C-terminus and N-terminus containing free amines. To generate somatic inhibitors, monomeric subunits are ligated with free amino acids at either the C- or N-terminus. modified to eliminate the amine, thereby allowing dimerization at the remaining free amino. Additionally, in some cases, the termini of one or more of the monomeric subunits may be trifluoromethyl. Penthyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, triflate Fluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid carboxylic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyridyl lan-4 carboxylic acid, succinic acid, and glutaric acid In some cases, the monomeric subunits are acylated with a free carboxyl end. The amino acid sequence includes both the terminal and free amino termini, allowing the user to select the desired termini. The subunits may be selectively modified to achieve merization. The monomeric subunits of the present invention are designed to provide a single specific amine for the desired dimerization. It will be understood that the amino acid sequence may be selectively modified to achieve this.

[0217] The C-terminal residue of the monomeric subunits disclosed herein is optionally an amide. It will be further understood that, in certain embodiments, dimerization at the C-terminus Suitable amino acids having a side chain with an amine functionality, as commonly understood in the art, It is understood that dimerization is promoted by using the N-terminal residue , which can be achieved through the free amine of the terminal residue, as is commonly understood in the art. or by using a suitable amino acid side chain with a free amine. That is generally understood.

[0218] The linker moieties connecting the monomeric subunits may be any suitable moiety compatible with the teachings herein. In at least one embodiment, the phosphorus Carrier moieties include cysteine, lysine, DIG, PEG4, PEG4-biotin, and PEG13 , PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, I DA, ADA, Boc-IDA, glutaric acid, isophthalic acid, 1,3-phenylenediacetic acid , 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, triazine, Boc-triazine Biotin, IDA-biotin, PEG4-biotin, AADA, suitable aliphatic, aromatic, and complex Aromatic and polyethylene having a molecular weight of approximately 400 Da to approximately 40,000 Da In certain embodiments, the linker is selected from the non-limiting group consisting of: PEG2 is HO2CCH2CH2OCH2CH2OCH2CH2CO2H. 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 one for each monomeric subunit. Dimerization occurs via an intermolecular disulfide bond formed between two cysteine ​​residues in In some embodiments, the peptide dimeric inhibitor comprises an anchor moiety and two cysteines. Dimerization occurs via both intermolecular disulfide bonds formed between amino acid residues. In embodiments, the intramolecular bond may be a thioether, lactam, or the like instead of a disulfide bond. , a triazole, a selenoether, a diselenide, or an olefin.

[0220] Those skilled in the art will appreciate that the linkers disclosed herein (e.g., C- and N-terminal linkers) It should be understood that the moieties are non-limiting examples of suitable linkers, and that the present invention is not limited to the use of any suitable linker. It will be understood that some embodiments of the present invention may include a car portion. The form may be two monomers selected from peptides shown in any of the tables herein. consists of subunits or comprises a sequence shown in any of the tables herein or consisting of the same, and The C- or N-terminus of the dimeric subunit (or internal amino acid residue) can be linked to any suitable linker. - moieties to provide dimeric peptide inhibitors with IL-23R inhibitory activity In certain embodiments, the linker is attached to the N- or C-terminus of one of the monomeric subunits. It binds to the end of the monomer subunit and to the internal amino acid residues of the other monomer subunit to form a dimer. In certain embodiments, the linker is a linker between an internal amino acid residue of one monomer subunit and The dimer is formed by binding to the internal amino acid residues of the other monomer subunit. In embodiments, the linker is attached to the N- or C-terminus of both subunits.

[0221] In certain embodiments, one or both of the monomeric subunits is represented by Formula I, II, I Any one of the sequences or structures of II, IV, V, XII-XVIIIh, or includes any of the peptides described herein, for example, 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 are independently absent, a bond (e.g., a covalent bond), or R , hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, and may be used alone or in combination with any of the above. containing PEGylated forms as any spacer;

[0225] Each R 2 are independently absent, a bond (e.g., a covalent bond), or OH is or NH2; L is a linker moiety; and each X is selected from any of the groups described herein. Thus, the compounds of formula (I), (II), (V), (III), (IV), or (XII) to (X VIIIh). In certain embodiments, one or both peptide monomer subunits of the peptide dimeric inhibitor may be The unit may be cyclized, for example, via an intramolecular bond between X4 and X9. In this embodiment, one or both peptide monomer subunits are linear and not cyclized. stomach.

[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 monomeric subunits The subunits have the structures shown herein, for example, in Tables 2, 3, 4, 5, or 6. .

[0227] In certain embodiments, each R 1 are independently a bond (e.g., a covalent bond), or Hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl alkyl, C1-C20 alkanoyl, and may be used singly or in combination with any of the above. In certain embodiments, the N-terminus of each subunit comprises a PEGylated form as a spacer. is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C 6 alkyl, C1-C20 alkanoyl, and alone; or The spacer may include PEGylated versions of any of the above, for example, acetyl.

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

[0229] In certain embodiments, each R 2 (or C-terminal portion) may independently be linked (e.g., covalently linked) In the case of a hydroxyl group, the hydroxyl group is 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 present 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, diethylene glycol Linker, iminodiacetic acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala- IDA) linker, or PEG linker.

[0232] In various embodiments of any of the peptide dimeric inhibitors, the peptide monomer subunits Each of the units is connected 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, each peptide The N-termini of the peptide monomer subunits are connected by a linker moiety. In certain embodiments of any of the peptide inhibitors, The C-termini are connected by a linker moiety. In certain embodiments, each peptide monomer subunit has a linker attached to an internal amino acid. They are connected by anchor parts.

[0233] Peptide inhibitor conjugates and biopolymers In certain embodiments, the peptide inhibitors of the present invention, including both monomers and dimers, , lipophilic substituents, and polymeric moieties, and one or more conjugated chemical substituents, may be referred to herein as a half-life extending moiety. Without being bound by any particular theory, Although it is not desired that the lipophilic substituents be present, they bind to albumin in the bloodstream, thereby promoting the release of peptides. It is believed to protect the peptide inhibitor from enzymatic degradation and thus enhance its half-life. In addition, the polymer moiety is believed to enhance half-life and reduce clearance from the bloodstream. It is being done.

[0234] In additional embodiments, peptide inhibitors, such as those represented by Formula (I), (II), (V), (II) Any of peptides I), (IV), or (XI) may be used to inhibit the activity of the inhibitor. The amino acid residue may further comprise a linker moiety attached thereto, e.g., the linker moiety may be a peptide blocker. to the side chain of any amino acid in a peptide inhibitor, to the N-terminal amino acid in a peptide inhibitor, or The inhibitor may be attached to the C-terminal amino acid of the inhibitor.

[0235] In additional embodiments, peptide inhibitors, such as those of Formula (I)-(VI) or (XI) One of the peptides may contain a half-life extending moiety attached to an amino acid residue present in the inhibitor. For example, the half-life extending moiety can be attached to the side chain of any amino acid of the peptide inhibitor. , attached to the N-terminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor It is possible.

[0236] In additional embodiments, peptide inhibitors, such as those of Formula (I)-(VI) or (XI) Any of the peptides may contain a linker moiety attached to an amino acid residue present in the inhibitor. The peptide inhibitor may further comprise a half-life extending moiety attached to the to the side chain of any amino acid, to the N-terminal amino acid of a peptide inhibitor, or It may be attached to a linker moiety attached to the C-terminal amino acid.

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

[0238] In certain embodiments, the peptide inhibitors of the present invention comprise a half-life extending moiety as shown in Table 8. Includes. [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 a linker moiety, e.g., a linker moiety shown in Tables 1, 7, or 9. The peptide inhibitor is attached via one of the following: [Table 9-1] [Table 9-2] [Table 9-3]

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

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

[0242] In certain embodiments, the compounds of the present invention include conjugated chemical substituents, i.e., half-life extending moieties. The half-life of the peptide inhibitors is significantly greater than that of the peptide inhibitors that have the same half-life but do not have the conjugated chemical substituents. At least 100%, at least 120%, at least 150%, or less than the half-life of the toxicant at least 200%, at least 250%, at least 300%, at least 400%, or In certain embodiments, the lipophilic substituent and / or poly The mer moiety may affect the permeability of peptide inhibitors across the epithelium and / or their activity in the lamina propria. In certain embodiments, the peptides of the invention comprising conjugated chemical substituents enhance retention of The permeability of the inhibitors across the epithelium and / or retention in the lamina propria is similar, but At least 100% of the half-life of a peptide inhibitor without conjugated chemical substituents, At least 120%, at least 150%, at least 200%, at least 250%, at least or at least 300%, at least 400%, or at least 500%.

