Peptide inhibitors of interleukin-23 receptor and their use in the treatment of inflammatory diseases

Abstract

The present invention provides novel peptide inhibitors of interleukin-23 receptor and related compositions, and methods of using these peptide inhibitors to treat or prevent a variety of diseases and conditions, including inflammatory bowel disease.

Description

[0001] Cross-references to related applications

[0002] This patent application claims priority to U.S. Provisional Application No. 62 / 961,624, filed January 15, 2020, which is incorporated herein by reference in its entirety for all purposes.

[0003] sequence list

[0004] This patent application was filed electronically via EFS-Web and includes a sequence list submitted electronically in .txt format. The .txt file contains a sequence list titled “056365_516001WO_Sequence_Listing_ST25.txt”, created on January 11, 2021, and is approximately 336 kilobytes in size. The sequence list contained in this .txt file is part of the specification and is incorporated herein by reference in its entirety. Technical Field

[0005] This invention relates to novel peptide inhibitors of interleukin-23 receptor (IL-23R) and their use in the treatment or prevention of a variety of diseases and conditions, including inflammatory bowel disease, Crohn's disease, ulcerative colitis and psoriasis. Background Technology

[0006] Interleukin-23 (IL-23R) cytokines have been shown to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and conditions such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Studies in mouse models of acute and chronic IBD have demonstrated the major role of IL-23R and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδT cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are abundant in the intestine. Elevated gene expression and protein levels of IL-23R have been found on the intestinal mucosal surface in IBD patients. It is believed that IL-23 promotes the production of pathogenic CD4+, which is responsible for the production of IL-6, IL-17, and tumor necrosis factor (TNF). + This effect is mediated by the production of a T cell population.

[0007] IL-23 is produced and enriched in the gut, where it is believed to play a significant role in regulating the balance between tolerance and immunity via T-cell-dependent and T-cell-independent intestinal inflammatory pathways through the action of T-helper cell 1 (Th1) and Th17-related interferons, and in limiting regulatory T-cell responses in the gut, thereby contributing to inflammation. Furthermore, the polymorphism of the IL-23 receptor (IL-23R) has been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the crucial role of the IL-23 pathway in intestinal homeostasis.

[0008] Psoriasis is a chronic skin disease affecting approximately 2% to 3% of the general population, and it has been shown to be mediated by the body's T-cell inflammatory response mechanisms. IL-23 is one of several interleukins involved in the pathogenesis of psoriasis, and it is believed to maintain chronic autoimmune inflammation by inducing interleukin-17 and regulating the activation of T memory cells and macrophages. Increased expression of IL-23 and IL-23R has been shown in tissues of patients with psoriasis, and in animal models of psoriasis, antibodies that neutralize IL-23 have shown IL-23-dependent inhibition of psoriasis development.

[0009] IL-23 is a heterodimer composed of a unique p19 subunit and a p40 subunit shared with IL-12. This IL-23 is involved in the production of interferon-γ (IFN-γ) by T helper cells 1 (T cells). H 1) Cytokines involved in cell development. Although both IL-23 and IL-12 contain p40 subunits, they exhibit different phenotypic characteristics. For example, animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 may have reduced CD4+ production in the CNS, which is responsible for the production of IL-6, IL-17, and TNF. + T cell counts decrease, leading to resistance. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. The binding of IL-23 to IL-23R activates Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, but Stat4 activation is substantially weaker than that of IL-12, and a different DNA-binding Stat complex forms a response to IL-23. IL-23R constitutively associates with Jak2 and Stat3 in a ligand-dependent manner. Compared to IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0010] Efforts have been made to identify therapeutic components that inhibit the IL-23 pathway for the treatment of IL-23-related diseases and conditions. Several antibodies binding to IL-23 or IL-23R have been identified, including ustekinumab, an antibody that binds to the p40 subunit of IL-23, which has been approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderate to severe active Crohn's disease, and moderate to severe active ulcerative colitis. In recent years, peptide inhibitors binding to IL-23R and inhibiting the binding of IL-23 to IL-23R have been identified (see, for example, U.S. Patent Application Publication No. US2013 / 0029907). Clinical trials using bevacizumab (which also targets the common p40 subunit) and tilatizumab, gusekumab, MEDI2070, and BI-655066 (which targets the unique p19 subunit of IL-23) in the treatment of Crohn's disease or psoriasis highlight the potential of IL-23 signaling blockade in the treatment of human inflammatory diseases. While these findings are promising, challenges remain in identifying stable and selective agents that preferentially target the IL-23 pathway in the gut for the treatment of intestinal inflammation, such as intestinal diseases including Crohn's disease, ulcerative colitis, and related conditions.

[0011] Clearly, there remains a need in the art for novel therapeutics targeting the IL-23 pathway, which can be used to treat and prevent IL-23-related diseases, including those associated with autoimmune inflammation in the gut. Furthermore, compounds and methods that specifically target IL-23R from the luminal side of the gut could provide therapeutic benefits to IBD patients with localized inflammation of the intestinal tissue. This invention addresses these needs by providing novel peptide inhibitors that bind to IL-23R to inhibit IL-23 binding and signaling and are suitable for oral administration. Summary of the Invention

[0012] This invention particularly provides a novel peptide inhibitor of IL-23R and related methods of use.

[0013] In a first aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises or consists of the amino acid sequence of formula (I):

[0014] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I)

[0015] in

[0016] X3 may be absent or be any amino acid;

[0017] X4 can be Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0018] X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln or Asp;

[0019] X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer or Val;

[0020] X7 is an unsubstituted Trp or a Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0021] X8 can be Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-high-Gln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl, Ac), Lys(propyl, Ac), or Trp;

[0022] X9 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0023] X10 is Tyr or a substituted Tyr, an unsubstituted Phe, or a Phe substituted with: halogroup, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, cycloalkyl, carboxyl, formamido, 2-aminoethoxy, or 2-acetaminoethoxy; and

[0024] X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

[0025] X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

[0026] X13 can be any amino acid;

[0027] X14 can be any amino acid;

[0028] and

[0029] i) X15 is any amino acid other than: His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is not...

[0030] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0031] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0032] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0033] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2;

[0034] or

[0035] ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4-triazole Ala, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than: THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is not...

[0036] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-NH2;

[0037] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0038] and

[0039] 5Pyal is a 5-pyrimidine-substituted alanine:

[0040]

[0041] and

[0042] X4 and X9 form disulfide bonds or thioether bonds;

[0043] and

[0044] This peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0045] In some embodiments, X15 is any amino acid other than His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is not:

[0046] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0047] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0048] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0049] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2.

[0050] In some embodiments, X15 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp.

[0051] In some embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc, aMeLeu, (D)Thr, bAla, Pro, or (D)Pro. In some embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc. In some embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is not present.

[0052] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (Ia), (Ib), (Ic), or (Id):

[0053] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-Sarc(Ia),

[0054] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-(D)NMeTyr(Ib),

[0055] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(Ic)

[0056] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[His']-X16(Id)

[0057] Where Pal is 2 Pal, 3 Pal, or 4 Pal; X16 does not exist;

[0058] Wherein 2Pal is 2-pyridyl-substituted alanine, and 3Pal is 3-pyridyl-substituted alanine.

[0059] Furthermore, 4Pal is a 4-pyridyl-substituted alanine.

[0060]

[0061] His' is His or 3-MeHis; X16 is absent; and X4 and X9 form a disulfide bond or a thioether bond;

[0062] Furthermore, X4 and X9 form disulfide bonds or thioether bonds.

[0063] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Ia):

[0064] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-Sarc(Ia)

[0065] X4 and X9 form disulfide bonds or thioether bonds.

[0066] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Ib).

[0067] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-(D)NMeTyr(Ib)

[0068] X4 and X9 form disulfide bonds or thioether bonds.

[0069] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Ic):

[0070] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(Ic)

[0071] Where Pal is 2 Pal, 3 Pal, or 4 Pal; X16 does not exist;

[0072] Wherein 2Pal is 2-pyridyl-substituted alanine, and 3Pal is 3-pyridyl-substituted alanine.

[0073] Furthermore, 4Pal is a 4-pyridyl-substituted alanine.

[0074]

[0075] Furthermore, X4 and X9 form disulfide bonds or thioether bonds.

[0076] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Id):

[0077] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[His']-X16(Id)

[0078] His' is His or 3-MeHis; X16 is absent; and X4 and X9 form a disulfide bond or a thioether bond.

[0079] In some embodiments, the monocyclic peptide is a peptide that is cyclized via a Pen-Pen disulfide bond or via an Abu-Cys or Abu-Pen thioether bond.

[0080] In some implementations, X5 is Cit, Glu, Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Gln, or Asp.

[0081] In some implementations, X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer, or Val.

[0082] In some implementations, X6 is (D)Asp, (D)Dap, or (D)Lys.

[0083] In some embodiments, X8 is Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-high-Gln, Cit, Glu, Phe, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), 1-Nal, 2-Nal, or Trp. In some embodiments, X8 is Lys(Gly) or Lys(bAla).

[0084] In some embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, or cyclohexylAla, Lys, or Aib.

[0085] In one specific embodiment, X15 is any amino acid, and X16 is Sarc, aMeLeu, (D)Thr, bAla, Pro, or (D)Pro.

[0086] In a more specific embodiment, X15 is any amino acid, and X16 is Sarc.

[0087] In a second aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises or consists of the following amino acid sequence of formula (IIIa), (IIIb), (IIIc), or (IIId):

[0088] Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(IIIa),

[0089] Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(IIIb),

[0090] Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X14-[Pal]-X16(IIIc), or

[0091] Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(IIId),

[0092] Wherein X6-X8 and X10-X14 are specific to formula (I); Pal is 2Pal, 3Pal or 4Pal; and X16 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond; and wherein the peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0093] In another aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises or consists of the following amino acid sequence of formula ((IVa), (IVb), (IVc), or (IVd):

[0094] Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(IVa),

[0095] Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(IVb),

[0096] Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-Sarc(IVc) or

[0097] Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(IVd),

[0098] Wherein X6-X8 and X10-X14 are specific to formula (I); X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond; and wherein the peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0099] In some embodiments, X5 is Cit, Glu, Gly, Lys, Asn, Ser, Pro, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Gln, or Asp. In some embodiments, X5 is Cit, Glu, Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Gln, or Asp.

[0100] In some embodiments, X8 is Gln, α-Me-Lys, α-MeLeu, α-MeLys(Ac), β-high Gln, Cit, Glu, Phe, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), 1-Nal, 2-Nal, or Trp. In some implementations, X8 is Lys(Gly) or Lys(bAla).

[0101] In some embodiments, X8 is Gln, α-Me-Lys, α-MeLeu, α-MeLys(Ac), β-high-Gln, Cit, Glu, Phe, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Dab(Ac), Dap(Ac), high-Lys(Ac), 1-Nal, 2-Nal, Trp, or Lys(R'); and R' is Aib, bAla, IVA, Ala, cyclohexanoic acid, octanoic acid, -C(O)CH2Ph ​​(-C(O)benzyl), trifluoropropionic acid, Gly, acetyl, valerate, or trifluoroacetyl; and R' is attached to the N-terminus of Lys. εIn some embodiments, X8 is Asn, α-Me-Lys, α-MeLeu, Aib, Cit, or Lys(R'). In some embodiments, X8 is Lys(R'). In some embodiments, R' is an acetyl group. In another embodiment, R' is Gly, Aib, Ala, or bAla. In some embodiments, R' is Gly or Aib.

[0102] In some implementations, X8 is Lys(Gly) or Lys(bAla).

[0103] In some embodiments, X4 is Abu, and X9 is Cys, (D)Cys, α-MeCys, (D)Pen, or Pen. In some embodiments, X4 is Cys, (D)Cys, α-MeCys, (D)Pen, or Pen; and X9 is Abu. In some embodiments, each X4 and X9 is independently Cys, (D)Cys, α-MeCys, (D)Pen, or Pen. In some embodiments, each X4 and X9 is independently Cys, (D)Cys, α-MeCys, (D)Pen, or Pen.

[0104] In one specific implementation, X3 does not exist.

[0105] In another specific aspect, the present invention provides a peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises or consists of the following amino acid sequence of formula (Z):

[0106] R 1 -XR 2 (Z)

[0107] Or its pharmaceutically acceptable salts or solvates, wherein

[0108] R 1 The polyglycolic acid form is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-6 alkyl, C1-C20 alkylyl group, and includes a spacer group alone or as any of the foregoing; X is an amino acid sequence of formula (I), (Ia), (Ib), (Ic), (Id), (II)-(XVIIId), or an amino acid sequence described in Table E1A, and R 2 It can be OH or NH2.

[0109] In some embodiments, the peptide inhibitor comprises or consists of the following amino acid sequence of formula (Z):

[0110] R 1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R 2 (Z')

[0111] Or its pharmaceutically acceptable salt, wherein

[0112] R 1 The polyethylene glycol form is hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, or C1-C20 alkylyl, and includes a spacer group alone or as any of the foregoing; and R 2 It can be OH or NH2.

[0113] In any specific embodiment of the peptide inhibitors disclosed herein, therein is a peptide inhibitor comprising an amino acid sequence of formula (II)-(XVIIId), wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

[0114] In specific embodiments, any of the peptide inhibitors described herein includes one or more half-life extension portions and / or one or more linker portions conjugated with the peptide inhibitor. In specific embodiments, the half-life extension portion is conjugated with the peptide inhibitor via one or more linker portions.

[0115] In some embodiments, any of the peptide inhibitors described herein further comprises a conjugated chemical substituent. In specific embodiments, the conjugated chemical substituent is a lipophilic substituent or polymeric moiety, such as Ac, Palm, γGlu-Palm, isoGlu-Palm, PEG2-Ac, PEG4-isoGlu-Palm, (PEG)5-Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4-butanediamine, isobutyl, Alexa488, Alexa647, or biotin. In some embodiments, the conjugated chemical substituent is polyethylene glycol with a molecular weight of 400 Da to 40,000 Da. In a specific embodiment, the peptide is conjugated at X8. In another specific embodiment, the peptide is conjugated at X9. In a more specific embodiment, the peptide is conjugated at X10.

[0116] In one related aspect, the present invention includes a peptide dimer inhibitor of the interleukin-23 receptor, wherein the peptide dimer inhibitor comprises two peptide monomer subunits linked via one or more linker portions, wherein each peptide monomer subunit comprises a sequence of formula (I), (Ia), (Ib), (Ic), (Id), (II)-(XVIIId) or any other sequence or structure set forth herein. In some embodiments, one or both peptide monomer subunits are cyclized via an intramolecular bond between X4 and X9. In some embodiments, one or both intramolecular bonds are disulfide bonds or thioether bonds. In some embodiments, the linker portion is any one of those shown in Table 2 or described herein. In some embodiments, the linker portion is a diethylene glycol linker portion, an iminodiacetic acid (IDA) linker portion, a β-iminodiacetic acid (β-Ala-IDA) linker portion, or a PEG linker portion. In a specific embodiment, the N-terminus of each peptide monomer subunit is linked via a linker portion. In a specific embodiment, the C-terminus of each peptide monomer subunit is linked via a linker portion. In some embodiments, the linking portion links an internal amino acid residue of at least one of such peptide monomer subunits to the N-terminus, C-terminus, or internal amino acid residue of another peptide monomer subunit.

[0117] In another related aspect, the present invention includes a polynucleotide comprising a sequence encoding one or two peptide monomer subunits encoding the peptide inhibitor or peptide dimer inhibitor of the present invention. The present invention also includes a carrier comprising the polynucleotide.

[0118] In another aspect, the present invention includes a pharmaceutical composition comprising the peptide inhibitor or peptide dimer inhibitor of the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, the pharmaceutical composition includes an enteric coating. In some embodiments, the enteric coating protects and releases the pharmaceutical composition into the lower gastrointestinal system of the subject.

[0119] In another aspect, the present invention includes a method for treating or preventing diseases associated with IL-23 signaling, including but not limited to inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (nontropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with congenital immune disorders such as leukopenia-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Praque syndrome, and Chediak-Higashi syndrome. The method comprises providing an effective amount of the peptide inhibitor or pharmaceutical composition of the present invention to a subject. In some embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In a specific embodiment, the peptide inhibitor or peptide dimer inhibitor inhibits the binding of interleukin-23 (IL-23) to the interleukin-23 receptor (IL-23R). In some embodiments, the pharmaceutical composition is provided to the subject via oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, spray, sublingual, buccal, non-enteric, rectal, intraocular, inhalation, vaginal, or local administration routes. In certain embodiments, the pharmaceutical composition is administered orally for the treatment of inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease. In some embodiments, the pharmaceutical composition is administered topically, non-enterically, intravenously, subcutaneously, peritoneally, or intravenously to a subject for the treatment of psoriasis. Detailed Implementation

[0120] definition

[0121] Unless otherwise defined herein, the scientific and technical terms used in this patent application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques described herein in conjunction with those of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry are nomenclature and techniques well known and commonly used in the art.

[0122] As used herein, unless otherwise specified, the following terms have their respective meanings.