[0243] In one embodiment, one or more amino acid residues in the peptide inhibitors of the invention (e.g., Ly The side chain of the s residue is conjugated (e.g., covalently attached) to a lipophilic substituent. The substituent may be covalently attached to an atom in the amino acid side chain or may be attached by one or more spacers The spacer, if present, may be a peptidomimetic In certain embodiments, the peptide inhibitor may be: The peptides disclosed in Tables 2-6 include any of the conjugate moieties shown.

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

[0245] The lipophilic substituent 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 is esterified with a spacer or lipophilic substituent. , for forming a sulfonyl ester, a thioester, an amide, or a sulfonamide Contains carboxy, hydroxy, thiol, amide, or amine groups. For example, lipophilic substituents Substituents include Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, It may be conjugated to Tyr, Trp, Cys or Dbu, Dpr, or Orn. In certain embodiments, a lipophilic substituent may be conjugated to Lys. An amino acid shown as Lys in any of the formulas provided can be, for example, Dbu , Dpr, or Orn, where a lipophilic substituent is attached. can be.

[0246] In certain embodiments, the peptide inhibitors of the present invention are, for example, peptides of chemical moieties. Enhanced stability or increased permeability through conjugation to one or more amino acid side chains within or may be modified to enhance drug-like properties. For example, lysine N(epsilon ) N, β-carboxyl of aspartic acid, or γ-carboxyl of glutamic acid can be appropriately functionalized. Thus, to produce modified peptides, The amino acids may be appropriately modified. In addition, in some cases, the side chains may be trifluoromethanesulfonates. butyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, trifluoro Methylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4-Fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran- 4. Acylation of a compound selected from the group consisting of carboxylic acids, succinic acid, glutaric acid, and bile acids Those skilled in the art will appreciate that a range of conjugates, e.g., PEG, isoglucan, It will be understood that lu, and combinations thereof may be linked. For example, amino acids having a peptide may be isosterically replaced, e.g., Lys may be replaced by Da. It is understood that the α-MeLys, α-MeLys, or α-MeLys may be substituted for Examples of modified residues in peptides are shown in Table 12. [Table 12-1] [Table 12-2] [Table 12-3]

[0247] In a further embodiment of the invention, alternatively or additionally, in the peptide inhibitors of the invention The side chains of one or more amino acid residues of to increase potency and / or half-life, and / or bioavailability, Such modifications can also be used to modify therapeutic proteins and peptides. It is also known to reduce the clearance (e.g., renal clearance) of

[0248] As used herein, "polyethylene glycol" or "PEG" refers to a compound having the general formula PEG is a polyether compound of the formula H-(O-CH2-CH2)n-OH. Depending on the molecular weight of the polymer, it may be polyethylene oxide (PEO) or polyoxyethylene (PO E), and PEO, PEE, or POG as used herein refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous. However, PEG is an oligomer and polymer with a molecular weight of less than 20,000 Da. PEO refers to polymers with a molecular weight of more than 20,000 Da, and POE refers to polymers with any molecular weight. PEG and PEO tend to refer to polymers with a liquid crystal structure depending on their molecular weight. Throughout this disclosure, the three names will be used interchangeably. PEG is prepared by polymerization of ethylene oxide and has a molecular weight of 300 Da to 10,000 Da. PEGs of different molecular weights and and PEO are used in different applications and have different physical properties (e.g., viscosity) due to the chain length effect. While they have similar chemical properties, the polymeric portion is preferably water-soluble. Suitable polymers are water soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. The moiety may be polyethylene glycol (PEG), a homo- or copolymer of PEG, P Monomethyl-substituted polymer of EG (mPEG), or polyoxyethyleneglycerol ( POG). See, e.g., Int. J. Hematology 68:1 (1998); BioconjugateChem.6:150(1995); and Crit.Rev See Therapy Drug Carrier Syst. 9:249 (1992). Also included are PEGs prepared for the purpose of extending half-life, such as mono-activated, Alkoxy-terminated polyalkylene oxides (POA), such as mono-methoxy-terminated poly(ethylene oxides) ethylene glycol (mPEG); bis-activated polyethylene oxide (glycol); Other PEG derivatives are also contemplated. Suitable polymers are substantially from about 200 Da to about Varies by weight in the range of 40,000 Da, or from about 200 Da to about 60,000 Da Da is typically selected for the purposes of the present invention. In a specific embodiment, 200 to 2,000 Da Alternatively, PEG with a molecular weight of 200-500 is used. Depending on the initiator used, different forms of PEG can also be used, with common initiators being monofunctional. Functional methyl ether PEG or methoxypoly(ethylene glycol), abbreviated as mPEG is.

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

[0250] PEG is also available in different forms, with branched PEGs being three-component groups arising from a central core group. Star PEGs have 10-100 PEG chains emanating from a central core group. G chains, whereas comb-type PEGs have multiple PEG chains typically grafted onto a polymer backbone. PEGs may also be linear. The number often included in the name of PEG indicates that they (e.g., PEG with n=9 has an average molecular weight of approximately 400 Daltons. and classified as PEG400).

[0251] As used herein, "PEGylation" refers to the attachment of a PEG structure to a peptide inhibitor of the invention. This is then referred to as a "PEGylated peptide inhibitor." In certain embodiments, the PEG of the PEGylated side chain has a molecular weight of about 200 to about 40,000. In some embodiments, a peptide of Formula I, Formula I', or Formula I'' is The spacer is PEGylated. In certain embodiments, the PEGylated spacer PE G is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PE In certain embodiments, the PEGylated spacer is PEG. is PEG3 or PEG8.

[0252] Other suitable polymer moieties are poly-amino acids, e.g., poly-lysine, poly-asparagine lactic acid, and poly-glutamic acid (e.g., Gombotz, et al. (1999) 5),Bioconjugate Chem.,vol.6:332-351;Hude cz,et al.(1992),Bioconjugate Chem.,vol.3 , 49-57, and Tsukada, et al. (1984), J. Natl. Ca (See Cancer Inst., vol. 73, :721-729). Polymer Section The polymeric portion may be linear or branched. In some embodiments, the polymeric portion is 50 0-40,000Da, e.g., 500-10,000Da, 1000-5000Da, Molecular weights of 10,000 to 20,000 Da or 20,000 to 40,000 Da do.

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

[0254] In some embodiments, the polymer moiety is attached to the amino, carboxyl, or or thiol groups (covalently). A particular example is the thiol group of a Cys residue. The amino acid groups of the carboxyl ... Xyl groups may also be involved.

[0255] Those skilled in the art will recognize suitable techniques to be used to carry out coupling reactions. For example, a PEG moiety having a methoxy group may be used in Nektar Therapeutics. Cys-thiol was synthesized by maleimide coupling using commercially available reagents from Cystics AL. Further details of suitable chemicals can be found in WO2008 / 1010 17 and the references listed above. Maleimide-functionalized PEGs have also been It may be conjugated to the side chain sulfhydryl group of a Cys residue.

[0256] As used herein, disulfide bond oxidation can be a single-step or two-step process. As used herein, for a single oxidation step, A methyl protecting group is often used during construction to allow for deprotection during cleavage followed by solution oxidation. If a second disulfide bond is required, the choice of native or selective oxidation is available. For selective oxidations requiring orthogonal protecting groups, Acm and trityl are preferred. Cleavage results in the removal of one protecting group of cysteine. This allows oxidation of the pair. A second oxidative deprotection step of the cysteine-protecting Acm group For spontaneous oxidation, trityl protecting groups are attached to all cysteines. The oxidation step is performed by a skilled artisan, allowing the peptide to fold naturally. The reader will be aware of suitable techniques to be used for this purpose.