[0123] Throughout this specification, variations of the word “comprise” or such as “comprises” or “comprising” should be understood to imply inclusion of the stated whole (or component) or group of whole (or component), but not to exclude any other whole (or component) or group of whole (or component).

[0124] Unless the context clearly indicates otherwise, the singular forms “a (or an)” and “the” include the plural.

[0125] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0126] The terms “patient,” “subject,” and “individual” are used interchangeably and refer to humans or non-human animals. These terms include mammals such as humans, primates, livestock (e.g., bovines, suidae), companion animals (e.g., canines, felines), and rodents (e.g., mice and rats).

[0127] As used herein, the term "peptide" broadly refers to a sequence of two or more amino acids linked together by peptide bonds. It should be understood that this term does not imply a specific length of the amino acid polymer, nor is it intended to suggest or distinguish between polypeptides produced using recombinant techniques, chemical or enzymatic synthesis, or naturally occurring polypeptides. The term peptide includes cyclic peptides.

[0128] As used herein, the terms “sequence identity,” “percentage of identity,” “percentage of homology,” or, for example, “a sequence that is 50% identical to…” refer to sequences that are identical on a nucleotide-to-nucleotide and amino acid-to-amino acid basis within a comparison window. Therefore, the “percentage of sequence identity” can be calculated as follows: Compare two best-aligned sequences within a comparison window; determine the number of positions in both sequences where identical nucleic acid bases (e.g., A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) are present to generate the number of matching positions; divide the number of matching positions by the total number of positions in the comparison window (i.e., the window size); and multiply the result by 100 to obtain the percentage of sequence identity.

[0129] The sequence similarity or sequence identity calculations between sequences are performed as follows (these terms are used interchangeably herein). To determine the percentage identity of two amino acid sequences or two nucleic acid sequences, sequences are aligned for optimal comparison purposes (e.g., gaps may be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences may be ignored for comparison purposes). In some embodiments, the reference sequence length for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the reference sequence length. The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecule is identical at that position.

[0130] The percentage of consistency between two sequences is a function of the number of common positions shared by such sequences. Considering the number of gaps and the length of each gap, such gaps need to be introduced to achieve optimal alignment of the two sequences.

[0131] Mathematical algorithms can be used to perform sequence comparisons and determine the percentage of similarity between two sequences. In some embodiments, the percentage of similarity between two amino acid sequences is determined using the Needleman and Wunsch (1970, J. Mol. Biol. 48:444-453) algorithm (which is incorporated into the GAP program in the GCG software package), using a Blossum 62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In another preferred embodiment, the percentage of similarity between two nucleotide sequences is determined using the GAP program in the GCG software package, using an NWSgapdna.CMP matrix, and gap weights of 40, 50, 60, 70, or 80, and length weights of 1, 2, 3, 4, 5, or 6. Another set of exemplary parameters includes a Blossum 62 scoring matrix, wherein the gap penalty is 12, the gap expansion penalty is 4, and the read frame transfer gap penalty is 5. The percentage of similarity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios 4:11-17) (which has been incorporated into the ALIGN program (version 2.0)) with a PAM120 weighted residue table, a gap length penalty of 12, and a gap penalty of 4.

[0132] The peptide sequences described herein can be used as "query sequences" to search public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (1990, J.Mol.Biol.215:403-10). BLAST nucleotide searches can be performed using the NBLAST program (score = 100, word length = 12) to obtain nucleotide sequences homologous to the nucleic acid molecules of this invention. BLAST protein searches can be performed using the XBLAST program (score = 50, word length = 3) to obtain amino acid sequences homologous to the protein molecules of this invention. For gap alignments to achieve comparative purposes, gap BLAST can be used as described by Altschul et al. (Nucleic Acids Res.25:3389-3402, 1997). When using BLAST and gap BLAST programs, the preset parameters of the corresponding programs (e.g., XBLAST and NBLAST) can be used.

[0133] As used herein, the term "conservative substitution" refers to the replacement of one or more amino acids with another bio-similar residue. Examples include the substitution of amino acid residues with similar characteristics, such as smaller amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids, and aromatic amino acids. See, for example, the table below. In some embodiments of the invention, one or more Met residues are substituted with orleucine (Nle), which is a bioisosteric form of Met but is less susceptible to oxidation than Met. Another example of conservative substitution with residues not typically found in endogenous mammalian peptides and proteins is the conservative substitution of Arg or Lys with, for example, ornithine, canavanine, aminoethylcysteine, or another basic amino acid. In some embodiments, one or more cysteine ​​residues of the peptide analogs of the invention may be substituted with another residue, such as serine. For further information on phenotypic silent substitutions in peptides and proteins, see, for example, Bowie et al., Science 247, 1306-1310, 1990. In the following embodiments, the conservative substitutions of amino acids are grouped according to their physicochemical properties. I: Neutral hydrophilic, II: Acids and amides, III: Basic, IV: Hydrophobic, V: Aromatic, large group of amino acids.

[0134] A N H M F S D R L Y T E K I W P Q V G C

[0135] In the following schemes, amino acids are grouped according to their conserved substitutions based on their physicochemical properties. VI: Neutral or hydrophobic, VII: Acidic, VIII: Basic, IX: Polar, X: Aromatic.

[0136] A E H M F L D R S Y I K T W P C G N V Q

[0137] As used herein, the term "amino acid" or "any amino acid" refers to any and all amino acids, including naturally occurring amino acids (e.g., α-amino acids), non-natural amino acids, modified amino acids, and non-natural amino acids. This includes both D-amino acids and L-amino acids. Natural amino acids include those found in nature, such as the 23 amino acids that combine into peptide chains to form the building blocks of numerous proteins. These stereoisomers are primarily L-stereomers, but some D-amino acids are found in bacterial envelopes and some antibiotics. Twenty "standard" natural amino acids are listed in the table above. "Non-standard" natural amino acids are pyrrolidine (found in methane-producing organisms and other eukaryotes), selenocysteine ​​(found in many non-eukaryotes and most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). "Non-natural" or "non-protein" amino acids are non-protein amino acids that are naturally occurring or chemically synthesized (i.e., amino acids not naturally encoded or found in the genetic code). More than 140 non-natural amino acids are known, and there are likely thousands of possible combinations. Examples of "non-natural" amino acids include β-amino acids (β...). 3 and β 2 The invention includes amino acids, proline derivatives and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, cyclic-substituted phenylalanine and tyrosine derivatives, linear nuclear amino acids, diamino acids, D-diamino acids, α-methyl amino acids, and N-methyl amino acids. Non-natural or unnatural amino acids also include modified amino acids. "Modified" amino acids include those that have been chemically modified to include groups or chemical moieties not naturally present on the amino acid (e.g., natural amino acids). According to some embodiments, the peptide inhibitor comprises an intramolecular bond between two amino acid residues present in the peptide inhibitor. It should be understood that the amino acid residues forming the bond will be slightly altered when bonded to each other compared to when they are not bonded to each other. References to specific amino acids are intended to cover amino acids in both their unbonded and bonded states. For example, the amino acid residues homoserine (hSer) or homoserine (Cl) in their unbonded form may be in the form of 2-aminobutyric acid (Abu) when participating in the intramolecular bond according to the invention. The invention includes peptide inhibitors containing crosslinks between X4 and X9, and peptide inhibitors not containing crosslinks between X4 and X9 (e.g., before crosslinking formation). Therefore, the names hSer and Abu are intended to indicate the same amino acid and can be used interchangeably.

[0138] Primarily, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Committee on the Nomenclature of Organic Chemistry and the IUPAC-IUB Committee on the Nomenclature of Biochemicals, as stated in Recommendations (1974) Biochemistry, 14(2), (1975). The degree to which the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from those recommendations will be clear to the reader. Some abbreviations used to describe the invention are defined in Table 1 below.

[0139] Table 1. Abbreviations for non-natural amino acids and their chemical components (unless all Ls specify, this applies to amino acid derivatives).

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] Throughout this specification, unless naturally occurring amino acids are represented by their full names (e.g., alanine, arginine, etc.), they are represented by their well-known three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise specified, the three-letter and one-letter abbreviations for amino acids refer to the L-isomer of the amino acid in question. As used herein, the term "L-amino acid" refers to the "L" isomer of the peptide, and conversely, the term "D-amino acid" refers to the "D" isomer of the peptide (e.g., Dasp, (D)Asp, or D-Asp; Dphe, (D)Phe, or D-Phe). Amino acid residues in the D-isomer form may be substituted with any L-amino acid residue, provided the desired function is retained in the peptide. When using one-letter abbreviations, D-amino acids may be conventionally represented in lowercase.

[0153] In the case of less common or non-naturally occurring amino acids, unless represented by their full name (e.g., sarcosine, ornithine, etc.), their residues are usually represented by three or four character codes, including: Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), 8Ado (8-amino-3,6-dioxanoic acid), Abu (2-aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenylalanine), Bip (β,β-diphenylalanine), and Ida (iminodiacetic acid).

[0154] As will be apparent to those skilled in the art, the peptide sequences disclosed herein are shown from left to right, with the left end of the sequence representing the N-terminus of the peptide and the right end representing the C-terminus. The sequences disclosed herein are those having a "Hy-" portion at the amino terminus (N-terminus) and a "-OH" or "-NH2" portion at the carboxyl terminus (C-terminus). In such cases, and unless otherwise specified, the "Hy-" portion at the N-terminus of the discussed sequence indicates a hydrogen atom corresponding to the presence of a free primary or secondary amino group at the N-terminus, while the "-OH" or "-NH2" portion at the C-terminus indicates a hydroxyl or amino group corresponding to the presence of an amide (CONH2) group at the C-terminus, respectively. In the sequences of this invention, the C-terminal "-OH" portion may be substituted with the C-terminal "-NH2" portion, and vice versa.

[0155] Those skilled in the art will understand that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, for example, by removing or replacing one or more hydrogen atoms through the bond. Therefore, as used herein, references to the presence of an amino acid or modified amino acid (e.g., at position X4 or position X9) in the peptide dimer of the present invention mean including the amino acid or modified amino acid form present in the peptide before and after the formation of the intramolecular bond.

[0156] As used herein, the term "dimer" broadly refers to a peptide comprising two or more monomeric subunits. Some dimers comprise two monomeric subunits, including those of formula (I) or the sequences set forth herein. The dimers of this invention include homodimers and heterodimers. The monomeric subunits of a dimer may be linked at their C-terminus or N-terminus, or may be linked via internal amino acid residues. The monomeric subunits of a dimer may be linked via the same site, or the monomeric subunits may be linked via different sites (e.g., C-terminus, N-terminus, or internal sites).

[0157] As used herein, the term "NH2" may refer to a free amino group present at the amino terminus of a peptide. As used herein, the term "OH" may refer to a free carboxyl group present at the carboxyl terminus of a peptide. Furthermore, as used herein, the term "Ac" refers to acetyl protection of a peptide by acylation of its C-terminus or N-terminus. In some peptides shown herein, NH2 is located at the C-terminus of the peptide to indicate an amino group.

[0158] As used in this article, the term "carboxyl group" refers to -CO2H.

[0159] As used herein, the term "electron isosteric substitution" refers to any amino acid or other similar moiety having chemical and / or structural properties similar to a specified amino acid. In some embodiments, electron isosteric substitution is a conservative substitution or an analogue of the specified amino acid.

[0160] As used herein, the term "cyclization" refers to a portion of a polypeptide molecule that is linked to another part of the molecule to form a dead loop (such as by forming a disulfide bridge or thioether bond).

[0161] As used herein, the term "subunit" refers to one of a pair of polypeptide monomers that bind together to form a dimer peptide composition.

[0162] As used in this article, the term "linking moiety" broadly refers to a chemical structure that can link or join two peptide monomer subunits together to form a dimer.

[0163] As used herein, the term "medically acceptable salt" refers to a salt or zwitterionic form of a compound or peptide of the present invention that is water-soluble, oil-soluble, or dispersible, suitable for treating diseases without adverse toxicity, irritation, or allergic reactions; that meets a reasonable benefit / risk ratio; and that is effective for its intended use. The salt may be prepared during the final isolation and purification of the compound or by reacting the amino groups separately with a suitable acid. Representative acid addition salts include, but are not limited to: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butates, camphorates, camphorsulfonates, diglucose, glyceryl phosphates, hemisulfates, heptanates, hexanoates, formates, trans-butenedioates, hydrochlorides, hydrobromides, hydroiodates, 2-hydroxyethanesulfonates (hydroxyethylsulfonates), lactates, maleates, mesitylenesulfonates, methanesulfonates, naphthalenesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, dihydroxynaphthaleneates, pectinates, persulfates, 3-phenylpropionates, picrates, pentanoates, propionates, succinates, tartrates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, p-toluenesulfonates, and undecanoates. Furthermore, the amino group in the compounds of the present invention can be ammonified in the following four stages: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and dipentyl sulfates; decyl, dodecyl, tetradecyl, and sterol chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Pharmaceutically acceptable salts may suitably be salts selected, for example, acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrates, and acetates. Examples of basic salts include salts in which the cation is selected from alkali metal cations (such as sodium or potassium ions), alkaline earth metal cations (such as calcium or magnesium ions), and substituted ammonium ions (such as N(R1)(R2)(R3)(R4)+ type ions), wherein R1, R2, R3, and R4 will generally independently represent hydrogen, a C1-6 alkyl group substituted as appropriate, or a C2-6 alkenyl group substituted as appropriate. Examples of relevant C1-6 alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl. Examples of potentially relevant C2-6 alkenyl groups include vinyl, 1-propenyl, and 2-propenyl.Other examples of pharmaceutically acceptable salts are described in *Encyclopaedia of Pharmaceutical Technology*, 3rd edition, James Swarbrick (ed.), Informa Healthcare USA (Inc.), NY, USA, 2007; and in *Remington's Pharmaceutical Sciences*, 17th edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and later editions), and *J. Pharm. Sci.* 66:2 (1977). Furthermore, for a review of suitable salts, see Stahl and Wermuth's *Handbook of Pharmaceutical Salts: Properties, Selection, and Use* (Wiley-VCH, 2002). Other suitable alkaline salts are formed from bases that form non-toxic salts. Representative examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, thiazoline, and zinc salts. They can also form hemisalts of acids and bases, such as hemisulfates and hemicalcium salts.

[0164] As used in this article, the term “N(α)methylation” describes the methylation of the α-amine of an amino acid, and is also commonly referred to as N-methylation.

[0165] As used herein, the term "symmetric methylation" or "Arg-Me-symmetric" describes the symmetric methylation of two nitrogen atoms in the arginine guanidine group. Conversely, the term "asymmetric methylation" or "Arg-Me-asymmetric" describes the methylation of a single nitrogen atom in the arginine guanidine group.

[0166] As used herein, the term "acylated organic compound" refers to various compounds having a carboxylic acid functional group used to acylate the N-terminus of an amino acid or monomer or dimer, such as a monomer subunit, prior to the formation of a C-terminal dimer. Non-limiting examples of acylated organic compounds include cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclopentanecarboxylic acid, 3,3,3-trifluoropropionic acid, 3-fluoromethylbutyric acid, and tetrahydro-2H-piperan-4-carboxylic acid.

[0167] The term "alkyl" includes straight-chain or branched-chain acyclic or cyclic saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and similar groups, while saturated branched-chain alkyl groups include, but are not limited to, isopropyl, secondary butyl, isobutyl, tertiary butyl, isopentyl, and similar groups. Representative saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and similar groups, while unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and similar groups.

[0168] "Halogen" or "halogen" refers to a substituent of bromine (Br), chlorine (Cl), fluorine (F), or iodine (I).

[0169] The term "haloalkyl" includes an alkyl structure in which at least one hydrogen atom is substituted with a halogen atom. In some embodiments in which two or more hydrogen atoms are substituted with halogen atoms, the halogen atoms are all identical to each other. In other embodiments in which two or more hydrogen atoms are substituted with halogen atoms, the halogen atoms are not all identical to each other.

[0170] "Alkoxy" refers to an (alkyl) O- group, where the alkyl group is as defined herein.

[0171] "Aryloxy group" refers to the (aryl) O- group, where the aryl group is as defined herein.

[0172] "Aminocarbonyl" or "formamide" refers to the -CONH2 group.

[0173] "2-Aminoethoxy" refers to the -OCH2CH2-NH2 group.

[0174] "2-Acetaminoethoxy" refers to the -OCH2CH2-N(H)C(O)Me group.

[0175] The term “mammal” refers to any mammal species, such as humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, livestock and the like.

[0176] As used herein, the term "therapeutic effective amount" for the peptide inhibitor of the present invention is intended to describe a sufficient amount of the peptide inhibitor to treat IL-23 / IL-23R-related diseases, including but not limited to any of the diseases and conditions described herein (e.g., reducing inflammation associated with IBD). In specific embodiments, the therapeutic effective amount will achieve the desired benefit / risk ratio applicable to any medical treatment.