[0257] Some chemical moieties, including poly(ethylene) glycol, e.g., lysine amino acid epsilon amino group in a residue, a thiol present in a cysteine ​​amino acid residue, or other Reacts with functional groups present in the 20 naturally occurring amino acids, such as the nucleophilic amino acid side chains of When multiple naturally occurring amino acids are reacted in a peptide inhibitor, these non-specific The differential chemical reactions involve the formation of one or more poly(ethylene)glycols at different positions within the peptide inhibitor. This results in a final peptide inhibitor containing multiple isomers of the peptide conjugated to the dimer chain.

[0258] One advantage of certain embodiments of the present invention is that the naturally occurring hydroxylase present in peptide inhibitors As a chemical compound that does not react with the amino acid, it has an inherent functional group that reacts with activated PEG. By incorporating one or more unnatural amino acid(s) that For example, azide and alkyne groups can be used to attach proteins. Therefore, unnatural amino acids do not react with all naturally occurring functional groups in the substrate. can be incorporated into one or more specific sites in peptide inhibitors without undesired non-specific reactions PEG or another modification is desirable. In certain embodiments, the specific chemistry involved in the reaction The material provides a stable covalent bond between the PEG chain and the peptide inhibitor. Such reactions can be carried out in mild aqueous conditions that are not damaging to most peptides. In certain embodiments, the unnatural amino acid residue is AHA.

[0259] The chemical moieties attached to natural amino acids are limited in number and range. Chemical moieties attached to natural amino acids are useful chemical moieties for attaching chemical moieties to target molecules. A significantly larger spectrum of substances is available. Unnatural amino acids, e.g. , unnatural amino acids that contain reactive sites or side chains to which chemical moieties can be attached, e.g., Essentially any protein, including any protein containing aldehyde- or keto-derivatized amino acids. The target molecule can also serve as a substrate for the attachment of chemical moieties.

[0260] Many chemical moieties can be attached to a particular molecule through a variety of methods known in the art. Various such methods are described in U.S. Pat. No. 8,568,706. As an illustrative example, the azide moiety may be a PEG or The azide moiety can serve as a reactive functional group and can be useful for the conjugation of chemical moieties such as azide, methyl azide, methyl methacrylate ... It is not present in most naturally occurring compounds (thus it is not (Azides also have a limited number of reactive partners.) The azide undergoes selective ligation with the hydroxyl group without significantly altering its molecular weight. One reaction that allows for the incorporation or introduction of azides into molecules can be easily introduced into biological samples. The reaction is a copper-mediated Huisgen [3+2] cycloaddition of azides. This reaction is useful for the synthesis of peptide inhibitors. It can be used for selective PEGylation of agents (Tornoe et al., J. Org. Ch em.67:3057,2002;Rostovtsev et al.,Angew. Chem., Int. Ed. 41:596, 2002; and Wang et al., J. Am. Chem. Soc. 125:3192, 2003, Speers et al. .,J.Am.Chem.Soc.,2003,125,4686).

[0261] Synthesis of peptide inhibitors The peptide inhibitors of the present invention can be synthesized by a number of techniques known to those skilled in the art. In certain embodiments, the monomeric subunits are synthesized using the techniques described in the accompanying examples. In certain embodiments, the present invention provides a method for the preparation of a medicament ... and a method for producing a peptide inhibitor (or a monomeric subunit thereof) of formula I, I I, or any of the amino acid sequences set forth in any of the tables herein Peptides having the amino acid sequences described herein include, but are not limited to: Chemically synthesizing peptides that contain, consist of, or consist essentially of peptides In other embodiments, the peptides are recombinantly synthesized instead of chemically synthesized. In certain embodiments, the peptide inhibitor is a dimer, The method involves synthesizing both monomeric subunits of a peptide dimeric inhibitor and then combining the two monomeric subunits. and dimerizing the dimeric subunits to generate a peptide dimeric inhibitor. In embodiments, dimerization occurs via any of the various methods described herein. In certain embodiments, the peptide inhibitor (or a monomeric subunit thereof) is The method involves cyclizing the peptide inhibitor (or its monomeric subunits) after its synthesis. In certain embodiments, cyclization can be carried out by various methods described herein. In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: The present invention provides a method for producing a peptide inhibitor (or a monomeric subunit thereof) of formula (I), II), (III), (IV), or any of the accompanying examples or tables. The amino acid sequences of the present invention include, but are not limited to, any of the amino acid sequences described herein. The present invention relates to a method for producing a peptide comprising, consisting of, or consisting of a peptide having an amino acid sequence as set forth in the present application. an intramolecular bond, e.g., a disulfide bond, between two amino acid residues in a peptide consisting essentially of , amide, or thioether bonds.

[0262] In related embodiments, the present invention provides a compound according to formula (I)-(IV) or any of the compounds of the accompanying examples or tables. A polynucleotide encoding a polypeptide having a sequence as set forth in any one of Includes do.

[0263] Additionally, the present invention provides vectors, e.g., expression vectors, comprising the polynucleotides of the present invention. Includes.

[0264] Treatment method In certain embodiments, the present invention provides a method for inhibiting IL-23 binding to IL-23R on cells. The method includes contacting IL-23 with a peptide inhibitor of the present invention. In certain embodiments, the cell is a mammalian cell. Inhibition of binding can be carried out in vitro or in vivo. The amount of the ATP can be determined by experimental methods and assays.

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

[0266] In some embodiments, the present invention relates to a condition or condition associated with IL-21 or IL-23R. or symptoms (e.g., activation of the IL-23 / IL-23R signaling pathway) The present invention provides a method for treating a subject, the method comprising administering to the subject a peptide inhibitor of the present invention. In one embodiment, inappropriate, unregulated, or elevated IL-23 or IL-2 Methods for treating a subject suffering from a condition or symptom characterized by 3R activity or signaling The present invention provides a method for detecting (partially or completely) binding of IL-23 to IL-23R in a subject. ) to the individual in an amount sufficient to inhibit the In this embodiment, the inhibition of IL-23 binding to IL-23R is achieved by administering to an organ or tissue of interest, e.g. For example, the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or occurs in the lymphatic vessels.

[0267] In some embodiments, the methods of the present invention involve the peptide inhibitors of the present invention. In certain embodiments, a subject in need thereof is provided with , diagnosed with or suffering from an IL-23 / IL-23R-associated disease or disorder In certain embodiments, the subject is a mammal. do.

[0268] In certain embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders. diseases such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease (IBD), and juvenile IBD, adolescent IBD, Crohn's disease, sarcoidosis, systemic lupus erythematosus, ankylosis In certain embodiments, the condition is psoriatic spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. The disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar psoriasis, pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, ectopic acne (acn e ectopica), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue ), seronegative arthropathy-associated enteropathy, microscopic colitis, collagenous colitis, eosinophils gastroenteritis / esophagitis, radiotherapy- or chemotherapy-associated colitis, leukocyte adhesion deficiency type 1 Colitis associated with disorders of the innate immune system, such as those in chronic granulomatous disease, glycogen storage disease type 1b, and Helicobacter pylori. Lemanski-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldry syndrome schitz syndrome, pouchitis after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin Phosphorus-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral enteropathy , pericholecystitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease is.