[0177] The term "analyte" for an amino acid, such as "Phe analog" or "Tyr analog," means an analog of the mentioned amino acid. Many amino acid analogs are known and available in the art, including Phe and Tyr analogs. In some embodiments, the amino acid analog, such as a Phe analog or a Tyr analog, comprises one, two, three, four, or five substitutions (compared to Phe or Tyr). In some embodiments, the substitutions are present in the side chain of the amino acid. In some embodiments, the Phe analog has the structure Phe(R) 2 ), where R 2 It can be Hy, OH, CH3, CO2H, CONH2, CONH2OCH2CH2NH2, t-Bu, OCH2CH2NH2, phenoxy, OCH3, Oalkyl, Br, Cl, F, NH2, N3, or guanidine. In some embodiments, R 2 The derivatives are CONH2OCH2CH2NH2, OCH3, CONH2, OCH3, or CO2H. Examples of Phe analogs include, but are not limited to: hPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH2), Phe(4-phenoxy), Phe(4-guanidine), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F), Phe(4-F), Phe(3,5Di F), 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-phenylphenylmethylalanine, Phe(4-CONH2), Phe(3,4-dimethoxy), Phe(4-CF3), Phe(2,3-Cl2), and Phe(2,3-F2). Examples of Tyr analogues include, but are not limited to: hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N3), and βhTyr.

[0178] IL-23R peptide inhibitors

[0179] Genome-wide association studies (GWAS) have confirmed a significant association between the IL-23 receptor (IL-23R) gene and inflammatory bowel disease (IBD), indicating that perturbations in IL-23 signaling may be associated with the pathogenesis of this disease and other inflammatory diseases and conditions. This invention provides compositions and methods for antagonizing the IL-23 pathway via IL-23R.

[0180] This invention generally relates to peptides possessing IL-23R antagonist activity, including both peptide monomers and peptide dimers. In some embodiments, this invention demonstrates a new paradigm for treating IBD and other diseases and conditions via oral delivery of IL-23 antagonists. IBD represents localized inflammation of the intestinal tissue; therefore, it is advantageous for therapeutic agents to act from the luminal side of the intestine, producing higher drug concentrations in the affected tissue, minimizing systemic availability, and resulting in improved efficacy and safety compared to systemic approaches. Oral administration of the compounds of this invention is expected to maximize drug concentrations in the affected intestinal tissue while limiting circulating drug concentrations, thereby providing an effective, safe, and sustained delivery for long-term treatment of IBD and other diseases and conditions.

[0181] In some embodiments, the present invention relates to various peptides or peptide dimers comprising hetero or homomonomer subunits that form cyclic structures via disulfide bonds or other bonds. In some embodiments, the disulfide bonds or other bonds are intramolecular bonds. It has been shown that the cyclic structure of the monomer subunits of peptide monomer inhibitors and peptide dimer inhibitors improves the performance and selectivity of the peptide inhibitor. In some embodiments, the peptide dimer inhibitor may include one or more intermolecular bonds connecting two monomeric peptide subunits within the peptide dimer inhibitor, such as an intermolecular bridge between two Pen residues, one in each peptide monomer subunit.

[0182] This invention provides a peptide inhibitor that binds to IL-23R, which may be a monomer or a dimer. In specific embodiments, the peptide inhibitor inhibits the binding of IL-23 to IL-23R. In some embodiments, IL-23R is human IL-23R, and IL-23 is human IL-23. In some embodiments, compared to a negative control peptide, the peptide inhibitor of this invention reduces the binding of IL-23 to IL-23R by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. The method for determining binding is known in the art and includes ELISA analysis, as described in the accompanying examples.

[0183] In some embodiments, the IC50 of the peptide inhibitor of the present invention 50 >1 mM, <1 mM, 500 nM to 1000 nM, <500 nM, <250 nM, <100 nM, <50 nM, <25 nM, <10 nM, <5 nM, <2 nM, <1 nM, or <5 mM, for example, to inhibit the binding of IL-23 to IL-23R (e.g., human IL-23 and human IL-23R). Methods for determining activity are known in the art and include any of the methods described in the accompanying examples.

[0184] In some embodiments, the peptide inhibitor of the present invention has increased stability, increased gastrointestinal stability, or increased stability in stimulated intestinal fluid (SIF) or simulated gastric juice (SGF) and / or under redox conditions (e.g., DTT) compared to a control peptide. In some embodiments, the control peptide is an unrelated peptide of the same or similar length. In a specific embodiment, the control peptide is a peptide having the same or highly correlated amino acid sequence as the peptide inhibitor (e.g., >90% sequence identity). In a specific embodiment, the control peptide is a peptide having the same or highly correlated amino acid sequence as the peptide inhibitor (e.g., >90% sequence identity) but without a cyclized structure, such as via an intramolecular bond between two amino acid residues within the control peptide, or being undimerized, or not containing a conjugate for stabilization. In a specific embodiment, the only difference between the peptide inhibitor and the control peptide is that the peptide inhibitor comprises one or more amino acid substitutions introduced into the peptide inhibitor, wherein the introduced amino residues form an intrasulfide or thioether bond with another amino acid residue in the peptide inhibitor. An example of a control for a peptide dimer inhibitor is a monomer having the same sequence as one of the monomer subunits present in the peptide dimer inhibitor. An example of a control for a peptide inhibitor comprising a conjugated peptide is a peptide having the same sequence but not including the conjugated portion. In some embodiments, the control peptide is a peptide corresponding to the IL-23 region that binds to IL-23R (e.g., a naturally occurring peptide).

[0185] Methods for determining the stability of peptides are known in the art. In some embodiments, the stability of the peptide inhibitor is determined using SIF analysis, such as that described in Example 3. In some embodiments, the stability of the peptide inhibitor is determined using SGF analysis, such as that described in Example 3. In specific embodiments, when exposed to SIF, SGF, or DTT, the peptide inhibitor has a half-life greater than 1 minute, greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, greater than 60 minutes, greater than 90 minutes, greater than 120 minutes, greater than 3 hours, or greater than 4 hours (e.g., in SIF, SGF, or DTT). In some embodiments, the temperature is about 25°C, about 4°C, or about 37°C, and the pH is physiological pH or about 7.4.

[0186] In some embodiments, the half-life is measured in vitro using any suitable method known in the art. For example, in some embodiments, the stability of the peptides of the present invention is determined by incubating the peptides with pre-warmed human serum (Sigma) at 37°C. Samples are collected at different time points, typically up to 24 hours, and the stability of the samples is analyzed by isolating the peptides or peptide dimers from serum proteins and subsequently analyzing the presence of the peptides or peptide dimers of interest using LC-MS.

[0187] In some embodiments, the peptide inhibitors of the present invention exhibit improved solubility or reduced aggregation characteristics compared to the control peptide. Solubility can be determined by any suitable method known in the art. In some embodiments, suitable methods known in the art for determining solubility include culturing the peptide in various buffers (acetate pH 4.0, acetate pH 5.0, Phos / citrate pH 5.0, Phos citrate pH 6.0, Phos pH 6.0, Phos pH 7.0, Phos pH 7.5, strong PBS pH 7.5, Tris pH 7.5, Tris pH 8.0, glycine pH 9.0, water, acetic acid (pH 5.0, and others known in the art)) and testing aggregation or solubility using standard techniques. These include, for example, visual precipitation, dynamic light scattering, circular dichroism, and fluorescent dyes to measure surface hydrophobicity and detect aggregation or fibrillation. In some embodiments, improved solubility means that the peptide is more soluble in a given liquid than a control peptide. In some embodiments, reduced aggregation means that the peptide exhibits less aggregation in a specified liquid under specified conditions than a control peptide.

[0188] In some embodiments, it is advantageous to achieve higher compound concentrations in intestinal tissue during oral delivery, and the peptide inhibitors of the present invention are stable in the gastrointestinal (GI) environment. Proteolytic metabolism in the gastrointestinal tract is driven by enzymes, including pepsin, trypsin, chymotrypsin, elastase, aminopeptidase, and carboxypeptidase A / B, which are secreted from the pancreas into the lumen or produced as brush border enzymes. Proteases typically cleave peptides and proteins in extended conformations. In the reducing environment of intestinal fluid, disulfide bonds can break, producing linear peptides and rapid proteolysis. This luminal redox environment is largely determined by the Cys / CySS redox cycle. In intestinal epithelial cells, relevant activities include various digestive enzymes such as CYP450 and UDP-glucuronidase. Finally, at 10 10 Up to 10 12 Concentrations of peptide inhibitors in the CFU / ml range present in the large intestine constitute another metabolic barrier. In some embodiments, the peptide inhibitors are stable to a variety of pH values, which are strongly acidic in the stomach (pH 1.5–1.9), tend to be alkaline in the small intestine (pH 6–7.5), and subsequently weakly acidic in the colon (pH 5–7). These peptide inhibitors are stable during their delivery through various gastrointestinal compartments, a process estimated to take 3–4 hours in the intestine and 6–48 hours in the colon.

[0189] In some embodiments, the peptide inhibitors of the present invention exhibit lower degradation (i.e., higher degradation stability) over a period of time, for example, by more than or about 10%, more than or about 20%, more than or about 30%, more than or about 40%, or more than or about 50% less degradation than a control peptide. In some embodiments, degradation stability is determined by any suitable method known in the art. In some embodiments, the degradation is enzymatic degradation. For example, in some embodiments, such peptide inhibitors have reduced sensitivity to degradation by trypsin, chymotrypsin, or elastase. In some embodiments, suitable methods known in the art for determining degradation stability include Hawe et al., J Pharm Sci, Vol. 101, No. 3, 2012, pp. 895-913, the entire contents of which are incorporated herein by reference. In some embodiments, such methods are used to select potent peptide sequences with enhanced shelf life. In specific embodiments, peptide stability is determined using SIF or SGF analysis, for example, PCT Publication WO 2016 / 011208.

[0190] In some embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated inflammation. In related embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated secretion of one or more cytokines, for example, by binding to IL-23R on the cell surface, thereby inhibiting the binding of IL-23 to the cell. In specific embodiments, the peptide inhibitors of the present invention inhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3, Stat4, or Stat5. Methods for determining inhibition of cytokine secretion and inhibition of signal transduction molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling can be determined by measuring the inhibition of phosphate-Stat3 levels in cell lysates, as described, for example, in PCT Publication No. WO 2016 / 011208.

[0191] In some embodiments, the peptide inhibitor exhibits increased redox stability compared to the control peptide. A variety of analyses known and applicable in the art can be used to determine redox stability. Any of these can be used to determine the redox stability of the peptide inhibitor of the present invention.

[0192] In some embodiments, the present invention provides various peptide inhibitors that bind or associate with IL-23R in vitro or in vivo to disrupt or block the binding between IL-23 and IL-23R. In some embodiments, such peptide inhibitors bind and / or inhibit human IL-23R. In some embodiments, peptide inhibitors bind and / or inhibit both human and rodent IL-23R. In some embodiments, peptide inhibitors bind and / or inhibit both human and rat IL-23R. In some embodiments, peptide inhibitors bind and / or inhibit human IL-23R, rat IL-23R, and cynomolgus monkey IL-23R. In specific embodiments, peptide inhibitors inhibit rat IL-23R and / or cynomolgus monkey IL-23R by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, and bind or inhibit human IL-23R, as determined, for example, by the analyses described herein. In some embodiments, the peptide inhibitor preferentially binds to and / or inhibits human IL-23R and / or rat IL-23R and / or cynomolgus monkey IL-23R compared to mouse IL-23R. In specific embodiments, the peptide inhibitor preferentially binds to rat IL-23R compared to mouse IL-23R. In specific embodiments, the peptide inhibitor preferentially binds to human IL-23R compared to mouse IL-23R. In specific embodiments, the peptide inhibitor preferentially binds to cynomolgus monkey IL-23R compared to mouse IL-23R. In some embodiments, the binding of the peptide inhibitor to mouse IL-23R is less than 75%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the binding of the same peptide inhibitor to human IL-23R and / or rat IL-23R and / or cynomolgus monkey IL-23R. In certain embodiments of peptide inhibitors that preferentially bind to and / or inhibit human IL-23R and / or rat IL-23R and / or cynomolgus monkey IL-23R compared to mouse IL-23R, the peptide inhibitor binds to IL-23R regions that are disrupted by the presence of additional amino acids present in mouse IL-23R (rather than human IL-23R, rat IL-23R, or cynomolgus monkey IL-23R). In some embodiments, the additional amino acids present in mouse IL-23R are located in a region corresponding to about amino acid residues 315 to about amino acid residues 340 of the mouse IL-23R protein, for example, the amino acid region NWQPWSSPFVHQTSQETGKR (SEQ ID NO: 447). In a specific embodiment, the peptide inhibitor binds to a region of human IL-23R from about amino acid residues 230 to about amino acid residues 370.

[0193] In some embodiments, the peptide inhibitor exhibits gastrointestinal restricted localization after oral administration. In specific embodiments, greater than 50%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% of the orally administered peptide inhibitor is located in gastrointestinal organs and tissues. In specific embodiments, the plasma concentration of the orally administered peptide inhibitor is less than 20%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of the peptide inhibitor concentration found in the small intestinal mucosa, colonic mucosa, or proximal colon.

[0194] The various peptide inhibitors of the present invention may be constructed solely from natural amino acids. Alternatively, peptide inhibitors may include non-natural amino acids, including but not limited to modified amino acids. In some embodiments, modified amino acids include natural amino acids that have been chemically modified to include groups or chemical moieties not naturally present on the amino acid. The peptide inhibitors of the present invention may additionally include one or more D-amino acids. Furthermore, the peptide inhibitors of the present invention may include amino acid analogs.

[0195] In some embodiments, the peptide inhibitor of the present invention comprises one or more modified or non-natural amino acids. In some embodiments of the present invention, the peptide inhibitor comprises one or more non-natural amino acids shown in Table 1. In some embodiments, the peptide inhibitor of the present invention comprises any of the others described herein, including but not limited to any of the others comprising the amino acid sequences or peptide inhibitor structures shown in any of the tables herein.

[0196] The present invention also includes any of the peptide inhibitors described herein in free or salt form. Therefore, embodiments of any of the peptide inhibitors described herein (and their associated methods of use) include pharmaceutically acceptable salts of the peptide inhibitor.

[0197] The present invention also includes variants of any of the peptide inhibitors described herein, including but not limited to any of the sequences shown in any of the tables herein, wherein one or more L-amino acid residues are substituted with a D-isomer of the amino acid residue, for example, L-Ala is substituted with D-Ala.

[0198] The peptide inhibitors described herein include isotopically labeled peptide inhibitors. In specific embodiments, the present invention provides peptide inhibitors that are identical to any of the peptide inhibitors having or presented herein in various formulas and structures, but in fact have one or more atoms replaced by atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, respectively such as 2 H, 3 H, 13 C 14 C 15 N、18 O、 17 O、 35 S, 18 F, 36 Cl. Certain isotopically labeled compounds described herein (e.g., those containing, such as) 3 H and 14 Compounds containing radioactive isotopes of C are suitable for drug and / or substrate tissue distribution analysis. Additionally, compounds such as deuterium (i.e.,...) are also suitable. 2 Isotope substitution of H can yield certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0199] The invention also includes any of the peptide monomer inhibitors described herein linked to a linker portion (including any of the specific linkers described herein). In a particular embodiment, the linker portion is linked to an N-terminal or C-terminal amino acid, while in other embodiments, the linker portion is linked to an inner amino acid. In a particular embodiment, the linker portion is linked to two inner amino acids, for example, inner amino acids in each of the two monomer subunits forming a dimer. In some embodiments of the invention, the peptide inhibitor is linked to one or more of the linkers shown.

[0200] This invention also includes peptides and peptide dimers comprising peptides having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the peptide sequence of the peptide inhibitors described herein. In specific embodiments, the peptide inhibitors of this invention comprise a nucleopeptide sequence and one or more N-terminal and / or C-terminal modifications (e.g., Ac and NH2) and / or one or more conjugated linkers and / or half-life extensions. As used herein, the nucleopeptide sequence is the amino acid sequence of a peptide without such modifications and conjugations.

[0201] In some embodiments, the peptide inhibitor or monomeric subunit of the peptide inhibitor of the present invention comprises, is substantially composed of, or is composed 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 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10 to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues, and one or more additional non-amino acid portions, such as conjugated chemical portions, for example, PEG or linking portions, as appropriate. In specific embodiments, the peptide inhibitor (or its monomeric subunit) of the present invention, including but not limited to peptide inhibitors of any embodiment of Formula I, comprises more than 10, more than 12, more than 15, more than 20, more than 25, more than 30, or more than 35 amino acids, for example, 35 to 50 amino acids. In some embodiments, the peptide inhibitor (or its monomeric subunit) comprises 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 specific embodiments, the monomeric subunit of the peptide inhibitor (or peptide monomer inhibitor) comprises or is composed of the following: 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acid residues. In specific embodiments, the monomeric subunit of the peptide inhibitor of the present invention comprises or consists of 10 to 23 amino acid residues and, where appropriate, one or more additional non-amino acid portions, such as conjugated chemical portions, e.g., PEG, or linker portions. In various embodiments, the monomeric subunit comprises or consists of 7 to 35 amino acid residues, 7 to 20 amino acid residues, 8 to 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 10 to 18 amino acid residues. In any of the various formulations described herein, in a particular embodiment…

[0202] Some of the exemplary peptide inhibitors described herein comprise 12 or more amino acid residues. However, the invention also includes peptide inhibitors comprising fragments of any of the peptide sequences described herein, including peptide inhibitors having 7, 8, 9, 10, or 11 amino acid residues. For example, the peptide inhibitors of the present invention comprise peptides comprising or composed of the following: X4-X9, X4-X10, X4-X11, X4-X12, X4-X13, X4-X14, or X4-X15.

[0203] In a specific embodiment of the invention, the amino acid sequence of the peptide inhibitor is not present in the antibody, or is not present in the V of the antibody. H or V L Within the district.

[0204] peptide inhibitors

[0205] The peptide inhibitors of the present invention comprise peptides comprising or consisting of any of the following: amino acid sequences described herein, compounds having any of the structures described herein (including compounds comprising any of the peptide sequences described herein), and dimers of such peptides and compounds. Exemplary peptides of the present invention comprise amino acid sequences or structures described in any of the accompanying tables.

[0206] In a first aspect, the present invention provides a monocyclic peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor comprises the amino acid sequence of formula (I).

[0207] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I)

[0208] in

[0209] X3 may be absent or be any amino acid;

[0210] X4 can be Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0211] X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln or Asp;

[0212] X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer or Val;

[0213] X7 is an unsubstituted Trp or a Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0214] X8 can be Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-high-Gln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl, Ac), Lys(propyl, Ac), or Trp;

[0215] X9 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0216] X10 is Tyr or a substituted Tyr, an unsubstituted Phe, or a Phe substituted with: halogroup, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, cycloalkyl, carboxyl, formamido, 2-aminoethoxy, or 2-acetaminoethoxy; and

[0217] X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

[0218] X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

[0219] X13 can be any amino acid;

[0220] X14 can be any amino acid;

[0221] and

[0222] i) X15 is any amino acid other than: His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is not...

[0223] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0224] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0225] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0226] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2;

[0227] or

[0228] ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4-triazole Ala, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than: THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is not...

[0229] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-NH2;

[0230] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0231] and

[0232] 5Pyal is a 5-pyrimidine-substituted alanine:

[0233] and

[0234] X4 and X9 form disulfide bonds or thioether bonds;

[0235] and

[0236] This peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0237] In some embodiments, the present invention provides a monocyclic peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of formula (I):

[0238] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I)

[0239] in

[0240] X3 may be absent or be any amino acid;

[0241] X4 can be Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0242] X5 is Cit, Glu, Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Gln or Asp;

[0243] X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer or Val;

[0244] X7 is an unsubstituted Trp or a Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0245] X8 is Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-high Gln, Cit, Glu, Phe, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly) or Trp;

[0246] X9 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0247] X10 is unsubstituted Phe or Phe substituted with the following groups: halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carboxyl, formamido, 2-aminoethoxy, or 2-acetaminoethoxy; and

[0248] X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

[0249] X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

[0250] X13 can be any amino acid;

[0251] X14 can be any amino acid;

[0252] and

[0253] i) X15 is any amino acid other than: His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is not...

[0254] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0255] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu] ]-[ Lys(Ac)]-NN-[Sarc]-NH2;

[0256] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0257] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[ Lys (Ac)]-N-[Aib]-[bA]-NH2;

[0258] or

[0259] ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is not...

[0260] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-NH2;

[0261] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0262] and

[0263] 5Pyal is a 5-pyrimidine-substituted alanine:

[0264] and

[0265] X4 and X9 form disulfide bonds or thioether bonds;

[0266] and

[0267] This peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0268] In some embodiments, the present invention provides a monocyclic peptide inhibitor of the interleukin-23 receptor or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of formula (I):

[0269] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I)

[0270] in

[0271] X3 may be absent or be any amino acid;

[0272] X4 can be Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0273] X5 can be any amino acid;

[0274] X6 can be any amino acid;

[0275] X7 is an unsubstituted Trp or a Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0276] X8 can be any amino acid;

[0277] X9 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0278] X10 is unsubstituted Phe or Phe substituted with the following groups: halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carboxyl, formamido, 2-aminoethoxy, or 2-acetaminoethoxy; and

[0279] X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

[0280] X12 can be any amino acid;

[0281] Each X13 and X14 can be any amino acid independently;

[0282] and

[0283] i) X15 is any amino acid other than His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the compound is not...

[0284] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0285] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0286] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0287] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2;

[0288] or

[0289] ii) X15 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the peptide inhibitor is not...

[0290] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-NH2;

[0291] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0292] and

[0293] 5Pyal is a 5-pyrimidine-substituted alanine:

[0294]

[0295] and

[0296] X4 and X9 form disulfide bonds or thioether bonds;

[0297] and

[0298] This peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0299] In some embodiments, X15 is any amino acid other than His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is not...

[0300] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0301] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0302] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0303] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2.

[0304] In some embodiments, X15 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp.

[0305] In some embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc, aMeLeu, (D)Thr, bAla, Pro, or (D)Pro. In some embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc. In some embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is not present.

[0306] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Ia):

[0307] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-Sarc(Ia)

[0308] X4 and X9 form disulfide bonds or thioether bonds.

[0309] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Ib).

[0310] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-(D)NMeTyr(Ib)

[0311] X4 and X9 form disulfide bonds or thioether bonds.

[0312] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Ic):

[0313] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(Ic)

[0314] Where Pal is 2 Pal, 3 Pal, or 4 Pal; X16 does not exist;

[0315] Wherein 2Pal is 2-pyridyl-substituted alanine, and 3Pal is 3-pyridyl-substituted alanine.

[0316] Furthermore, 4Pal is a 4-pyridyl-substituted alanine.

[0317]

[0318] Furthermore, X4 and X9 form disulfide bonds or thioether bonds.

[0319] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (Id):

[0320] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[His']-X16(Id)

[0321] His' is His or 3-MeHis; X16 is absent; and X4 and X9 form a disulfide bond or a thioether bond.

[0322] In some embodiments, X15 is any amino acid; X16 is bA, aMe(D)Tyr, (D)NMeTyr, Sarc, Pro, or (D)Pro; and the peptide inhibitor is not...

[0323] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0324] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0325] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0326] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2.

[0327] In some embodiments, X15 is any amino acid; X16 is bA, aMe(D)Tyr, (D)NMeTyr, Sarc, Pro, or (D)Pro, and the peptide inhibitor is not...

[0328] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2; or

[0329] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[0330] In some embodiments, X15 is 3Quin, His, (D)His, 3-Pal, or 4-Pal; and X16 is (D)NMeTyr or Sarc. In some embodiments, X15 is 3Quin, His, (D)His, 3-Pal, or 4-Pal; and X16 is (D)NMeTyr. In some embodiments, X15 is 3Quin, His, (D)His, 3-Pal, or 4-Pal; and X16 is Sarc.

[0331] In some embodiments, X15 is any amino acid; X16 is (D)NMeTyr or Sarc; and the peptide inhibitor is not...

[0332] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2; or

[0333] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[0334] In some embodiments, X15 is 3Quin, Asn, His, (D)His, (D)Leu, (D)Lys, 3-Pal, 4-Pal, Phe, substituted Phe, (D)Thr, substituted Trp, or (D)Val; X16 is (D)NMeTyr or Sarc; and the peptide inhibitor is not...

[0335] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2; or

[0336] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[0337] In some implementations, X16 is (D)NMeTyr.

[0338] In some implementations, X16 is Sarc; and the peptide inhibitor is not.

[0339] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0340] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2;

[0341] In some embodiments, X15 is His, (D)Lys, 3-Pal, or 4-Pal; X16 is (D)NMeTyr or Sarc; and the peptide inhibitor is not...

[0342] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[0343] In some implementations, X15 is Asn, His, (D), His, (D)Leu, (D)Lys, 3-Pal, substituted or unsubstituted Phe, (D)Thr, or (D)Val; X16 is (D)NMeTyr.

[0344] In some embodiments, X15 is 3Quin, Asn, His, (D)His, (D)Leu, (D)Lys, 3-Pal, 4-Pal, or a substituted Trp; X16 is Sarc; and the peptide inhibitor is not...

[0345] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2; or

[0346] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[0347] In some embodiments, X15 is (3-Me)His, 3-Pal, or 4-Pal; and X16 is absent, or is Sarc or (D)NMeTyr.

[0348] In some implementations, X15 is 3-Pal; and X16 is Sarc.

[0349] In some embodiments, X15 is Asn, His, (D)Lys, or 3-Pal; X16 is (D)NMeTyr or Sarc; and the peptide inhibitor is not...

[0350] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2; or

[0351] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[0352] In some embodiments, X15 is 5-Pyal, (D)His, (1-Me)His, (3-Me)His, 2-Pal, or 3-Pal; and X16 is absent; and the peptide inhibitor is not:

[0353] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-NH2.

[0354] In some implementations, X15 is 5-Pyal, (1-Me)His, or (3-Me)His; and X16 is not present.

[0355] In some implementations, X15 is 5-Pyal or (3-Me)His; and X16 is not present.

[0356] In some implementations, X4 or X9 is Cys, (D)Cys, α-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfide bond.

[0357] In some implementations, X4 is Cys, (D)Cys, or α-MeCys.

[0358] In some implementations, X4 is (D)Pen, Pen, or Pen (sulfoxide).

[0359] In some implementations, X4 is Pen. In some implementations, X4 is Abu.

[0360] In some implementations, X9 is Cys, (D)Cys, or α-MeCys.

[0361] In some implementations, X9 is Pen or (D)Pen.

[0362] In some implementations, X9 is Pen.

[0363] In some implementations, X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

[0364] In some implementations, X4 is Pen and X9 is Cys, and the bond is a disulfide bond.

[0365] In some implementations, X4 or X9 is Abu; and the bond between X4 and X9 is a thioether bond.

[0366] In some embodiments, X4 is Abu and X9 is Cys, (D)Cys, or α-MeCys. In some embodiments, X9 is Pen or (D)Pen. In one particular embodiment, X9 is Pen. In a more particular embodiment, X9 is Cys. In the most particular embodiment, X4 is Abu and X9 is Cys.

[0367] In some implementations, X4 is Abu and X9 is Cys or Pen, and the bond is a thioether bond.

[0368] In some implementations, X4 is Abu and X9 is Cys, and the bond is a thioether bond.

[0369] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (IIa), (IIb), or (IIc):

[0370] Pen-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16(IIa),

[0371] Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16(IIb), or

[0372] Abu-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16(IIc),

[0373] Wherein X5-X8 and X10-X14 are for the formula (I); X15 is His, (D)His or substituted or unsubstituted His, 2Pal, 3Pal or 4Pal, and X16 is any amino acid; or X15 is any amino acid and X16 is Sarc; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or the peptide inhibitor is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0374] In some implementations, X15 is 2Pal, 3Pal, or 4Pal, and X16 is any amino acid.

[0375] In some implementations, X15 is any amino acid, and X16 is Sarc.

[0376] In some implementations, X15 is any amino acid and X16 is (D)NMeTyr.

[0377] In some implementations, X15 is His or 3MeHis; and X16 is any amino acid.

[0378] In some implementations, X5 is Asn, Ser, Gln, or Glu.

[0379] In some implementations, X5 is either Asn or Gln.

[0380] In some implementations, X5 is Asn. In some implementations, X5 is Ser.

[0381] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (IIIa), (IIIb), (IIIc), or (IIId):

[0382] Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(IIIa),

[0383] Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(IIIb),

[0384] Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X14-[Pal]-X16(IIIc), or

[0385] Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(IIId),

[0386] Where X6-X8 and X10-X14 are for formula (I); Pal is 2 Pal, 3 Pal, or 4 Pal; and

[0387] X16 can be any amino acid;

[0388] Wherein 2Pal is 2-pyridyl-substituted alanine, and 3Pal is 3-pyridyl-substituted alanine.

[0389] Furthermore, 4Pal is a 4-pyridyl-substituted alanine.

[0390]

[0391] Furthermore, the peptide inhibitor is cyclized via Pen-Pen disulfide bonds or Abu-Cys or Abu-Pen thioether bonds.

[0392] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh):

[0393] Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(IVa),

[0394] Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(IVb),

[0395] Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-Sarc(IVc),

[0396] Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(IVd),

[0397] Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(IVe),

[0398] Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(IVf),

[0399] Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-(D)NMeTyr(IVg), or

[0400] Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(IVh),

[0401] Where X6-X8 and X10-X14 are specific to formula (I); X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0402] In some implementations, X6 is Thr.

[0403] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (Va), (Vb), (Vc), or (Vd):

[0404] Pen-Asn-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(Va),

[0405] Pen-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(Vb),

[0406] Abu-Asn-Thr-X7-X8-Cys-X10-X11-X12-X13-X14-[Pal]-X16(Vc), or

[0407] Abu-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-[Pal]-X16(Vd),

[0408] Where X7-X8 and X10-X14 are for formula (I); Pal is 2 Pal, 3 Pal, or 4 Pal; and

[0409] X16 can be any amino acid;

[0410] Wherein 2Pal is 2-pyridyl-substituted alanine, and 3Pal is 3-pyridyl-substituted alanine.

[0411] Furthermore, 4Pal is a 4-pyridyl-substituted alanine.

[0412]

[0413] Furthermore, the peptide inhibitor is cyclized via Pen-Pen disulfide bonds or Abu-Cys or Abu-Pen thioether bonds.

[0414] In some embodiments, the peptide inhibitor comprises an amino acid sequence of the formula (VIe), (VIf), (VIg), or (VIh):

[0415] Pen-Asn-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(VIa),

[0416] Pen-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(VIb),

[0417] Abu-Asn-Thr-X7-X8-Cys-X10-X11-X12-X13-X14-X15-Sarc(VIc),

[0418] Abu-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-Sarc(VId),

[0419] Pen-Asn-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIe),

[0420] Pen-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIf),

[0421] Abu-Asn-Thr-X7-X8-Cys-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIg) or

[0422] Abu-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIh),

[0423] Wherein X7-X8 and X10-X14 are specific to formula (I); X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0424] In some implementations, X8 is Gln, α-Me-Lys, α-MeLys(Ac), Lys(Ac), or Glu.

[0425] In some implementations, X8 is Gln. In some implementations, X8 is Lys(Ac).

[0426] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (VIIa), (VIIb), (VIIc), or (VIId):

[0427] Pen-Asn-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-[Pal]-X16(VIIa),

[0428] Pen-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-[Pal]-X16(VIIb),

[0429] Abu-Asn-Thr-X7-Gln-Cys-X10-X11-X12-X13-X14-[Pal]-X16(VIIc)(SEQ ID NO:448) or

[0430] Abu-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-[Pal]-X16(VIId),

[0431] Where X7 and X10-X14 are for formula (I); Pal is 2Pal, 3Pal or 4Pal; and X16 is any amino acid;

[0432] Wherein 2Pal is 2-pyridyl-substituted alanine, and 3Pal is 3-pyridyl-substituted alanine.

[0433] Furthermore, 4Pal is a 4-pyridyl-substituted alanine.

[0434]

[0435] Furthermore, the peptide inhibitor is cyclized via Pen-Pen disulfide bonds or Abu-Cys or Abu-Pen thioether bonds.

[0436] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), or (VIIIh):

[0437] Pen-Asn-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-Sarc(VIIIa),

[0438] Pen-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-Sarc(VIIIb), Abu-Asn-Thr-X7-Gln-Cys-X10-X11-X12-X13-X14-X15-Sarc(VIIIc) (SEQ ID NO: 449),

[0439] Abu-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-Sarc(VIIId),

[0440] Pen-Asn-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIIIe)(SEQID NO:450),

[0441] Pen-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIIIf)(SEQID NO:451),

[0442] Abu-Asn-Thr-X7-Gln-Cys-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIIIg)(SEQID NO:452) or

[0443] Abu-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-(D)NMeTyr(VIIIh) (SEQID NO:453),

[0444] Where X7 and X10-X14 are specific to formula (I); X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0445] In some embodiments, X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetaminoethoxy)], or Phe(4-CONH2).

[0446] In some embodiments, X10 is Phe[4-(2-aminoethoxy)] or Phe[4-(2-acetaminoethoxy)]. In some embodiments, X10 is Phe[4-(2-aminoethoxy)].

[0447] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (IXa), (IXb), (IXc), or (IXd):

[0448] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-[Pal]-X16(IXa)(SEQID NO:454),

[0449] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-[Pal]-X16(IXb)(SEQID NO:455),

[0450] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-[Pal]-X16(IXc)(SEQID NO:456), or

[0451] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-[Pal]-X16(IXd)(SEQID NO:457),

[0452] Where X7 and X11-X14 are for formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)];

[0453] Pal can be 2 Pal, 3 Pal, or 4 Pal; and X16 can be any amino acid;

[0454] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0455]

[0456] Furthermore, the peptide inhibitor is cyclized via Pen-Pen disulfide bonds or Abu-Cys or Abu-Pen thioether bonds.