[0269] In certain related embodiments, the present invention provides a method for detecting IL-23 or IL-23R signaling. (or the binding of IL-23 to IL-23R) and providing a method for doing so in a subject, and providing a subject with a peptide inhibitor of the invention. In certain related embodiments, the present invention provides a method for the treatment of IL-23 or IL-23R in the gastrointestinal tract. It is necessary to selectively inhibit signal transduction (or the binding of IL-23 to IL-23R). and a method for doing so in a subject in need thereof, comprising orally administering the peptide inhibitors of the present invention. In certain embodiments, the method comprises administering the antibody to a subject by administering the antibody to gastrointestinal tissue (e.g., small intestine or The exposure of administered peptide inhibitors in the peritoneal cavity (or colon) is at least 10 times higher than that in the blood. fold, at least 20 times, at least 50 times, or at least 100 times higher. In one embodiment, the present invention provides a method for inhibiting IL23 or IL23R signaling (or IL2) in the gastrointestinal tract. In a subject in need thereof, and a method of administering to a subject a peptide inhibitor, the peptide inhibitor comprising administering to a subject a peptide inhibitor selected from the group consisting of I It does not block the interaction between IL-6 and IL-6R and antagonizes the IL-12 signaling pathway. In further related embodiments, the present invention provides a method for treating gastrointestinal inflammation and / or gastrointestinal The present invention also provides a method for inhibiting neutrophil infiltration by administering the peptide inhibitors of the present invention to a subject in need thereof. In some embodiments, the methods of the invention include providing a peptide inhibitor of the invention. A therapeutic agent (i.e., a first therapeutic agent) is combined with a second therapeutic agent to treat a patient in need thereof. In certain embodiments, the second therapeutic agent is a peptide inhibitor. before, and / or at the same time as, and / or after the agent is administered to the subject. In certain embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In another embodiment, the method includes administering a third therapeutic agent to the subject. In embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

[0270] In certain embodiments, the peptide inhibitor, or a pharmaceutical composition comprising the peptide inhibitor, The drug is suspended in a sustained release matrix. As used herein, a sustained release matrix is ​​an enzymatic Materials that are decomposable by hydrolysis or acid-base hydrolysis or by dissolution ( When inserted into the body, the matrix The sustained release matrix is ​​preferably a liposome, polylactide, or the like. Polylactic acid, polyglycolide (polymer of glycolic acid), polylactide coglycolide Poly(lactic acid and glycolic acid copolymer), polyanhydride, poly(ortho)ester, poly Peptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, Lipids, polysaccharides, nucleic acids, polyamino acids, phenylalanine, tyrosine, isoleucine, etc. Amino acids, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silyl The preferred biodegradable matrix is ​​selected from biocompatible materials such as cellulose, cellulose acetate, cellulose acetate cellulose, and the like. The forms are polylactide, polyglycolide, or polylactide-co-glycolide (lactic acid and glycolic acid). The matrix is ​​one of the following:

[0271] In certain embodiments, the present invention provides a method for the preparation of a compound comprising administering to a subject ... and a pharmaceutical composition comprising an acceptable carrier, diluent, or excipient. The carrier, diluent, or excipient may be any type of non-toxic solid, semi-solid, or liquid filler. refers to an agent, diluent, encapsulating material, or formulation aid. Prevention of microbial activity is achieved by various antimicrobial agents. 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. There may be cases where this is the case.

[0272] In certain embodiments, the composition is administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (such as by powder, ointment, drops, suppository, or transdermal patch); by inhalation ( The drug may be administered intraocularly (intraocularly), intranasally (intranasally), or buccally. The term "parenteral" as used herein includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and related forms. This refers to modes of administration including intranodal injection and infusion. Thus, in certain embodiments, the composition The product is formulated for delivery by any of these routes of administration.

[0273] In certain embodiments, the pharmaceutical composition for parenteral injection is a pharmaceutically acceptable sterile Aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterilized immediately before use Suitable aqueous and non-aqueous solutions include sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, methylcellulose ... Glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl Cellulose and suitable mixtures thereof, β-cyclodextrin, vegetable oil (olive oils, as well as injectable organic esters such as ethyl oleate. Mobility can be improved, as required in the case of dispersions, for example, by the use of coating materials such as lecithin. This can be maintained by maintaining a consistent particle size and by the use of surfactants. It may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of pharmaceutical forms is achieved by using drugs that slow absorption, such as aluminum monostearate and gelatin. This can be brought about by the inclusion of a retarding agent.

[0274] Injectable depot forms include polylactide-polyglycolide, poly(orthoesters), poly (anhydrides), and one or more biodegradable poly(ethylene glycol)s such as (poly)glycols, e.g., PEG. by forming a microencapsulated matrix of peptide inhibitors within a polymer The ratio of peptide to polymer and the nature of the particular polymer used will vary. The release rate of the peptide inhibitor can be controlled accordingly. Alternatively, peptide inhibitors can be entrapped in liposomes or microemulsions containing It is prepared.

[0275] Injectable formulations may be prepared by, for example, filtration through a bacteria-retaining filter or by injecting immediately prior to use. in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium. It can be sterilized by incorporating a sterilizing agent.

[0276] Topical administration includes administration to the skin or mucous membranes, including the lungs or the surface of the eye. The compositions are available in solutions and in aqueous and non-aqueous formulations, including those for inhalation and intranasal administration. It may include a suspension and may be prepared as a dry powder, which may be pressurized or non-pressurized. In powdered compositions, the active ingredient may be in finely divided form, e.g., up to 100 microns in diameter. and the like. The present invention relates to a method for preparing a pharmaceutical composition comprising administering to a subject ... Suitable inert carriers include sugars such as lactose, Examples include:

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

[0278] A further form of topical administration is to the eye. The peptide inhibitor is maintained in contact with the ocular surface for a sufficient period of time to The agent is administered to the cornea and internal regions of the eye, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, to allow penetration through the iris / ciliary body, lens, choroid / retina, and sclera. It may be delivered in a pharmaceutically acceptable ophthalmic vehicle. The pharmaceutically acceptable ophthalmic vehicle may be Alternatively, the peptide of the present invention may be applied to a skin, for example, an ointment, vegetable oil, or an encapsulating material. The inhibitor may be injected directly into the vitreous and aqueous humor.

[0279] Compositions for rectal or vaginal administration include suppositories, which are solid at room temperature but liquid at body temperature. cocoa butter, which is a soluble fiber and therefore melts in the rectum or vaginal cavity and releases the active compounds; Suitable non-irritating excipients or carriers, such as polyethylene glycol or a suppository wax and the peptide inhibitor of the present invention.

[0280] The peptide inhibitors of the present invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes generally consist of phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable substance capable of forming liposomes can be used. Any lipid capable of being metabolized may be used. The present composition in liposome form may contain the peptides of the present invention. In addition to the tide inhibitors, stabilizers, preservatives, excipients, etc. may be contained. In embodiments, the lipids include phosphatidylcholines (lecithins), both natural and synthetic, and and serine-containing phospholipids. Methods to form liposomes are known in the art. .

[0281] Pharmaceutical compositions used in the present invention suitable for parenteral administration generally contain sodium chloride, glycerol, Phosphorus, glucose, mannitol, sorbitol, etc., are used to make the solution isotonic with the recipient's blood. The pharmaceutical composition may comprise sterile aqueous solutions and / or suspensions of the peptide inhibitors.

[0282] In some embodiments, the present invention provides pharmaceutical compositions for oral delivery. The compositions and peptide inhibitors may be used in conjunction with the methods, techniques, and / or delivery methods described herein. It can be prepared for oral administration according to any of the vehicles. The peptide inhibitors of the present invention may be any peptides not disclosed herein but known in the art. and modifications within the system or delivery vehicle that are compatible for use in oral delivery of peptides. It will be understood that the above may be combined.

[0283] In certain embodiments, formulations for oral administration may be prepared using a method to artificially increase the permeability of the apical wall. adjuvants for the preparation of emulsions (e.g., resorcinol and / or non-ionic surfactants, e.g., For example, polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether. enzyme inhibitors to inhibit enzymatic degradation (e.g., pancreatic trypsin inhibitors, inhibitors, diisopropyl fluorophosphate (DFF), or trasylol) In certain embodiments, the peptide inhibitor in a solid dosage form for oral administration may comprise: Sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maize Lutitol, dextrin, starch, agar, alginate, chitin, chitosan, pectin Gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, and mixed with at least one additive such as a synthetic or semi-synthetic polymer or glyceride. These dosage forms may also contain other types of additives, such as inert diluents, lubricants, etc. Preservatives, e.g., sorbic acid, ascorbic acid, Corbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrants, May also contain additives, thickeners, buffers, pH adjusters, sweeteners, flavorings, or fragrances. Cut.

[0284] In certain embodiments, oral dosage forms or units adapted for use with the peptide inhibitors of the present invention The dose may be determined by the mixture of the peptide inhibitor with the non-drug component or excipient, as well as the component or component. The composition may contain other non-recyclable materials that may be considered as casing. may comprise at least one of a liquid, a solid, and a semi-solid dosage form. In the form, an oral dosage form is provided containing an effective amount of the peptide inhibitor, and the dosage form may be a pill, a tablet, or the like. , capsules, gels, pastes, beverages, syrups, ointments, and suppositories In some cases, the peptide inhibitor is administered in a delayed release manner in the small intestine and / or colon of a subject. Oral dosage forms are provided that are designed and configured to achieve this.

[0285] In one embodiment, an oral pharmaceutical composition comprising a peptide inhibitor of the present invention induces peptide depletion in the small intestine. It contains an enteric coating designed to delay the release of the inhibitor. In some embodiments, the peptide inhibitors of the present invention and the approach are combined in a delayed release pharmaceutical formulation. In some embodiments, pharmaceutical compositions are provided that include a protease inhibitor, such as riboflavin. The pharmaceutical composition of the present invention includes an enteric coating that is soluble in gastric fluid at a pH of about 5.0 or greater. In at least one embodiment, hydroxypropyl methylcellulose phthalate, cellulose Cellulose acetate phthalate, and cellulose acetate trimellitate Derivatives of cellulose, and similar derivatives of cellulose and other carbohydrate polymers. Pharmaceutical compositions comprising an enteric coating comprising a polymer having dissociable carboxylic acid groups is provided.

[0286] In one embodiment, the pharmaceutical composition comprising the peptide inhibitor of the present invention is contained within an enteric coating. The enteric coating provides a controlled release of the pharmaceutical composition within the lower gastrointestinal system of a subject. It is designed to protect and release the drug and to avoid systemic side effects. In addition to the administration of steroids, the peptide inhibitors of the present invention can be administered in any suitable oral drug delivery system or formulation. The molecule may be encapsulated within, coated on, engaged with, or otherwise associated with the molecule. In some embodiments, the peptide inhibitors of the present invention are polymer hydrogels, nanoparticles, microparticles, or the like. The present invention is provided in a lipid carrier system comprising at least one of a lipid carrier, a micelle, and other lipid systems.

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

[0288] Various biological response systems may also be combined with one or more peptide inhibitors of the present invention to administer orally In some embodiments, the peptide inhibitors of the present invention can be provided as pharmaceuticals for delivery. , hydrogels, and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly( Methacrylic acid [PMAA], cellulose, Eudragit (registered trademark), chitosan, alginate), to provide therapeutic agents for oral administration. Other embodiments provide for optimizing drug residence times for the peptide inhibitors disclosed herein. or a method for extending the surface of the peptide inhibitor by hydrogen bonding, linked mucin Polymers with, or / and modified to include mucoadhesive properties through hydrophobic interactions These modified peptide molecules are then modified to enhance the growth of the peptide in a subject, in accordance with a desired feature of the present invention. Furthermore, the targeted mucoadhesive system can be used to target the drug on the surface of enterocytes and M-cells. The peptide inhibitors can be specifically bound to the receptor, thereby further enhancing uptake of the particles containing the peptide inhibitors. Increase to.

[0289] Other embodiments include methods for oral delivery of peptide inhibitors of the present invention, Inhibitory agents may increase paracellular or transcellular penetration of peptides across the intestinal mucosa. For oral delivery of therapeutic agents, the compound is provided to the subject in combination with a permeation enhancer that promotes transport of the compound. Various penetration enhancers and methods for this purpose 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 invention comprise a peptide inhibitor of the invention. and one or more permeation enhancers. Examples of absorption enhancers include, for example, bile salts, fatty acids, , surfactants (anionic, cationic, and non-anionic) chelating agents, Zonul ar OT, ester, cyclodextrin, dextran sulfate, azone, crown ace Examples of suitable glycerols include EDTA, sucrose esters, and phosphotidylcholine. Although enhancers are typically not carriers themselves, they are also widely associated with other carriers. This increases oral bioavailability through transport of peptides and proteins across the intestinal mucosa. Such substances may be added to the formulation as excipients or as a means to improve the It can be incorporated to form non-specific interactions with targeted peptide inhibitors.

[0291] Those that promote tight junction penetration and are generally recognized as safe (Generally Recognized as Safe) Dietary ingredients confirmed as "Well Recognized As Safe (GRAS)" and / or other naturally occurring substances, such as asglycerides ceride), acylcarnitines, bile salts, and medium-chain fatty acids. The sodium salt of the acid (MCFAS) has also been suggested to be a permeation enhancer. The MCFAS studied was sodium caprate, a salt of capric acid, which: Contains 2-3% of fatty acids in the milk fat fraction. To improve ampicillin absorption, the excipient in the suppository formulation (Doktacillin®) It is primarily used as a vehicle. Another dietary MCFAS, sodium caprylate (8 The permeability characteristics of cellulose (carbon) were found to be lower in vitro when compared to sodium caprate. Sodium caprylate and peptide drugs were mixed with other excipients in oil. It was formulated in a soluble oil suspension (OS) to produce an oil suspension (OS) that enhanced permeability (Tuvia, S. et al.,Pharmaceutical Research,Vol.31,No. .8, pp.2010-2021(2014).

[0292] For example, in one embodiment, the permeation enhancer is combined with a peptide inhibitor and the permeation enhancer are medium-chain fatty acids, long-chain fatty acids, bile salts, amphiphilic surfactants, and chelating agents. In certain embodiments, the medium chain fatty acid salt is a compound that inhibits paracellular permeability of the intestinal epithelium. In one embodiment, sodium caprylate N-[hydroxybenzoyl]amino-containing penetration enhancers are used in combination with the peptide inhibitors of the present invention. Once in the blood circulation, the penetration enhancer is used to form a weak non-covalent association with Upon reaching the membrane, it favors membrane transport and further dissociation. In another embodiment, the peptide of the present invention The inhibitors are conjugated to oligoarginines, which allow the peptides to penetrate into various cell types. Furthermore, in at least one embodiment, non-covalent binding enhances penetration of the peptides of the present invention. and a peptide inhibitor selected from the group consisting of cyclodextrins (CDs) and dendrimers. and a penetration enhancer, wherein the penetration enhancer reduces peptide aggregation and inhibits peptide aggregation. Increases the stability and solubility of the drug molecule.

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

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

[0295] In certain embodiments, the peptide inhibitors of the present invention are administered in various dosage forms, e.g., emulsions, liposomes, microspheres, The compound is formulated in a formulation vehicle such as a sphere, or nanoparticle.

[0296] One embodiment of the present invention is treating a subject with a peptide inhibitor of the present invention that has an increased half-life. In one embodiment, the present invention provides a method for administering once daily (qd) or In vitro or in vivo concentrations sufficient for twice-daily (bid) administration of a therapeutically effective amount a peptide having a half-life of at least several hours to a day (e.g., when administered to a human subject) In another embodiment, the peptide inhibitor is administered once a week (qw .) has a half-life of 3 days or more sufficient for administration of a therapeutically effective amount. In some forms, peptide inhibitors are administered as biweekly (biw) or once-monthly treatments. In another embodiment, the peptide inhibitor has a half-life of 8 days or more sufficient for administration of the desired amount. The agent has a longer half-life compared to underivatized or unmodified peptide inhibitors. In another embodiment, the peptide inhibitor is derivatized or modified to have a serum half-life of It contains one or more chemical modifications to increase its activity.

[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 form exists, It may be used in the form of a pharmaceutically acceptable salt.

[0298] The total daily dosage of the peptide inhibitors and compositions of the present invention may be determined within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject can be determined by the attending physician within the scope of the present invention. Bell also considers a) the disease being treated and the severity of the disease, b) the activity of the specific compound being used, c) the specific composition used, the patient's age, weight, general health, sex, and diet d) the administration time, route of administration, and excretion rate of the specific peptide inhibitor used; e) f) duration of treatment, in combination with or in conjunction with the specific peptide inhibitor used It depends on a variety of factors, including concurrent medications, as well as similar factors well known in the medical field. do.

[0299] In certain embodiments, the compound is administered to a human or other mammalian host in a single or divided dose. The total daily dose of the peptide inhibitor of the present invention to be administered is, for example, 0.0001 to 300 mg / day. mg / kg body weight, or amounts such as 1-300 mg / kg body weight.