[0457] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), (Xg), or (Xh):

[0458] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-Sarc(Xa)(SEQ IDNO:458),

[0459] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-Sarc(Xb)(SEQ IDNO:459),

[0460] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15-Sarc(Xc)(SEQ IDNO:460),

[0461] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-Sarc(Xd)(SEQ IDNO:461),

[0462] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-(D)NMeTyr(Xe) (SEQ ID NO: 462),

[0463] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-(D)NMeTyr(Xf) (SEQ ID NO: 463),

[0464] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15-(D)NMeTyr(Xg) (SEQ ID NO:464), or

[0465] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-(D)NMeTyr(Xh) (SEQ ID NO: 465),

[0466] Where X7 and X11-X14 are for the formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0467] In some embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeLys, α-MeLeu, Ala, cyclohexylAla, Lys, or Aib.

[0468] In some embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeLys, or α-MeLeu.

[0469] In some embodiments, X12 is α-MeLeu. In some embodiments, X12 is THP.

[0470] In some embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), α-MeArg, α-MeGlu, α-MeLeu, α-MeLys, α-Me-Asn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Lys, polyethylene glycolated Lys, b-high-Glu, or Lys(Y2-Ac); wherein Y2 is an amino acid. In some embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), α-MeArg, α-MeGlu, α-MeLys, α-Me-Asn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Lys, or b-high-Glu.

[0471] In some implementations, X13 is Glu, Gln, Lys(Ac), or Lys.

[0472] In some implementations, X13 is Lys(Ac) or Lys.

[0473] In some implementations, X13 is Lys(Ac). In some implementations, X13 is Glu.

[0474] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (XIa), (XIb), (XIc), or (XId):

[0475] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-[Pal]-X16(XIa) (SEQ ID NO:466),

[0476] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-[Pal]-X16(XIb) (SEQ ID NO:467),

[0477] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-[Pal]-X16(XIc) (SEQ ID NO:468), or

[0478] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-[Pal]-X16(XId) (SEQ ID NO:469),

[0479] Where X7, X11, X14, and X14 are specific to formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid;

[0480] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0481]

[0482] Furthermore, the peptide inhibitor is cyclized via Pen-Pen disulfide bonds or Abu-Cys or Abu-Pen thioether bonds.

[0483] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (XIIa), (XIIb), (XIIc), (XIId), (XIIe), (XIIIf), (XIIg), or (XIIh):

[0484] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-Sarc(XIIa) (SEQ ID NO:470),

[0485] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-Sarc(XIIb) (SEQ ID NO:471),

[0486] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-Sarc(XIIc) (SEQ ID NO:472),

[0487] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-Sarc(XIId) (SEQ ID NO:473),

[0488] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-(D)NMeTyr(XIIe) (SEQ ID NO:474),

[0489] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-(D)NMeTyr(XIIf) (SEQ ID NO: 475),

[0490] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-(D)NMeTyr(XIIg) (SEQ ID NO:476), or

[0491] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-X14-X15-(D)NMeTyr(XIIh) (SEQ ID NO:477),

[0492] Where X7, X11 and X14 are for the formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0493] In some implementations, X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, β-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, α-MeGln, α-MeAsn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), or Lys(Ac). In some implementations, X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Ala, (D)Ala, β-Ala, His, Thr, Gln, Ser, (D)Ser, Tic, Trp, α-MeGln, α-MeAsn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), or Lys(Ac).

[0494] In some implementations, X14 is Asn.

[0495] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (XIIIa), (XIIIb), (XIIIc), or (XIIId):

[0496] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XIIIa) (SEQ ID NO:478),

[0497] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XIIIb) (SEQ ID NO:479),

[0498] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XIIIc) (SEQ ID NO:480), or

[0499] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XIIId) (SEQ ID NO:481),

[0500] Where X7 and X11 are for the formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; Pal is 2Pal, 3Pal or 4Pal; and X16 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0501] In some embodiments, the peptide inhibitor comprises an amino acid sequence of the formula (XIVa), (XIVb), (XIVc), (XIVd), (XIVe), (XIVf), (XIVg), or (XIVh):

[0502] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XIVa) (SEQ ID NO:482),

[0503] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XIVb) (SEQ ID NO:483),

[0504] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XIVc) (SEQ ID NO:484),

[0505] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XIVd) (SEQ ID NO:485),

[0506] Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XIVe) (SEQ ID NO:486),

[0507] Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XIVf) (SEQ ID NO:487),

[0508] Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XIVg) (SEQ ID NO:488), or

[0509] Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XIVh) (SEQ ID NO:489),

[0510] Where X7 and X11 are for the formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0511] In some implementations, X7 is the unreplaced Trp.

[0512] In some embodiments, X7 is a Trp substituted with the following: cyano, halogen, alkyl, haloalkyl, hydroxy or alkoxy; and X11 is as described in formula (I).

[0513] In some embodiments, X7 is a Trp substituted with the following: cyano, halogen, alkyl, haloalkyl, hydroxy, or alkoxy; and the substitution is located at the 4-, 5-, 6-, or 7-position.

[0514] In some embodiments, X7 is a Trp substituted with the following: cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxyl, OMe, or OEt; and the substitution is located at the 4-, 5-, 6-, or 7-position.

[0515] In some implementations, X7 is a Trp substituted with the following: 5-F, 6-F, 7-F, 5-Cl, 6-Cl, 7-Cl, 5-Me, 6-Me, 7-Me, 5-OH, 6-OH, 7-OH, 5-OMe, 6-OMe, or 7-OMe.

[0516] In some implementations, X7 is a Trp that is replaced by the following: 7-Me, 5-F, 7-F, 6-Cl, 6-Me, 4-OMe, 5-OMe, or 5-Br.

[0517] In some implementations, X7 is Trp replaced by the following: 7-Me, 6-Me, 4-OMe, or 6-Cl.

[0518] In some implementations, X7 is Trp, which replaces 7-ME.

[0519] In some embodiments, X7 is a Trp substituted with the following: phenyl, substituted phenyl, or thiophene.

[0520] In some embodiments, X7 is a Trp substituted with the following: cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, phenyl, substituted phenyl, or thiophene.

[0521] In some embodiments, X7 is a Trp substituted with: i) an unsubstituted or substituted phenyl group: cyano, halogen, alkyl, haloalkyl, arylhydroxy, alkoxy, or haloalkoxy; or ii) thiophene.

[0522] In some embodiments, X7 is a Trp substituted with the following: unsubstituted or substituted phenyl groups: Me, Et, n-Pr, i-Pr, t-Bu, OMe, OEt, Cl, F, CF3, OCF3, phenyl, substituted phenyl or amide group.

[0523] In some embodiments, X7 is a 7-ME-substituted Trp. In some embodiments, X7 is a 7-Ph-substituted Trp.

[0524] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (XVa), (XVb), (XVc), or (XVd):

[0525] Pen-Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVa) (SEQ ID NO:490),

[0526] Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVb) (SEQ ID NO:491),

[0527] Abu-Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVc) (SEQ ID NO:492), or

[0528] Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVd) (SEQ ID NO:493),

[0529] Wherein X11 is for the formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; Pal is 2Pal, 3Pal or 4Pal; and X16 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0530] In some embodiments, the peptide inhibitor comprises an amino acid sequence of the formula (XVIa), (XVIb), (XVIc), (XVId), (XVIe), (XVIIf), (XVIg), or (XVIh):

[0531] Pen-Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIa) (SEQ ID NO:494),

[0532] Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIb) (SEQ ID NO:495),

[0533] Abu-Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIc) (SEQ ID NO:496),

[0534] Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVId) (SEQ ID NO:497),

[0535] Pen-Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIe) (SEQ ID NO:498),

[0536] Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIf) (SEQ ID NO:499),

[0537] Abu-Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIg) (SEQ ID NO:500), or

[0538] Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIh) (SEQ ID NO:501),

[0539] Where X11 is for the formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0540] In some embodiments, X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy) or 1-Nal.

[0541] In some implementations, X11 is 2-Nal or 1-Nal.

[0542] In some implementations, X11 is 2-Nal.

[0543] In some embodiments, the peptide inhibitor comprises an amino acid sequence of formula (XVIIa), (XVIIb), (XVIIc), or (XVIId):

[0544] Pen-Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVIIa) (SEQ ID NO:502),

[0545] Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVIIb) (SEQ ID NO: 503),

[0546] Abu-Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVIIc) (SEQ ID NO:504), or

[0547] Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-[Pal]-X16(XVIId) (SEQ ID NO:505),

[0548] Wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)]; Pal is 2Pal, 3Pal or 4Pal; and X16 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0549] In some embodiments, the peptide inhibitor comprises the amino acid sequence of formula (XVIIIa), (XVIIIb), (XVIIIc), (XVIIId), (XVIIIe), (XVIIIf), (XVIIIg), or (XVIIIh):

[0550] Pen-Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIIIa) (SEQ ID NO:506),

[0551] Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIIIb) (SEQ ID NO:507),

[0552] Abu-Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIIIc) (SEQ ID NO:508),

[0553] Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-Sarc(XVIIId) (SEQ ID NO:509),

[0554] Pen-Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIIIe) (SEQ ID NO: 510),

[0555] Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIIIf) (SEQ ID NO: 511),

[0556] Abu-Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIIIg) (SEQ ID NO:512), or

[0557] Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[α-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr(XVIIIh) (SEQ ID NO: 513),

[0558] Where F(4-2-ae) is Phe[4-(2-aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or an Abu-Cys or Abu-Pen thioether bond.

[0559] In some implementations, X15 is 2Pal, 3Pal, 4Pal, His, (D)His, Lys, (D)Lys, Leu, (D)Leu, 2Quin, or 3Quin.

[0560] In some implementations, X15 is 3Pal, 4Pal, His, (D)His, (D)Lys, or (D)Leu.

[0561] In some implementations, X15 is 3Pal, His, (D)Lys, or (D)Leu.

[0562] In some implementations, X15 is His.

[0563] In some implementations, X15 is 3Pal.

[0564] In some implementations, X16 is not present.

[0565] In one specific implementation, X3 does not exist.

[0566] In some implementations, with respect to formula (XVa)-(XVIIIh), W(7-Me) is replaced by W(7-Ph).

[0567] In some implementations, with respect to formula (XVa)-(XVIIIh), W(7-Me) is replaced by W or unsubstituted Trp.

[0568] In some implementations, Gln is substituted with Lys(Ac) for formula (VIIa)-(XVIIIh).

[0569] In some implementations, aMeLeu is replaced by THP with respect to formula (XIa)-(XVIIIh).

[0570] In some embodiments, the peptide inhibitor comprises the structure of formula (Z):

[0571] R 1 -XR 2 (Z)

[0572] Or its pharmaceutically acceptable salt, wherein

[0573] R 1 The form is a polyethylene glycolated form comprising hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, or C1-C20 alkylyl, and includes a spacer group alone or as any of the foregoing; X is an amino acid sequence of any of formulas (I), (Ia), (Ib), (Ic), (Id), or (II)-(XVIIId); and R 2 It can be OH, NH2, or NHMe.

[0574] In some embodiments, the peptide inhibitor comprises the structure of formula (Z):

[0575] R 1 -XR 2 (Z)

[0576] Or its pharmaceutically acceptable salt, wherein

[0577] R 1 The group is hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, C1-C20 alkylyl, and includes a polyethylene glycolated form, either alone or as a spacer group for any of the foregoing; X is the amino acid sequence of any of formulas (I), (II)-(XVIIId), or the amino acid sequence described in any of Table E1; and R 2 It can be OH or NH2.

[0578] In some embodiments, the peptide inhibitor comprises or consists of the following amino acid sequence of formula (Z):

[0579] R 1 -X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R 2 (Z')

[0580] Or its pharmaceutically acceptable salt, wherein

[0581] R 1 The polyethylene glycol form is hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, or C1-C20 alkylyl, and includes a spacer group alone or as any of the foregoing; and R 2 It can be OH, NH2, or N(H)Me.

[0582] In some embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (Z):

[0583] R 1 -X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R 2 (Z')

[0584] Or its pharmaceutically acceptable salt, wherein

[0585] R 1 The polyethylene glycol form is hydrogen, Ac, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl-C1-6 alkyl, or C1-C20 alkylyl, and includes a spacer group alone or as any of the foregoing; and R 2 It can be OH or NH2.

[0586] In some embodiments, the peptide inhibitor comprises or consists of the following amino acid sequence of formula (Z):

[0587] R 1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R 2 (Z')

[0588] Or its pharmaceutically acceptable salt, wherein

[0589] X3 may be absent or be any amino acid;

[0590] X4 can be Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0591] X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln or Asp;

[0592] X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer or Val;

[0593] X7 is an unsubstituted Trp or a Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0594] X8 can be Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-high-Gln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl, Ac), Lys(propyl, Ac), or Trp;

[0595] X9 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen (sulfoxide);

[0596] X10 is Tyr or a substituted Tyr, an unsubstituted Phe, or a Phe substituted with: halogroup, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, cycloalkyl, carboxyl, formamido, 2-aminoethoxy, or 2-acetaminoethoxy; and

[0597] X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with the following: cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy.

[0598] X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

[0599] X13 can be any amino acid;

[0600] X14 can be any amino acid;

[0601] and

[0602] i) X15 is any amino acid other than: His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is not...

[0603] Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

[0604] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-NN-[Sarc]-NH2;

[0605] Ac-[(D)Arg]-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or

[0606] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Aib]-[bA]-NH2;

[0607] or

[0608] ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4-triazole Ala, or 5Pyal; and X16 is absent, is (D)aMeTyr, (D)NMeTyr, or any amino acid other than: THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is not...

[0609] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-NH2;

[0610] Wherein 2Pal is 2-pyridyl-substituted alanine, 3Pal is 3-pyridyl-substituted alanine, and 4Pal is 4-pyridyl-substituted alanine.

[0611] and

[0612] 5Pyal is a 5-pyrimidine-substituted alanine:

[0613] and

[0614] X4 and X9 form disulfide bonds or thioether bonds;

[0615] and

[0616] This peptide inhibitor inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0617] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z'), where X4 or X9 is Cys, (D)Cys, α-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfide bond. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z'), where X4 is (D)Pen, Pen, or Pen (sulfoxide). In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z'), where X4 is Pen. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z'), where X9 is Pen or (D)Pen. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z'), where X9 is Pen. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z'), where X4 and X9 are both Pen, and the bond is a disulfide bond.

[0618] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') that comprises the structure of formula (Z'):

[0619] R 1 -X3-Pen-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16-R 2 (Z'-A)

[0620] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0621] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-A), where X5 is Asn, Ser, Gln, or Glu.

[0622] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-A), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0623] R 1 -X3-Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16-R 2 (Z'-B) where the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0624] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-B), where X6 is Asp or Thr.

[0625] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-B), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0626] R 1 -X3-Pen-Asn-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16-R 2 (Z'-C)

[0627] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0628] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-C), where X8 is Gln, α-Me-Lys, α-MeLys(Ac), Lys(Ac), or Glu. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-C), where X8 is Cit, Lys(Ac), Lys(benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl, Ac), Lys(propyl, Ac), Gln, 4-adamantyl-Phe, (4-AcNH)Phe, or Tyr. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-C), where X8 is Lys(Ac).

[0629] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-C), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0630] R 1 -X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-X10-X11-X12-X13-X14-X15-X16-R 2 (Z'-D)

[0631] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0632] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-D), where X10 is Phe or a substituted Phe, Tyr or a substituted Tyr. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-D), where X10 is Phe or a substituted Phe. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-D), where X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetaminoethoxy)] or Phe(4-CONH2). In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-D), where X10 is Phe[4-(2-aminoethoxy)] or Phe[4-(2-acetaminoethoxy)]. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-D), where X10 is Phe[4-(2-aminoethoxy)].

[0633] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-D), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0634] R 1 -X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16-R 2 (Z'-E)(SEQ ID NO:514)

[0635] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0636] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-E), wherein X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy) or 1-Nal. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-E), wherein X11 is 2-Nal or 1-Nal. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-E), wherein X11 is 2-Nal.

[0637] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-E), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0638] R 1-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-X12-X13-X14-X15-X16-R 2 (Z'-F)(SEQ ID NO:515)

[0639] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0640] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-F), wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeLys, α-MeLeu, Ala, cyclohexyl-Ala, Lys, or Aib. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-F), wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Accx, Acvc, α-MeLys, or α-MeLeu. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-F), wherein X12 is THP.

[0641] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-F), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0642] R 1 -X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-X13-X14-X15-X16-R 2 (Z'-G)(SEQ ID NO:516)

[0643] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0644] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-G), where X13 is Aib, Glu, Cit, Gln, Lys(Ac), α-MeArg, α-MeGlu, α-MeLeu, α-MeLys, α-Me-Asn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Lys, or b-high-Glu. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-G), where X13 is Aib, Glu, Cit, Gln, Lys(Ac), α-MeArg, α-MeGlu, α-MeLys, α-Me-Asn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), Lys, or b-high-Glu. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-G), where X13 is Glu, Gln, Lys(Ac), or Lys. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-G), where X13 is α-methylGlu, Glu, or Lys(Ac). In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-G), where X13 is Glu.