[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 where the peptide inhibitor chelates Detection and evaluation of enteritis by microPET imaging, labeled with a methyl group or detectable label, and may be used for diagnostic purposes. In one embodiment, the peptide inhibitor is a bifunctional peptide. In another embodiment, the peptide inhibitor is radiolabeled. The labeled peptide inhibitor is then administered orally or rectally to the subject. The labeled peptide inhibitor is included in the drinking water. Following uptake of the peptide inhibitor, MicroPET imaging is used to visualize inflammation throughout the subject's intestines and digestive tract. It can be done. [Example]

[0301] Example 1 Synthesis of peptide inhibitors The peptide monomers of the present invention were prepared by Protein Technology's Symphony Synthesized using Merrifield solid-phase synthesis technology on a monolithic multichannel synthesizer. HBTU (O-benzotriazole-N,N,N',N'-tetramethyl-uronium -hexafluoro-phosphoric acid), diisopropylethylamine (DIEA) coupling conditions Peptides were conjugated using the conditions. For some amino acid couplings, yAOP(7-azabenzotriazol-1-yloxy)tripyrrolidinophosponium (tripyrrolidinophosponium) hexafluorophosphate) and DIEA conditions were used. For peptides with C-terminal amides, Rink Ami MBHA resin (100-200 mesh, 0.57 mmol / g) was used, and the C terminal For peptides with terminal amino acids, preloaded Wa The coupling reagent (HBTU and DIEA premixed) was used. Similarly, an amino acid solution was prepared at a concentration of 100 mmol. The peptide inhibitors of the present invention were synthesized based on medicinal chemistry optimization and / or phage display. These were identified based on the screening method to identify those with superior binding and / or inhibitory properties. I did it.

[0302] construction Peptides were assembled using standard Symphony protocols. Peptide sequences was constructed as follows: 4 resins (250 mg, 0.14 mmol) in each reaction vial were added. Wash twice with 2 mL of DMF, then with 2.5 mL of 20% 4-methylpropional over 10 min. The resin was then filtered and washed with DMF (4 The resin was washed twice with 1 mL of HCl and re-treated with N-methylpiperidine for another 30 minutes. Washed with DMF (4 mL) three times, 2.5 mL of amino acids, and 2.5 mL of HB The addition of the TU-DIEA mixture was continued. After 45 minutes of frequent stirring, the resin was filtered and DMSO was added. For a typical peptide of the present invention, double coupling After the coupling reaction was completed, the resin was washed with DMF three times (4 mL each) to obtain This was followed by coupling of the next amino acid.

[0303] Ring-closing metathesis to form olefins The resin (100 μmol) was dissolved in 2 mL of DCM (3 × 1 min), followed by 2 mL of DCE (3 × 1 min), followed by washing with 2 mL of a 6 mM solution of Grubbs' first generation catalyst in DCE. The solution was treated with 4.94 mg mL-1 (20 mol %) of HCl (based on resin substitution). After refluxing under nitrogen overnight (12 hours), the resin was drained. After washing with CM (4 mL), it was dried and cleaved.

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

[0305] The cleaved peptide was precipitated in cold diethyl ether and purified by two cycles of 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). The mixture was then filtered and analyzed by electrospray ionization mass spectrometry (ESI-MS) (Mi The quality of the linear peptides was verified using chromatographic analysis (Chromass / Waters ZQ) and then Purified.

[0306] Disulfide bond formation by oxidation Peptides containing free thiols (e.g., diPen) can be synthesized using the common Fmoc-SPP method. The cleavage reagent (90% thiamin mononitrate) was added to the Rink Amide-MBHA resin according to the S procedure. Trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% triisopropyl The peptide was cleaved from the resin by treatment with propylsilane. The product was precipitated in cold diethyl ether followed by two washes with ethyl ether. The crude peptide was poured off, a second aliquot of cold ether was added, and the procedure was repeated. The compound was dissolved in acetonitrile:water (7:3 with 1% TFA), filtered, and the desired A crude peptide, which was a pure unoxidized peptide, was obtained.

[0307] Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys The crude cleaved peptides with either X4 and X9 were dissolved in 20 mL of water: The solution was dissolved in acetonitrile and then saturated iodine in acetic acid with stirring until the yellow color persisted. The solution was stirred for 15 min and the reaction was monitored by analytical HPLC and LCMS. When the reaction was complete, solid ascorbic acid was added until the solution became clear. This solvent mixture was then diluted with water and then loaded onto a reverse phase HPLC machine. Purified (Luna C18 supported, 10 μl, 100 A, mobile phase A: containing 0.1% TFA Mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient 5% B (The mixture was then diluted to 50% B over 60 min at a flow rate of 15 mL / min.) The fractions containing the product were freeze-dried in a lyophilizer.

[0308] Thioether bond formation Peptides containing a free thiol (e.g., Cys) and hSer(OTBDMS) onto Rink Amide-MBHA resin according to the general Fmoc-SPPS procedure. The resin was heated for 2 h with PPh3 (10 equiv.) and Cl3CCN (10 equiv.) in DCM. Chlorination was carried out by treating with cleavage reagent (90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% triisopropylsilane) The peptide was cleaved from the resin by the treatment with The filtrate was poured off and washed twice with ethyl ether. An aliquot of cold ether was added and the procedure was repeated. The crude peptide was purified with acetonitrile: The desired uncyclized crude peptide was dissolved in a 7:3 mixture of 1% TFA and filtered. Got Chid.

[0309] A free thiol (e.g., , Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys) and The crude peptide containing hydroxyl group and alkyl halide (hSer(Cl)) was added to 0.1 MT The cyclization was allowed to occur overnight at room temperature. The mixture was 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 μL, Mobile phase A: Water containing 0.1% TFA) Mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B (The eluate was then converted to 50% B over 60 min at a flow rate of 15 mL / min.) The pure product was then The fractions containing were freeze-dried in a freeze-dryer.

[0310] purification Analytical reversed-phase, Gemini C18 column (4.6 mm x 250 mm) (Phenom High-performance liquid chromatography (HPLC) was performed on a semi-preparative reversed-phase HPLC column. C was measured using a Gemini 10 μm C18 column (22 mm × 250 mm) (Phenom enex) or Jupiter 10 μm, 300 A °C 18 column (21.2 mm × 2 50 mm (Phenomenex). Separation was achieved using a linear gradient of buffer B in A (mobile phase A) at a flow rate of 1000 s (preparative). Mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile containing 0.1% TFA (ACN)). Buffer A in A was added at a flow rate of 1 mL / min (analytical) and 15 mL / min (preparative). Separation was achieved using a linear gradient of B (Mobile phase A: water containing 0.15% TFA, Mobile phase B: acetonitrile (ACN) containing 0.1% TFA.

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

[0312] Assays to determine peptide activity were performed as described below. The results of the assay are provided in Tables E1 and E2. Human ELISA is described below. The IL23-IL23R competitive binding assay described in the Rat ELISA is as follows: The rat IL-23R competitive binding ELISA assay described below is shown, and pStat3 HTRF demonstrates DB cell IL-23R pSTAT3 cell assay described below The peptides shown in Table E1 were formed between two Pen residues in these peptides. The peptides shown in Table E2 are cyclized via disulfide bridges. Cyclization occurs via a thioether bond between residues. Table E2 shows an example of a thioether cyclization. provides a typical structure, which is indicated in the tables by the term "cyclo", where the cyclic region is The term "cyclo" is immediately followed by parentheses. For a given peptide, residue A While bu is present where indicated, other embodiments, e.g., embodiments relating to non-cyclized forms, may be used. In embodiments, Abu may be referred to as a hSer(Cl) or homoSer residue.