[0645] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-G), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0646] R 1 -X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-X14-X15-X16-R 2 (Z'-H)(SEQ ID NO:517)

[0647] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0648] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-H), in which X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, β-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, α-MeGln, α-MeAsn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), or Lys(Ac). In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-H), where X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Ala, (D)Ala, β-Ala, His, Thr, Gln, Ser, (D)Ser, Tic, Trp, α-MeGln, α-MeAsn, α-MeLys(Ac), Dab(Ac), Dap(Ac), high-Lys(Ac), or Lys(Ac). In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-H), where X14 is Asn.

[0649] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-H), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0650] R 1 -X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-X15-X16-R 2 (Z'-I)(SEQ ID NO:518)

[0651] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0652] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-I), wherein X7 is a Trp or a Trp substituted with an alkyl or phenyl group; and the substitution is located at the 4-, 5-, 6-, or 7-position. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-I), wherein X7 is a Trp or a Trp substituted with the following: Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, or phenyl; and the substitution is located at the 4-, 5-, 6-, or 7-position. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-I), wherein X7 is a Trp or a Trp substituted with the following: 5-Me, 6-Me, 7-Me, 5-phenyl, 6-phenyl, or 7-Ph. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-I), wherein X7 is a Trp or a Trp substituted with the following: 7-Me, 6-Me, or 7-Ph. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-I), wherein X7 is a Trp substituted with 7-ME.

[0653] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-I), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0654] R 1 -X3-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-X15-X16-R 2 (Z'-J)(SEQ ID NO:519)

[0655] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0656] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-J), wherein X3 is absent or is (D)Arg. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-J), wherein X3 is absent. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-J), wherein X3 is (D)Arg.

[0657] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-J), wherein the peptide inhibitor comprises the structure of formula (Z'):

[0658] R 1 -Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-X15-X16-R 2 (Z'-K)(SEQ ID NO:520)

[0659] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0660] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-J), wherein X3 is absent or is (D)Arg; X4 is Abu, Cys, (D)Cys, α-MeCys, or Pen; X5 is Ala, (allyl)Gly, Ile, Leu, Asn, Nle, or Gln; X6 is Asp or Thr; X7 is (7-methyl)Trp, (4-F)-Trp, or Trp; X8 is Cit, Lys(Ac), Lys(benzyl, Ac), Lys(butyl, Ac), Lys (isobutyl, Ac), Lys (propyl, Ac), Gln, 4-adamantyl-Phe, (4-AcNH)Phe or Tyr; X9 is Cys, α-MeCys or Pen; X10 is Phe or substituted Phe, Tyr or substituted Tyr; X11 is 2-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acpx, Acvc, α-MeLys or α-MeLeu; X13 is α-methylGlu, Glu or Lys(Ac); and X14 is Asn.

[0661] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R 1 It is an H or C1-C20 alkyl acyl group.

[0662] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R 1 It can be H or Ac.

[0663] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R 1 It is Ac.

[0664] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R 2It is NH2 or N(H)Me. In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R... 2 It is NH2.

[0665] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R 1 X3 is Ac; X4 is Pen; X5 is Asn;

[0666] X6 is Thr; X7 is Trp or (7-Me)Trp or (7-Ph)Trp; X8 is Lys(Ac); X9 is Pen; X10 is Phe (2-aminoethoxy); X11 is 2-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP); X13 is Gln; X14 is Asn; and R 2 It is NH2 or N(H)Me.

[0667] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where R 1 X3 is Ac; X4 is Pen; X5 is Asn;

[0668] X6 is Thr; X7 is 7-methylTrp; X8 is Lys(Ac); X9 is Pen; X10 is Phe(2-aminoethoxy); X11 is 2-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP); X13 is Glu; X14 is Asn; and R 2 It is NH2 or N(H)Me.

[0669] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), wherein X15 is Aib, β-Ala, (D)Phe, (D)Lys, (D)Leu, (D)Orn, substituted (D)Phe, (D)Arg, (D)Val, (D)Tyr, Phe, Hph, Asn, 4-amino-4-carboxy-tetrahydropyran (THP), substituted Tyr or Tyr; and X16 is β-Ala, (D)NMeTyr, (D)Pro, NMeTyr, Pro or Sarc.

[0670] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), wherein X15 is 3Pal, substituted 3Pal, 4Pal, 4-triazole-Ala, (D)His, His, or substituted His; and X16 is absent, or is Aib, α-MePro, (D)Leu, (D)NMeTyr, (D)Pro, (D)Tyr, substituted Gly, MeLeu, MeNLe, Pro, Paf, 4-di-fluoro-Pro, Sarc, or Tyr.

[0671] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), in which X15 is (D)His, substituted His, 2Pal, 3Pal, 4Pal, 4-triazole Ala, or 5Pyal; and X16 is absent, or is (D)NMeTyr or Sarc.

[0672] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), in which X15 is (3-Me)His or 3Pal; and X16 is absent or is Sarc.

[0673] In some embodiments, the peptide inhibitor comprises the structure of formula (Z'):

[0674] Ac-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-[3-Pal]-X16-NH2(Z'-L) (SEQ ID NO:521)

[0675] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0676] In some embodiments, the peptide inhibitor comprises the structure of formula (Z'):

[0677] Ac-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-X15-Sarc-NH2(Z'-M) (SEQ ID NO:522)

[0678] F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[0679] In some embodiments, the peptide inhibitor is a peptide inhibitor of formula (Z') to (Z'-K), where X15 is 3Pal and X16 is Sarc.

[0680] In some aspects, the present invention provides a peptide inhibitor of the interleukin-23 receptor, wherein the peptide inhibitor comprises or is any of the amino acid sequences set forth in any of Tables E1A and E1B; or a pharmaceutically acceptable salt thereof. In some aspects, the present invention provides a peptide inhibitor of the interleukin-23 receptor, wherein the peptide inhibitor comprises or is any of the amino acid sequences set forth in any of Tables E1; or a pharmaceutically acceptable salt thereof.

[0681] In some aspects, the present invention provides a peptide inhibitor of the interleukin-23 receptor, wherein the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[0682] Ac-[(D)Arg]-[Abu]-QT-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-dK-[Sarc]-NH2(SEQ ID NO:1);

[0683] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu)]-[Sarc]-NH2 (SEQ ID NO: 2);

[0684] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-EN-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:3);

[0685] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)His]-[Sarc]-NH2 (SEQ ID NO: 4);

[0686] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:5);

[0687] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-EN-[(D)Leu)]-[Sarc]-NH2(SEQ ID NO:6);

[0688] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 7);

[0689] Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-[(D)NMeTyr]-NH2(SEQ ID NO:8);

[0690] Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-[(D)NMeTyr]-NH2(SEQ ID NO:9);

[0691] Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-NF-[(D)NMeTyr]-NH2(SEQ ID NO:10);

[0692] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:11);

[0693] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 12);

[0694] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:13);

[0695] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 14);

[0696] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:15);

[0697] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:16);

[0698] Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:17);

[0699] Ac-[Abu]-QT-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:18);

[0700] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NOS: 20, 25);

[0701] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 21);

[0702] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:22);

[0703] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:23);

[0704] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:24);

[0705] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 25);

[0706] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:26);

[0707] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:27);

[0708] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:28);

[0709] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 29);

[0710] Ac-[Pen]-NT-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:30);

[0711] Ac-[Pen]-NT-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:31);

[0712] Ac-[Pen]-NT-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:32);

[0713] Ac-[Pen]-NT-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:33);

[0714] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Et)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:34);

[0715] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4-Me)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:35);

[0716] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Me)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:36);

[0717] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4-OMe)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:37);

[0718] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-i-Pr)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:38);

[0719] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-nPr)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:39);

[0720] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-OMe)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:40);

[0721] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Cl)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:41);

[0722] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(5-OMe)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:42);

[0723] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(3-MePh)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:43);

[0724] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Ph)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:44);

[0725] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Et)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:45);

[0726] Ac-[Pen]-NT-[W(7-(2-FPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:46);

[0727] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[(D)NMeTyr]-NH2 (SEQ ID NO: 47);

[0728] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 48);

[0729] Ac-[Pen]-NT-[W(7-(2-OMePh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:49);

[0730] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Ph)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:50);

[0731] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:51);

[0732] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:52);

[0733] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:53);

[0734] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:54);

[0735] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:55);

[0736] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:56);

[0737] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)NMeTyr]-NH2(SEQ ID NO:57);

[0738] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NF-[(D)NMeTyr]-NH2 (SEQ ID NO: 58);

[0739] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:59);

[0740] Ac-[Pen]-ST-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:60);

[0741] Ac-[Pen]-ST-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:61);

[0742] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)NMeTyr]-NH2(SEQ ID NO:62);

[0743] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[(D)Asn]-H-[Sarc]-NH2(SEQ ID NO:63);

[0744] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EGH-[Sarc]-NH2(SEQ ID NO:64);

[0745] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[h(Ser)]-H-[Sarc]-NH2(SEQ ID NO:65);

[0746] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENHP-NH2(SEQ ID NO:66);

[0747] Ac-[Pen]-NT-[W(7-(2-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:67);

[0748] Ac-[Pen]-NT-[W(7-3BiPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:68);

[0749] Ac-[Pen]-NT-[W(7-(phenanthrene-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:69);

[0750] Ac-[Pen]-NT-[W(7-(4-anthracene-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:70);

[0751] Ac-[Pen]-NT-[W(7-(1-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:71);

[0752] Ac-[Pen]-NT-[W(7-(4BiPh))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:72);

[0753] Ac-[Pen]-NT-[W(7-(3,5-t-Bu-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:73);

[0754] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2 (SEQ ID NO:74);

[0755] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2 (SEQ ID NO:75);

[0756] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[2Pal]-NH2(SEQ ID NO:78);

[0757] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[2Pal]-NH2(SEQ ID NO:79);

[0758] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-NH2(SEQ ID NO:80);

[0759] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:81);

[0760] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[(D)NMeTyr]-NH2(SEQ ID NO:82);

[0761] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-ENH-[(D)NMeTyr]-NH2 (SEQ ID NO: 83);

[0762] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-Phe[4-aminomethyl]-[(D)NMeTyr]-NH2(SEQ ID NO:84);

[0763] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-N-[(D)His]-NH2(SEQ ID NO:85);

[0764] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)His]-NH2(SEQ ID NO:86);

[0765] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-[(D)NMeTyr]-NH2(SEQ ID NO:87);

[0766] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-[(D)NMeTyr]-NH2(SEQ ID NO:88);

[0767] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NN-[(D)NMeTyr]-NH2 (SEQ ID NO: 89);

[0768] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val]-[(D)NMeTyr]-NH2 (SEQ ID NO: 90);

[0769] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Thr]-[(D)NMeTyr]-NH2(SEQ ID NO:91);

[0770] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-NH2(SEQ ID NO:92);

[0771] Ac-[Abu]-NT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:93);

[0772] Ac-[Abu]-NT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:94);

[0773] Ac-[Abu]-NT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:95);

[0774] Ac-[Abu]-NT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:96);

[0775] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:97);

[0776] Ac-[Abu]-NT-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:98);

[0777] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:99);

[0778] Ac-[(D)Arg]-[Abu]-ST-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:100);

[0779] Ac-[(D)Arg]-[Abu]-NT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:101);

[0780] Ac-[(D)Arg]-[Abu]-NT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:102);

[0781] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 103);

[0782] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104);

[0783] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 105);

[0784] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106);

[0785] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:107);

[0786] Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:108);

[0787] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:109);

[0788] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:110);

[0789] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:111);

[0790] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:112);

[0791] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:113);

[0792] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[bA]-NH2(SEQ ID NO:114);

[0793] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-[Sarc]-NH2(SEQ ID NO:115);

[0794] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:116);

[0795] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:117);

[0796] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Quin]-[Sarc]-NH2(SEQ ID NO:118);

[0797] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[7-aza-tryptophan]-[Sarc]-NH2(SEQ ID NO:119);

[0798] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO: 120);

[0799] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:121);

[0800] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO: 122);

[0801] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:123);

[0802] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:124);

[0803] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:125);

[0804] Ac-[Pen]-NT-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:126);

[0805] Ac-[Pen]-NT-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:127);

[0806] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[bA]-NH2 (SEQ ID NO: 130);

[0807] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:131);

[0808] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:132);

[0809] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 133, 141);

[0810] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:134);

[0811] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:135);

[0812] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:136);

[0813] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-acetaminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:137);

[0814] Ac-[Pen]-ET-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:138);

[0815] Ac-[Pen]-ET-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:139);

[0816] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:140);

[0817] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:141);

[0818] Ac-[Pen]-NT-[W(7-(3-formamidophenyl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:142);

[0819] Ac-[Pen]-NT-[W(7-pyrimidin-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:143);

[0820] Ac-[Pen]-NT-[W(7-imidazopyridyl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:144);

[0821] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[NMe(Lys)]-[Lys(Ac)]-N-[His_3Me]-NH2(SEQ ID NO:145);

[0822] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His_3Me]-NH2(SEQ ID NO:146);

[0823] Ac-[Pen]-NT-[W(7-(4Quin))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:147);

[0824] Ac-[Pen]-NT-[(W(7-(3-pyrazol-1-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:148 151);

[0825] Ac-[Pen]-NT-[(W(7-(5-Et))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:149);

[0826] Ac-[Pen]-NT-[W(5-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:150);

[0827] Ac-[Pen]-NT-[(W(7-(3-pyrazol-1-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:151);

[0828] Ac-[Pen]-NT-[W(7-indazol-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:152);

[0829] Ac-[Pen]-NT-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:153);

[0830] Ac-[Pen]-NT-[W(5-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:154);

[0831] Ac-[Pen]-NT-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:155);

[0832] Ac-[Pen]-NT-[W(4-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:156);

[0833] Ac-[Pen]-NT-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:157);

[0834] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NOs:158, 162, 284);

[0835] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:159, 285);

[0836] Ac-[Pen]-NT-[W(5-Ca)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:160);

[0837] Ac-[Pen]-NT-[Trp_4aza]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:161);

[0838] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:162);

[0839] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:163);

[0840] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(5Pyal)]-NH2(SEQ ID NO:164);

[0841] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys]-[Lys(Ac)]-N-[(5Pyal)]-NH2(SEQ ID NO:165);

[0842] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(1-Me)His]-NH2(SEQ ID NO:166);

[0843] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(1-Me)His]-NH2(SEQ ID NO:167); or

[0844] Ac-[Pen]-NT-[W(7-Me]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:168);

[0845] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond;

[0846] Or its pharmaceutically acceptable salt.

[0847] In some aspects, the present invention provides a peptide comprising or being the following:

[0848] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-NH2(SEQ ID NO:80);

[0849] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104);

[0850] Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:108);

[0851] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:110);

[0852] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:112);

[0853] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Quin]-[Sarc]-NH2(SEQ ID NO:118);

[0854] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:124); or

[0855] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:125);

[0856] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-Cys thioether bond;

[0857] Or its pharmaceutically acceptable salt.

[0858] In some aspects, the present invention provides a peptide comprising or being the following:

[0859] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 105);

[0860] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106);

[0861] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:117);

[0862] Ac-[Pen]-NT-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:126);

[0863] Ac-[Pen]-NT-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:127);

[0864] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:134);

[0865] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:135);

[0866] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:136);

[0867] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-acetaminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:137); or

[0868] Ac-[Pen]-ET-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:139);

[0869] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond;

[0870] Or its pharmaceutically acceptable salt.