[0313] IL23-IL23R competitive binding ELISA Immulon® 4HBX plates were pre-treated with 50 ng / well of IL23R_hu The wells were coated with FC and incubated overnight at 4°C. The wells were washed four times with PBST. Block with PBS containing 3% skim milk for 1 hour at room temperature, then block with PBST for 4 hours. 2 nM diluted in assay buffer (PBS containing 1% skim milk) Serial dilutions of test peptides and IL-23 were added to each well at a final concentration of After incubating for 2 hours, the wells were washed and 50 ng of IgG diluted in assay buffer was added. / well goat anti-p40 polyclonal antibody (R&D Systems #AF309) Bound IL-23 was detected by incubating with 1000 μL of IL-23 at room temperature for 1 hour. The wells were washed again four times with PBST. Then, the wells were diluted 1:5000 in assay buffer. The secondary antibody, HRP-conjugated donkey anti-goat IgG (Jackson ImmunoRes (Scientific Research Laboratories #705-035-147) was added and the mixture was stirred at room temperature. Incubated for 30 minutes. Finally, the plate was washed as above. TMB One Component HRP Membrane Substrate enables signal The reaction mixture was visualized, quenched with 2M sulfuric acid, and read spectrophotometrically at 450 nm. The IC50 values ​​for the various test peptides determined from these data are shown in Tables E1 and E2. Shown in Figure 2.

[0314] Rat IL-23R competitive binding ELISA Assay plates were coated with 300 ng / well of rat IL-23R_huFC. The wells were washed, blocked, and washed again. Serial dilutions of test peptides and IL-23 at final concentrations of 1 M were added to each well and incubated at room temperature. The wells were washed and then incubated for 2 hours with goat anti-p40 polyclonal antibody. Bound IL-23 was detected using HRP-conjugated donkey anti-goat IgG. Signal with ne Component HRP Membrane Substrate The results were visualized and quenched with 2M sulfuric acid. The IC50 values ​​for the peptides 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 primarily mediated by signal transducer and activator of transcription 3 (STAT3). Phosphorylation of STAT3 (to give pSTAT3) is thought to be mediated by R This cellular assay results in the upregulation of ORC and pro-inflammatory IL-17. pS in IL-23R-expressing DB cells stimulated with IL-23 in the presence of Test the level of TAT3. RPMI supplemented with 10% FBS and 1% glutamine DB cells (ATCC # 30-2001) cultured in -1640 medium (ATCC # CRL-2289) at 5 x 10E5 cells / well in 96-well tissue culture plates. Serial dilutions of test peptides and IL-23 at a final concentration of 0.5 nM were added to each well. Add to wells and incubate at 37°C for 30 minutes in a 5% CO2 humidified incubator. The changes in phospho-STAT3 levels in the cell lysates were measured using the manufacturer's Two P Cisbio HTRF pSTAT3 C according to the late assay protocol. The results were obtained using a cellular assay kit. The IC50 values ​​are shown in Tables E1, E2, and E3. * = ≤ 1 nM; ** = 1 nM 10nM; ***=10nM~100nM; ****=>100nM. Unless otherwise indicated, The data was undetermined. [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] The above U.S. patents, ... All published U.S. patent applications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature are No. 6,299,333, filed Dec. 1, 2004, which are incorporated herein by reference in their entireties.