[0871] In some embodiments, the peptide inhibitor comprises or is any of the following amino acid sequences:

[0872] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)Lys]-[(D)NMeTyr]-NH2(SEQ ID NO:201),

[0873] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)His]-[(D)NMeTyr]-NH2(SEQ ID NO:202),

[0874] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Orn]-[(D)NMeTyr]-NH2 (SEQ ID NO: 203),

[0875] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Ser]-[(D)NMeTyr]-NH2 (SEQ ID NO: 204),

[0876] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-[(D)NMeTyr]-NH2 (SEQ ID NO: 205),

[0877] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)Tyr]-NH2(SEQ ID NO:206),

[0878] Ac-[Pen]-NT-[W(7-Me)]-[(D)Tyr]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 207),

[0879] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENHP-NH2(SEQ ID NO:208),

[0880] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)Pro]-NH2(SEQ ID NO:209),

[0881] Ac-[Pen]-NT-[W(7-Me)]-[Phe(4-CONH2)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 210),

[0882] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-(D)Phe[4-NH2]-[Sarc]-NH2(SEQ ID NO:211),

[0883] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-NH2(SEQ ID NO:212),

[0884] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NHN(H)Me (SEQ ID NO: 213),

[0885] Ac-[Pen]-NT-[W(7-Me)]-[Phe(4-NH(Ac))]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 214),

[0886] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-[(D)NMeTyr]-NH2 (SEQ ID NO: 215),

[0887] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2(SEQ ID NO:216),

[0888] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)His]-[(D)NMeTyr]-NH2 (SEQ ID NO: 217),

[0889] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO: 218),

[0890] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO: 219),

[0891] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO: 220),

[0892] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-ENHN(H)Me (SEQ ID NO: 221),

[0893] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-P-NH2(SEQ ID NO:222),

[0894] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-[(D)Pro]-NH2(SEQ ID NO:223),

[0895] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[bAla]-[Sarc]-NH2(SEQ ID NO:224),

[0896] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Val]-[Sarc]-NH2(SEQ ID NO:225),

[0897] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Arg]-[Sarc]-NH2(SEQ ID NO:226),

[0898] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[Hph]-[Sarc]-NH2(SEQ ID NO:227),

[0899] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-Phe[4-NH2]-[Sarc]-NH2(SEQ ID NO:228),

[0900] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-Phe[4-NH2]-[Sarc]-NH2(SEQ ID NO:229),

[0901] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-ENF-[Sarc]-NH2(SEQ ID NO:230),

[0902] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[THP]-[Sarc]-NH2(SEQ ID NO:231),

[0903] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:232),

[0904] Ac-[(D)Arg]-[Cys]-NT-[W(7-Me)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-ENH-[Sarc]-NH2(SEQ ID NO:233),

[0905] Ac-[(D)Arg]-[Cys]-NT-[W(7-Me)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:234),

[0906] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:235),

[0907] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[Sarc]-NH2 (SEQ ID NO: 236),

[0908] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val]-[Sarc]-NH2 (SEQ ID NO: 237),

[0909] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Arg]-[Sarc]-NH2 (SEQ ID NO: 238),

[0910] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Hph]-[Sarc]-NH2 (SEQ ID NO: 239),

[0911] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH2 (SEQ ID NO: 240),

[0912] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH2 (SEQ ID NO: 241),

[0913] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-NH2(SEQ ID NO:242),

[0914] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Phe(4-CF3)]-[Sarc]-NH2 (SEQ ID NO: 243),

[0915] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-Tyr_CHF2-[Sarc]-NH2 (SEQ ID NO: 244),

[0916] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[THP]-P-NH2 (SEQ ID NO:245),

[0917] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO: 246),

[0918] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:247),

[0919] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-[Sarc]-NH2(SEQ ID NO:248),

[0920] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[Phe(2-aminomethyl)]-[Sarc]-NH2(SEQ ID NO:249),

[0921] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Pro(4,4diF)]-NH2(SEQ ID NO:250),

[0922] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[aMePro]-NH2(SEQ ID NO:251),

[0923] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Aib]-NH2(SEQ ID NO:252),

[0924] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[His(3-Me)]-[Sarc]-NH2 (SEQ ID NO: 253),

[0925] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2(SEQ ID NO:261),

[0926] Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2(SEQ ID NO:262),

[0927] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:266),

[0928] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me(SEQ ID NO:267),

[0929] [(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:270),

[0930] Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:271),

[0931] Pr-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-(N-propionylamino)ethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:272),

[0932] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-(N-(4-hydroxy-3-methylphenyl)propionylamino)ethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:273),

[0933] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(5-Me)]-[Sarc]-NH2(SEQ ID NO:276),

[0934] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(5-NH2)]-[Sarc]-NH2(SEQ ID NO:277),

[0935] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-N(H)Me(SEQ ID NO:278),

[0936] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:279),

[0937] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Gly(N-cyclohexylmethyl)]-NH2(SEQ ID NO:280),

[0938] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Gly(N-isobutyl)]-NH2(SEQ ID NO:281),

[0939] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(3-Me)]-NH2(SEQ ID NO:282),

[0940] Ac-[(D)Arg]-[aMeCys]-NT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:283),

[0941] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:284),

[0942] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 159, 285),

[0943] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 286),

[0944] Ac-[Pen]-[Gly(allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:287),

[0945] Ac-[Pen]-[Gly(allyl)]-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:288),

[0946] Ac-[Pen]-[Gly(allyl)]-T-(W(4-F)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:289),

[0947] Ac-[Pen]-ND-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:290),

[0948] Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:291),

[0949] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:299),

[0950] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:308),

[0951] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[(D)Tyr]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:309),

[0952] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:310),

[0953] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:311),

[0954] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:332),

[0955] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-butyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:333),

[0956] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-isobutyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:334),

[0957] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:335),

[0958] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[aMeLeu]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 339),

[0959] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[aMeLeu]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:347), or

[0960] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:373),

[0961] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond;

[0962] Or its pharmaceutically acceptable salt.

[0963] In some implementations, the peptide is

[0964] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104),

[0965] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106),

[0966] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 158, 162, 284),

[0967] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 247, 266),

[0968] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2(SEQ ID NO:261), or

[0969] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me(SEQ ID NO:267),

[0970] The peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0971] In some implementations, the peptide is

[0972] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104),

[0973] The peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0974] In some implementations, the peptide is

[0975] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106),

[0976] The peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0977] In some implementations, the peptide is

[0978] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 158, 162, 248),

[0979] The peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0980] In some implementations, the peptide is

[0981] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 247, 266), wherein the peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0982] In some implementations, the peptide is

[0983] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2 (SEQ ID NO:261), wherein the peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0984] In some implementations, the peptide is

[0985] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me(SEQ ID NO:267),

[0986] The peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0987] In some implementations, the peptide is

[0988] [N3-acid]-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:274) or

[0989] [FPrp triazole Me acid]-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:275),

[0990] The peptide inhibitor is cyclized via Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0991] In some embodiments, X15 is Arg, (D)Arg, aMeArg, His, (D)His, Sar, 2-Pal, or 3-Pal; wherein 2-Pal is a 2-pyridyl-substituted alanine, and 3-Pal is a 3-pyridyl-substituted alanine.

[0992]

[0993] In some embodiments, X11 is 3-Quin, and wherein 3-Quin is Ph of Phe with 3-quinolinyl substitution or is NH-C(3-quinolinylmethyl)(H)-C(O)- or:

[0994]

[0995] In some aspects, the present invention provides a peptide inhibitor of the interleukin-23 receptor, wherein the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[0996] In some embodiments, the peptide is the following, or a pharmaceutically acceptable salt thereof:

[0997] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2;(SEQ ID NO:52)

[0998]

[0999] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-NH2;(SEQ ID NO:80)

[1000]

[1001] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2; (SEQ ID NO: 103)

[1002]

[1003] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:104)

[1004]

[1005] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:106)

[1006]

[1007] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:107)

[1008]

[1009] Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:108)

[1010]

[1011] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:109)

[1012]

[1013] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:110)

[1014]

[1015] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:111)

[1016]

[1017] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:112)

[1018]

[1019] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2;(SEQ ID NO:113)

[1020]

[1021] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[bA]-NH2;(SEQ ID NO:114)

[1022]

[1023] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:116)

[1024]

[1025] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:117)

[1026]

[1027] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Quin]-[Sarc]-NH2;(SEQ ID NO:118)

[1028]

[1029] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:121)

[1030]

[1031] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:123)

[1032]

[1033] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2;(SEQ ID NO:124)

[1034]

[1035] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2;(SEQ ID NO:125)

[1036]

[1037] Ac-[Pen]-NT-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:127)

[1038]

[1039] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:134)

[1040]

[1041] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:136)

[1042]

[1043] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMe(Lys)]-[Lys(Ac)]-N-[His_3Me]-NH2;(SEQ ID NO:145)

[1044]

[1045] Ac-[Pen]-NT-[W(7-(4Quin))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:147)

[1046]

[1047] Ac-[Pen]-NT-[(W(7-(3-pyrazol-1-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:148)

[1048]

[1049] Ac-[Pen]-NT-[(W(7-(5-Et-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:149)

[1050]

[1051] Ac-[Pen]-NT-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:153)

[1052]

[1053] Ac-[Pen]-NT-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:155)

[1054]

[1055] Ac-[Pen]-NT-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:157)

[1056]

[1057] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:158)

[1058]

[1059] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:162)

[1060]

[1061] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:163)

[1062]

[1063] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:286)

[1064]

[1065] Ac-[Pen]-[Gly(allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:287)

[1066]

[1067] Ac-[Pen]-N-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:290)

[1068]

[1069] Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:291)

[1070]

[1071] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:308)

[1072]

[1073] Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2;(SEQ ID NO:311)

[1074] or

[1075] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[aMeLeu]-EN-[3Pal]-[Sarc]-NH2; (SEQ ID NO: 339)

[1076]

[1077] In some aspects, the present invention provides a peptide inhibitor of the interleukin-23 receptor, wherein the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1078] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2;(SEQ ID NO:261)

[1079]

[1080] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2; (SEQ ID NO: 299)

[1081]

[1082] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2; (SEQ ID NO: 310)

[1083]

[1084] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:332)

[1085]

[1086] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-butyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:333)

[1087]

[1088] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:335)

[1089]

[1090] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[aMeLeu]-EN-[3Pal]-[Sarc]-NH2; (SEQ ID NO: 347)

[1091]

[1092] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-LN-[3Pal]-[Sarc]-NH2; (SEQ ID NO: 351)

[1093]

[1094] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2;(SEQ ID NO:373)

[1095]

[1096] Other characteristics of peptide inhibitors

[1097] Any of the peptide inhibitors of the present invention may be further defined, for example as described below. It should be understood that each of the other defining features described herein can be applied to any peptide inhibitor, wherein the amino acid specified at a particular position allows for the presence of other defining features. In specific embodiments, these features may be present in any of the peptides of formula (I)-(XVIIId).

[1098] In various implementation schemes, R 1 The PEGylated form comprises a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, or C1-C20 alkylyl group, and includes a spacer group (e.g., acetyl) alone or as any of the foregoing. It should be understood that, in addition to the typical amino group located at the amino terminus of the peptide, R... 1 It can be replaced or exists. It should be further understood that R... 1 It may not exist. In some embodiments, the peptide inhibitor comprises an N-terminus selected from: hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-C6 alkyl, or C1-C20 alkylyl, and includes a polyethylene glycol-modified form alone or as a spacer group for any of the foregoing (e.g., acetyl). In a particular embodiment of any of the peptide inhibitors described herein, R 1 Or the N-terminus may be divided into hydrogen. In some embodiments, R 1 For example, a covalent bond.

[1099] In certain embodiments of any of the peptide inhibitors having any of the various formulas set forth herein, R 1 Alternatively, the N-terminal portion may be selected from conjugated amides of methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octyl, dodecanoic acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid. In some embodiments, R 1 Or the N-terminus is divided into pGlu. In some embodiments, R 1 It is hydrogen. In the specific implementation scheme, R 1 The peptide inhibitor is acetyl, and thus the peptide inhibitor is acylated at its N-terminus, for example to cover or protect the N-terminal amino acid residue, such as the N-terminal Pen residue.

[1100] In certain embodiments of any of the peptide inhibitors described herein, R 1 Or the N-terminus may be divided into acids. In some embodiments, R 1The N-terminus may be divided into acids selected from the following: acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, octanoic acid, lauric acid, hexadecanoic acid, 4-biphenylacetic acid, 4-fluorophenylacetic acid, gallic acid, pyroglutamic acid, cyclopentylpropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, caloic acid, succinic acid, malic acid, maleic acid, trans-butenedioic acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, 4-methylbicyclo(2.2.2)-oct-2-en-1-carboxylic acid, glucohepanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, alkyl sulfonic acid, and aryl sulfonic acid.

[1101] In the specific implementation plan, R 1 The N-terminus may be divided into alkyl sulfonic acids selected from the following: methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, and 2-hydroxyethanesulfonic acid.

[1102] In the specific implementation plan, R 1 The N-terminus may be divided into aryl sulfonic acids selected from the following: benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonic acid.

[1103] peptide dimers

[1104] In some embodiments, the present invention includes dimers of monomeric peptide inhibitors described herein, including dimers of any of the monomeric peptide inhibitors described herein or in the accompanying table. These dimers fall within the scope of the general term "peptide inhibitor" as used herein. Exemplary dimers of the present invention are also indicated in the accompanying table, which indicate the dimerizing monomeric subunit in parentheses and the linking portion. Unless otherwise specified, the subunit is linked via its C-terminus. The term "dimer" as used in peptide dimers refers to a compound in which two peptide monomeric subunits are linked. The peptide dimer inhibitors of the present invention may comprise two identical monomeric subunits, producing a homodimer, or two dissimilar monomeric subunits, producing a heterodimer. Cysteine ​​dimers comprise two peptide monomeric subunits linked via a disulfide bond between a cysteine ​​residue in one monomeric subunit and a cysteine ​​residue in another monomeric subunit.

[1105] In some embodiments, the peptide inhibitor of the present invention may be active in a dimer configuration, particularly when free cysteine ​​residues are present in the peptide. In some embodiments, this occurs in the form of a synthetic dimer or, particularly, when a free cysteine ​​monomeric peptide is present and dimerization occurs under oxidative conditions. In some embodiments, the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

[1106] In some embodiments, the monomeric subunits of the present invention can dimerize via a suitable linker, such as a disulfide bridge between two cysteine ​​residues (one in each peptide monomeric subunit) or via another suitable linker (including, but not limited to, those defined herein). Some monomeric subunits are shown to have C-termini and N-termini both comprising a free amine. Thus, to produce peptide dimer inhibitors, monomeric subunits can be modified to eliminate the C-terminal or N-terminal free amine, thereby allowing dimerization to occur at the remaining free amine. Furthermore, in some cases, the ends of one or more monomeric subunits are acylated with an acylated organic compound selected from the group consisting of: trifluoropentyl, acetyl, octanoyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-piperan-4-carboxylic acid, succinic acid, and glutaric acid. In some cases, the monomer subunit comprises both a free carboxyl terminus and a free amino terminus, thereby allowing the user to selectively modify the subunit to achieve dimerization at the desired end. Therefore, those skilled in the art will understand that the monomer subunit of the present invention can be selectively modified to achieve a single specific amine for desired dimerization.

[1107] Furthermore, it is understood that the C-terminal residues of the monomer subunits disclosed herein are, in cases, amides. Additionally, it should be understood that in some embodiments, as is generally understood in the art, dimerization at the C-terminus is promoted by using a suitable amino acid having a side chain (with an amine functional group). Regarding the N-terminal residues, it should generally be understood that dimerization can be achieved via a free amine at the residue tip, or by using a suitable amino acid side chain having a free amine, as is generally understood in the art.

[1108] The connecting portion for linking the monomer subunits may include any structure, length, and / or size compatible with the teachings herein. In at least one embodiment, the connecting portion is selected from the non-limiting group consisting of: cysteine, lysine, DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, glutaric acid, isophthalic acid, 1,3-epenylated diacetic acid, 1,4-epenylated diacetic acid, 1,2-epenylated diacetic acid, tri ... Boc-3 IDA-Biotin, PEG4-Biotin, AADA, suitable aliphatic, aromatic, heteroaromatic compounds, and polyethylene glycol linking motifs with a molecular weight of about 400 Da to about 40,000 Da. In some embodiments, PEG2 is HO2CCH2CH2OCH2CH2OCH2CH2CO2H. Non-limiting examples of suitable linking motifs are provided in Table 2.

[1109] Table 2. Illustrative Connectives

[1110]

[1111]

[1112]

[1113] In some embodiments, the peptide dimer inhibitor dimers via a linker moiety. In some embodiments, the peptide dimer inhibitor dimers via an intermolecular disulfide bond formed between two cysteine ​​residues, one in each monomer subunit. In some embodiments, the peptide dimer inhibitor dimers via both a linker moiety and an intermolecular disulfide bond formed between two cysteine ​​residues. In some embodiments, the intramolecular bond is a thioether, lactam, triazole, selenide, diselenide, or olefin bond, rather than a disulfide bond.

[1114] Those skilled in the art will understand that the linking portions (e.g., C-terminal and N-terminal links) disclosed herein are non-limiting examples of suitable linking portions, and the invention may include any suitable linking portion. Therefore, some embodiments of the invention include homodimeric or heterodimeric peptide inhibitors composed of two monomeric subunits selected from peptides shown in any of the tables herein or comprising sequences presented in any of the tables herein, wherein the C-terminus or N-terminus of the respective monomeric subunit (or internal amino acid residues) is linked by any suitable linking portion to provide a dimeric peptide inhibitor having IL-23R inhibitory activity. In some embodiments, a linker binds to the N-terminus or C-terminus of one monomeric subunit constituting the dimer and an internal amino acid residue of the other monomeric subunit. In some embodiments, a linker binds to an internal amino acid residue of one monomeric subunit constituting the dimer and an internal amino acid residue of the other monomeric subunit. In other embodiments, a linker binds to the N-terminus or C-terminus of both subunits.

[1115] In a specific implementation, one or both of the monomeric subunits include any of the formulas (I)-(XVIIId), or the sequence or structure of any of the peptides shown in Tables E1A and E1B or described herein.