[0317] From the foregoing, it will be appreciated that, although specific embodiments of the present invention have been described herein for purposes of illustration, various It will be understood that modifications can 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) Peptide inhibitors of the interleukin-23 receptor, or pharmaceutically acceptable salts thereof, are also or a solvate thereof, wherein the peptide inhibitor is represented by formula (V): X0-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X1 2-X13-X14-X15-X16-X17-X18-X19-X20-X21-X2 2-X23(V) (SEQ ID NO: 238) wherein: X0 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X1 is Gly, Arg, Phe, Glu, Gln, Thr, (D)Arg, (D)Ph e, (D)Glu, (D)Thr, (D)Leu, (D)Gln, alpha-MeArg , alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-M eAsn, alpha-MeTyr or absent; X2 is (D)Asp, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, T hr, Leu, (D)Gln, (D)Asn, IsoGlu, Gly, Arg, Phe, Glu, Gln, Thr, (D)Glu, (D)Thr, (D)Leu, alpha-Me Arg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha alpha-MeAsn, alpha-MeTyr, or absent; X3 is (D)Arg, (D)Tyr, Gly, alpha-MeArg, alpha-Me Phe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha α-MeTyr, Lys(Ac), Lys(Y1-Ac) or absent, wherein 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: Thr, Alb, Asp, Dab, Gly, Pro, Ser, alpha-MeG ln, 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), P he(3-Me), Phe(4-Me), Trp(7-Aza), or Phe(3,4 -dimethoxy); X8: Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLy s(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-M eLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Na l, 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-acetyl 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-M eLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, Al Alpha-MeLeu, Alpha-MeLys, Alpha-MeAsn, Alpha-MeTy r, Ala, cyclohexyl Ala, 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(A c) 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, L ys, Leu, Asn, n-Leu, Gln, Ser, Tic, Trp, alpha-Me Gln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Da p(Ac), homo-Lys(Ac), or Lys(Ac); X15: Asn, Aib, beta-Ala, Cit, Gln, Asp, alpha-Me Gln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Da b(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-MeL ys, 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)Se r, (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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, 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, Al Alpha-MePhe, Alpha-MeLeu, Alpha-MeLys, Alpha-MeAs n, alpha-MeTyr, alpha-MeAsp, or absent; the peptide inhibitor is cyclized via the bond between X4 and X9, and the peptide inhibitor is , inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor, A peptide inhibitor of the telokin-23 receptor, or a pharmaceutically acceptable salt thereof, Solvate. (Item 2) The bond between X4 and X9 is a disulfide bond or a thioether bond. A peptide inhibitor as described in item 1. (Item 3) X4 is Pen, X9 is Pen, and the bond is a disulfide bond. 2. A peptide inhibitor according to claim 1. (Item 4) Item 3, wherein the peptide inhibitor has the structure of formula (III): . (Item 5) the peptide inhibitor comprises an amino acid sequence of formula (IIIa) or set forth in Table E1. Item 3. A peptide inhibitor according to item 3. (Item 6) X4 is Abu, X9 is Cys, and the bond is a thioether bond. 2. A peptide inhibitor according to claim 1. (Item 7) 7. The peptide inhibitor of claim 6, wherein the peptide inhibitor has the structure of formula (IV): (Item 8) the peptide inhibitor comprises an amino acid sequence of formula (IVa) or set forth in Table E2; Item 7. The peptide inhibitor according to item 6. (Item 9) one or more half-life extending moieties and / or one or more linkers conjugated to said peptide inhibitor 9. The peptide inhibitor according to any one of items 1 to 8, further comprising an anchor moiety. (Item 10) the half-life extending moiety is conjugated to the peptide inhibitor via one or more linker moieties; 10. The peptide inhibitor according to item 9, (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 may be used alone or in combination with any of the above. PEGylated form as a spacer in any of the above; X is a compound represented by the formula (I), the formula (II), the formula (I IIa), amino acid sequences of formula (IVa), formula (V), and formulas (XII) to (XVIIIh), or an amino acid sequence set forth in any of Tables E1, E2, or E3; R 2 is OH or NH. . (Item 12) A peptide dimer inhibitor of the interleukin-23 receptor, comprising the peptide dimer The inhibitor comprises two peptide monomer subunits connected via one or more linker moieties. each peptide monomer subunit having the formula (I), (II), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIj ... Va), the amino acid sequence or structure of formula (V), formula (XII) to (XVIIIh), or a peptide comprising an amino acid sequence set forth in any of Tables E1, E2, or E3; Tide dimer inhibitors. (Item 13) The one or more linker moieties may be a diethylene glycol linker, an iminodiacetic acid (ID A) Linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or PE 13. The peptide dimer inhibitor according to item 12, wherein the G linker is (Item 14) the N-termini of each peptide monomer subunit are connected by said linker moiety; or the C-terminus of each peptide monomer subunit is connected by the linker moiety. 14. The peptide dimer inhibitor according to item 12 or 13. (Item 15) X is a group of formula XII: X2-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X 14-X15-X16(XII) (SEQ ID NO: 275) wherein: X2 is Arg, (D)Arg, Gln, or absent; X3 is (D)Arg, Phe, (D)Phe, Lys, (D)Lys, Lys(Y1- (D) Lys(Y1-Ac), or absent, wherein Y1 is an amino acid or Y1 is not present; X4 is Cys, (D)Cys, alpha-MeCys, Abu, (D)Pen, Pe n, (D) Pen sulfoxide, or Pen sulfoxide; X5 is Cit, Lys, Asn, Asp, Glu, Lys(Ac), or Gln the law of nature; X7 is Trp, substituted Trp, or 1-Nal, wherein the substituted Trp is halo or is Trp substituted with azaTrp; X8 is Gln, Lys, Lys(Ac), a-MeLeu, Cit, Glu, 1-Na l, 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, tetrahydro lopilan Ala, Lys(Peg12), or Deg; X13 is Glu, β-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or or (D) Lys(Y2-Ac); wherein Y2 is an amino acid or Y2 is non-existent; X14 is Asn, Asp, Cit, or Lys(Ac); X15 is Asn, Lys, Lys(Ac), Cit, Asp, Gly, Ala, bA la, or Sarc; X16 is an amino acid or is absent; In the formula, X4 and X9 can form a disulfide bond or a thioether bond. 13. The peptide inhibitor according to claim 11 or the peptide dimer inhibitor according to claim 12, Agent. (Item 16) X is a group of formula XIII: X3-X4-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)]- (2-Nal)-X12-X13-X14-Asn-X16(XIII) (SEQ ID NO: 27 6). The peptide inhibitor or peptide dimer inhibitor according to item 15, (Item 17) X4 and X9 are linked together to form a disulfide or thioether bond. 16. The peptide inhibitor or peptide dimer inhibitor according to item 15, (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: 2 77); or X3-Pen-X5-T-Trp-X8-X9-Phe[4-(2-aminoethoxy)] -(2-Nal)-X12-X13-X14-Asn-X16(XIVb) (SEQ ID NO: 2 78). (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: 2 79); X3-Pen-Asn-T-Trp-X8-X9-Phe[4-(2-aminoethoxy) ]-(2-Nal)-X12-X13-X14-Asn-X16(XVb) (SEQ ID NO: 2 80); X3-Abu-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy) ]-(2-Nal)-X12-X13-X14-Asn-X16(XVc) (SEQ ID NO: 2 81); or X3-Pen-Gln-T-Trp-X8-X9-Phe[4-(2-aminoethoxy) ]-(2-Nal)-X12-X13-X14-Asn-X16(XVd) (SEQ ID NO: 2 82). (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: No. 283); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIb)(SEQ ID NO: No. 284); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIc)(SEQ ID NO: No. 285); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVId)(SEQ ID NO: No. 286); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIe)(SEQ ID NO: No. 287); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIf)(Sequence No. No. 288); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIg)(SEQ ID NO: No. 289); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-X12-X13-X14-Asn-X16(XVIh)(Sequence No. 290) according to the peptide inhibitor or peptide dimer inhibitor according to item 15. . (Item 21) X is the 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(XVI Ia) (SEQ ID NO: 291); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ib) (SEQ ID NO: 292); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ic) (SEQ ID NO: 293); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Id) (SEQ ID NO: 294); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ie) (SEQ ID NO: 295); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI If)(SEQ ID NO:296); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI Ig) (SEQ ID NO: 297); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[THP-Ala]-X13-Asn-Asn-X16(XVI 16. The peptide inhibitor or peptide according to item 15, wherein the peptide is in accordance with formula Ih) (SEQ ID NO: 298). Dodimer inhibitors. (Item 22) X is the formula XVIIIa, XVIIIb, XVIIIc, XVIIId, XVIIIe, XVIIIf, XVIIIg, or XVIIIh: X3-Abu-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIa) (SEQ ID NO: 299); X3-Pen-Asn-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIb) (SEQ ID NO: 300); X3-Abu-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIc) (SEQ ID NO: 301); X3-Pen-Gln-T-Trp-X8-Cys-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IId) (SEQ ID NO: 302); X3-Abu-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIe) (SEQ ID NO: 303); X3-Pen-Asn-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIf)(SEQ ID NO:304); X3-Abu-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIg) (SEQ ID NO: 305); or X3-Pen-Gln-T-Trp-X8-Pen-Phe[4-(2-aminoethoxy) )]-(2-Nal)-[a-MeLeu]-X13-Asn-Asn-X16(XVI IIh) (SEQ ID NO: 306), Tide dimer inhibitors. (Item 23) X3 is Gln, Glu, Lys(Ac), or a-MeLeu. 23. The peptide inhibitor or peptide dimer inhibitor of any one of claims 22. (Item 24) X8 is Lys(Y1-Ac) or (D)Lys(Y1-Ac), and Y1 is G Lu, Phe, Trp, Pro, or Arg, according to any one of items 15 to 23. A peptide inhibitor or peptide dimer inhibitor as described above. (Item 25) X13 is Glu, b-homoGlu, Lys, (D)Lys, Lys(Y2-Ac), or (D) Lys(Y2-Ac), where Y2 is an amino acid or is absent. 25. The peptide inhibitor or peptide dimer inhibitor according to any one of items 15 to 24. . (Item 26) X16 is Sar, Lys, (D)Lys, Ahx, b-Ala, Gly, Arg, ( D)Arg, Ile, Gln, (D)Gln, Tyr, Ser, (D)Ser, (D)T Any of items 15-25 that is yr, Ala, Trp, Asp, or (D) Asp 2. The peptide inhibitor or peptide dimer inhibitor according to claim 1. (Item 27) abu and Pen; abu and Cys; Pen and Pen; or Pen and Any one of items 15 to 26, wherein Cys are linked together to form a disulfide bond. 2. A peptide inhibitor or peptide dimer inhibitor according to claim 1. (Item 28) 12. The peptide inhibitor according to any one of items 1 to 11, further comprising a conjugated chemical substituent. 15. The peptide dimer inhibitor according to any one of items 12 to 14. (Item 29) Item 16. The conjugated chemical substituent is a lipophilic substituent or a polymer moiety. Peptide inhibitors or peptide dimers of. (Item 30) The conjugated chemical substituents are Ac, Palm, GamaGlu-Palm (gamaGlu -Palm), isoGlu-Palm, PEG2-Ac, PEG4-isoGlu-Pal m, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IV A, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin. 2. A peptide inhibitor or peptide dimer according to claim 1. (Item 31) The conjugated chemical substituents are polyethylene having a molecular weight of 400 Da to 40,000 Da. 16. The peptide inhibitor or peptide dimer according to item 15, which is ethylene glycol. (Item 32) A peptide inhibitor according to any one of items 1 to 11 or any one of items 12 to 14. One or both peptide monomer subunits of the peptide dimeric inhibitor of claim 1 A polynucleotide comprising a sequence encoding the (Item 33) 33. A vector comprising the polynucleotide according to Item 32. (Item 34) A 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) The enteric coating protects and releases the pharmaceutical composition within the lower gastrointestinal system of a subject. Item 36. The pharmaceutical composition according to Item 35. (Item 37) Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease ( Non-tropical sprue), seronegative arthropathy associated with enteropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, leukocyte adhesion disorder Colitis associated with innate immune disorders such as those in type 1, chronic granulomatous disease, and glycogen storage disease 1 Type B, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wisco syndrome Watt-Aldrich syndrome, pouchitis after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer , pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis , chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft-versus-host disease 33. A method for treating a subject, comprising administering to the subject a therapeutically effective amount of a peptide inhibitor according to any one of items 1 to 32. or a pharmaceutical composition according to any one of items 34 to 36. providing a composition. (Item 38) The pharmaceutical composition may be administered orally, parenterally, intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, intrathecally, by inhalation, or the like. , vapor, spray, sublingual, buccal, parenteral, rectal, ocular, inhalation, topical, vaginal, or local administration 38. The method of claim 37, wherein the administration is administered to the subject by a route. (Item 39) Inflammatory bowel disease (IBD), ulcerative colitis, or ulcerative colitis, wherein the pharmaceutical composition is orally administered to the subject. 38. The method according to item 37 for treating enteritis and Crohn's disease. (Item 40) The pharmaceutical composition is administered to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously. 38. The method of claim 37 for treating psoriasis, provided in

Claims

[Claim 1] The invention described in the specification.

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