[1116] In some embodiments, the peptide dimer inhibitor has the structure of formula XII:

[1117] (R 1 -XR 2 )2-L(XII)

[1118] Or its pharmaceutically acceptable salt.

[1119] Among them, each R 1Independently, it is non-existent, a bond (e.g., a covalent bond), or R. 1 The polyethylene glycolated form is selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-6 alkyl, and C1-C20 alkylyl, and includes a spacer group alone or as any of the foregoing.

[1120] Each R 2 Independently, it is absent, bonded (e.g., covalent), or selected from OH or NH2; L is the linking moiety; and each X is an independently selected peptide monomer subunit comprising the sequence of formula (I)-(XVIIId) as described herein. In some embodiments, one or both peptide monomer subunits of the peptide dimer inhibitor are cyclized, for example, via an intramolecular bond between X4 and X9. In some embodiments, one or both peptide monomer subunits are linear or acyclic.

[1121] In the specific implementation plan, each R 1 The polyethylene glycolate is a PEGylated form of a bond that is independently a bond (e.g., a covalent bond), or selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-6 alkyl, C1-C20 alkylyl, and includes a spacer group alone or as any of the foregoing. In a specific embodiment, the N-terminus of each subunit includes a portion selected from: hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 arylC1-6 alkyl, C1-C20 alkylyl, and includes a PEGylated form of a spacer group alone or as any of the foregoing.

[1122] In certain embodiments of any of the peptide inhibitors having any of the various formulas set forth herein, each R 1 (Or the N-terminal portion) is selected from conjugated amides of methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octyl, dodecanoic acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

[1123] In the specific implementation plan, each R 2 (Or the C-terminal portion) is an independent bond (e.g., a covalent bond), or selected from OH or NH2.

[1124] In a particular embodiment of any of the peptide dimer inhibitors described herein, R 1 One or both of them are hydrogen.

[1125] In certain embodiments of the peptide dimer inhibitor of the present invention, the linker portion (L) is any of the linkers described herein or shown in Table 1 or 7. In some embodiments, L is a lysine linker portion, a diethylene glycol linker portion, an iminodiacetic acid (IDA) linker portion, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker portion, or a PEG linker portion.

[1126] In various embodiments of any of the peptide dimer inhibitors, each of the peptide monomer subunits is linked to a linker portion via its N-terminus, C-terminus, or internal amino acid residue. In some embodiments of any of the peptide dimer inhibitors, the N-terminus of each peptide monomer subunit is linked via a linker portion. In some embodiments of any of the peptide dimer inhibitors, the C-terminus of each peptide monomer subunit is linked via a linker portion. In some embodiments of any of the peptide dimer inhibitors, each peptide monomer subunit is linked via a linker portion linked to an internal amino acid.

[1127] Peptide inhibitor conjugates and biopolymers

[1128] In some embodiments, the peptide inhibitors of the present invention, comprising both monomers and dimers, include one or more conjugated chemical substituents, such as lipophilic substituents, and a polymeric moiety, which may be referred to herein as a half-life-extending moiety. Without wishing to be bound by any particular theory, it is believed that the lipophilic substituents bind to albumin in the bloodstream, thereby shielding the peptide inhibitor from enzymatic degradation and thus enhancing its half-life. Additionally, the polymeric moiety is believed to enhance the half-life and reduce clearance from the bloodstream.

[1129] In an additional embodiment, the peptide inhibitor, such as any of the peptides of formula (I)-(XVIIId), further includes a linking portion connected to an amino acid residue present in the inhibitor, such as a linking portion that may bind to a side chain of any amino acid of the peptide inhibitor, an N-terminal amino acid of the peptide inhibitor, or a C-terminal amino acid of the peptide inhibitor.

[1130] In an additional embodiment, the peptide inhibitor, such as any of the peptides of formula (I)-(XIV), further includes a half-life extension portion linked to an amino acid residue present in the inhibitor, such as the half-life extension portion being able to bind to the side chain of any amino acid of the peptide inhibitor, the N-terminal amino acid of the peptide inhibitor, or the C-terminal amino acid of the peptide inhibitor.

[1131] In an additional embodiment, the peptide inhibitor, such as any of the peptides of formula (I)-(XIV), further includes a half-life extension portion connected to a linking portion, the linking portion being connected to an amino acid residue present in the inhibitor, such as the half-life extension portion being able to bind to a linking portion connected to a side chain of any amino acid of the peptide inhibitor, an N-terminal amino acid of the peptide inhibitor, or a C-terminal amino acid of the peptide inhibitor.

[1132] In a specific implementation, the peptide inhibitor comprises a half-life extension portion having the structure shown below, wherein n = 0 to 24 or n = 14 to 24:

[1133]

[1134] In some embodiments, the peptide inhibitor of the present invention comprises the extended half-life portion shown in Table 8.

[1135] Table 8. Illustrative examples of half-life extension

[1136]

[1137]

[1138] In some embodiments, the extended half-life portion binds directly to the peptide inhibitor, while in other embodiments, the extended half-life portion binds to the peptide inhibitor via a linker portion, such as any of the portions depicted in Tables 1, 2, or 4.

[1139] Table 4. Illustrative Connectivity

[1140]

[1141]

[1142]

[1143] In specific embodiments, the peptide inhibitor of the present invention comprises any of the linking portions shown in Table 2 or 4 and any of the half-life extension portions shown in Table 3, including any of the following combinations shown in Table 5.

[1144] Table 5. Illustrative combinations of linkers and half-life extensions in peptide inhibitors

[1145]

[1146]

[1147]

[1148]

[1149]

[1150] In some implementations, multiple linkers may be present between the peptide and the conjugated portion, such as the half-life extension portion (as depicted in Table 6).

[1151] Table 6. Illustrative combinations of linkers and half-life extensions in peptide inhibitors

[1152]

[1153] In some embodiments, the half-life of the peptide inhibitor of the present invention, including a conjugated chemical substituent (i.e., a half-life-extending portion), is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the half-life of the same peptide inhibitor (but without the conjugated chemical substituent). In some embodiments, the lipophilic substituent and / or polymeric portion enhance the permeability of the peptide inhibitor through epithelial cells and / or its retention in the lamina propria. In some embodiments, the permeability of the peptide inhibitor of the present invention, including a conjugated chemical substituent, through epithelial cells and / or its retention in the lamina propria is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the half-life of the same peptide inhibitor (but without the conjugated chemical substituent).

[1154] In some embodiments, the side chains of one or more amino acid residues (e.g., Lys residues) in the peptide inhibitor of the present invention are conjugated (e.g., covalently linked) to a lipophilic substituent. The lipophilic substituent may be covalently bonded to an atom in the amino acid side chain, or alternatively may be conjugated to the amino acid side chain via one or more spacer groups. When present, the spacer groups provide the distance between the peptide analog and the lipophilic substituent. In specific embodiments, the peptide inhibitor comprises any of the conjugated moieties shown in the peptides disclosed in Tables 2 to 6.

[1155] In some embodiments, the lipophilic substituent may comprise a hydrocarbon chain having 4 to 30 carbon atoms, for example at least 8 or 12 carbon atoms, and preferably 24 carbon atoms or less, or 20 carbon atoms or less. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. In some embodiments, the hydrocarbon chain is partially substituted to form a portion of an amino acid side chain or spacer group, such as an acyl, sulfonyl, N, O, or S atom. In some embodiments, the hydrocarbon chain is substituted with an acyl group, and thus the hydrocarbon chain may form a portion of an alkanoyl group (e.g., alkanoyl, hexanoyl, lauroyl, myristoyl, or stearyl).

[1156] The lipophilic substituent may be conjugated with any amino acid side chain of the peptide inhibitor of the present invention. In some embodiments, the amino acid side chain includes a carboxyl, hydroxyl, thiol, amide, or amino group for forming an ester, sulfonyl ester, thioester, amide, or sulfonamide with the spacer group or lipophilic substituent. For example, the lipophilic substituent may be conjugated with: Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys, or Dbu, Dpr, or Orn. ​​In some embodiments, the lipophilic substituent is conjugated to Lys. An amino acid represented as Lys in any of the formulas provided herein may be replaced, for example, with Dbu, Dpr, or Orn in which a lipophilic substituent is added.

[1157] In some embodiments, the peptide inhibitors of the present invention may be modified via conjugation of the chemical moiety with one or more amino acid side chains within the peptide, for example to enhance stability, improve permeability, or enhance pharmaceutical characteristics. For example, the N(ε) of lysine N(ε), the β-carboxyl group of aspartic acid, or the γ-carboxyl group of glutamic acid may be appropriately functionalized. Thus, to produce a modified peptide, the amino acids within the peptide may be appropriately modified. Furthermore, in some cases, the side chains are acylated with an acylated organic compound selected from the group consisting of: trifluoropentyl, acetyl, octanoyl, butyl, pentyl, hexyl, palmitic, trifluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-piperan-4-carboxylic acid, succinic acid, glutaric acid, or cholic acid. Those skilled in the art will understand that a range of conjugates may be linked, such as PEG4, isoglu, and combinations thereof. Those skilled in the art will understand that the amino acids in a peptide can be isochorically substituted; for example, Lys can be replaced with Dap, Dab, α-MeLys, or Orn. ​​Examples of modified residues within peptides are shown in Table 7.

[1158] Table 7. Examples of peptides modified with lysine, Asp, and Asn

[1159]

[1160]

[1161] In other embodiments of the invention, alternatively or additionally, the side chains of one or more amino acid residues in the peptide inhibitor of the invention are conjugated to the polymerization moiety, for example, to improve solubility and / or in vivo (e.g., in plasma) half-life and / or bioavailability. Such modifications are also known to reduce the clearance (e.g., renal clearance) of therapeutic proteins and peptides.

[1162] As used herein, “polyethylene glycol” or “PEG” refers to a polyether compound of the general formula H-(O-CH2-CH2)n-OH. As used herein, PEG is also referred to as polyethylene oxide (PEO) or polyethylene oxide (PCE), depending on its molecular weight, PEO, PEE, or POG, and refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but PEG often refers to oligomers and polymers with a molecular weight below 20,000 Da, PEO to polymers with a molecular weight above 20,000 Da, and POE to polymers of any molecular weight. PEG and PEO are liquids or low-melting-point solids, depending on their molecular weight. Throughout this invention, the three names are used interchangeably. PEG is prepared by the polymerization of ethylene oxide and is commercially available in a wide range of molecular weights from 300 Da to 10,000,000 Da. Although PEG and PEO with different molecular weights can be used in different applications and have different physical properties (e.g., viscosity) due to chain length effects, their chemical properties are almost identical. The polymerized portion is preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymerized portions include polyethylene glycol (PEG), homopolymers or copolymers of PEG, monomethyl-substituted polymers of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998); Bioconjugate Chem. 6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also covered are PEGs prepared for the purpose of extending half-life, such as monoactivated, alkoxy-terminated polyoxyethylene (POA), such as monomethoxy-terminated polyethylene glycol (mPEG); and also dual-activated polyethylene oxide (glycol) or other PEG derivatives. For the purposes of this invention, suitable polymers are typically selected, with a weight generally ranging from about 200 Da to about 40,000 Da, or from about 200 Da to about 60,000 Da. In some embodiments, PEG with a molecular weight of 200 to 2,000 or 200 to 500 is used. Depending on the initiator used in the polymerization method, different forms of PEG may also be used; common initiators are monofunctional methyl ether PEG or methoxy poly(ethylene glycol), abbreviated as mPEG.

[1163] Low molecular weight PEG can also be used as a pure oligomer, referred to as monodisperse, homogeneous, or discrete. It is used in some embodiments of the present invention.

[1164] PEG can also be obtained in different geometries: branched PEG has three to ten PEG chains derived from a central core group; star-shaped PEG has 10 to 100 PEG chains derived from a central core group; and comb-shaped PEG has multiple PEG chains typically grafted onto the polymer backbone. PEG can also be linear. The number usually included in the PEG name indicates its average molecular weight (e.g., PEG with n=9), which will have an average molecular weight of approximately 400 Daltons and will be labeled PEG 400.

[1165] As used herein, “polyglycolization” refers to the operation of covalently coupling a PEG structure to the peptide inhibitor of the present invention, and is hereinafter referred to as “polyglycolized peptide inhibitor”. In some embodiments, the PEG of the PEGylated side chain is a PEG having a molecular weight of about 200 to about 40,000. In some embodiments, the spacer group of the peptide of formula I, formula I', or formula I'' is PEGylated. In some embodiments, the PEG of the PEGylated spacer group is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In some embodiments, the PEG of the PEGylated spacer group is PEG3 or PEG8.

[1166] Other suitable polymeric moieties include polyamino acids, such as polylysine, polyaspartic acid, and polyglutamic acid (see, for example, Gombotz et al. (1995), Bioconjugate Chem. Vol. 6: 332-351; Hudecz et al. (1992), Bioconjugate Chem., Vol. 3, 49-57; and Tsukada et al. (1984), J. Natl. Cancer Inst., Vol. 73, 721-729). The polymeric moieties can be linear or branched. In some embodiments, the molecular weight is 500-40,000 Da, for example 500-10,000 Da, 1,000-5,000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

[1167] In some embodiments, the peptide inhibitor of the present invention may comprise two or more such polymeric moieties, in which case the total molecular weight of all such moieties will generally fall within the range provided above.

[1168] In some embodiments, the polymeric moiety (via covalent bond) is coupled to the amino, carboxyl, or thiol group of the amino acid side chain. Some examples are the thiol group of the Cys residue and the ε-amino group of the Lys residue, and may also involve the carboxyl groups of the Asp and Glu residues.

[1169] Those skilled in the art will readily appreciate suitable techniques for performing the coupling reaction. For example, the methoxylated PEG moiety can be coupled to the Cys thiol group via a maleimide linker using a reagent available from Nektar Therapeutics AL. For details on suitable chemical methods, see also WO 2008 / 101017 and the references cited above. Maleimide-functionalized PEG can also be conjugated with the thiosulfate group on the side chain of the Cys residue.

[1170] As used herein, disulfide bond oxidation can occur in a single step or as a two-step process. For a single oxidation step, as used herein, a triphenylmethyl protecting group is typically employed during assembly, allowing deprotection during cleavage, followed by solution oxidation. When a second disulfide bond is required, we have the option of native or selective oxidation. For selective oxidation requiring orthogonal protecting groups, Acm and triphenylmethyl are used as protecting groups for cysteine. Cleavage removes one cysteine ​​protecting pair, thus allowing oxidation of this pair. A second deprotection step involving the cysteine-protected Acm group is then performed. For native oxidation, a triphenylmethyl protecting group is used for all cysteines, allowing for the native folding of the peptide. Those skilled in the art will readily appreciate suitable techniques that can be used to perform the oxidation steps.

[1171] If the dry chemical components (including poly(ethylene glycol)) react with functional groups present in twenty naturally occurring amino acids (such as the ε-amino group in lysine amino acid residues, thiols present in cysteine ​​amino acid residues, or other nucleophilic amino acid side chains), these non-specific chemical reactions, when multiple naturally occurring amino acids react in a peptide inhibitor, produce a final peptide inhibitor containing numerous isomers of a peptide conjugated with one or more poly(ethylene glycol) strands at different positions within the peptide inhibitor.

[1172] One advantage of certain embodiments of the invention includes the ability to add one or more chemical moieties (such as PEG) by incorporating one or more non-natural amino acids that have unique functional groups that react with the activated PEG via a chemical reaction without reacting with naturally occurring amino acids present in the peptide inhibitor. For example, azides and alkynes do not react with all naturally occurring functional groups in proteins. Therefore, non-natural amino acids can be incorporated into one or more specific sites in the peptide inhibitor where PEG or another modification is required, without undesirable non-specific reactions. In some embodiments, specific chemical methods involved in the reaction create a stable covalent link between the PEG strand and the peptide inhibitor. Furthermore, such reactions can be carried out under mild aqueous conditions without impairing most of the peptide. In some embodiments, the non-natural amino acid residue is AHA.

[1173] The number and range of chemical moieties that can be attached to natural amino acids are limited. In contrast, a significantly wider range of applicable chemicals can be used to attach chemical moieties to target molecules, enabling the attachment of the chemical moieties. Essentially, any target molecule can act as a substrate for attaching the chemical moieties, including any protein (or a portion thereof) containing non-natural amino acids, such as non-natural amino acids containing a reactive site or side chain (where the chemical moieties can be attached), or aldehyde or ketone-derived amino acids.

[1174] Many chemical moieties can be conjugated or linked to a particular molecule via various methods known in the art. Several such methods are described in U.S. Patent No. 8,568,706. As an illustrative example, the azide moieties can be applied to conjugated chemical moieties, such as PEG or other moieties described herein. The azide moieties act as reactive functional groups and are not present in most naturally occurring compounds (therefore they do not react with the native amino acids of naturally occurring compounds). Azides also undergo selective conjugation with a limited number of reactive complexes, and azides are less frequently introduced into biological samples without significantly altering the molecular size. One reaction that allows the incorporation or introduction of azides into a molecule is the copper-mediated Huisgen [3+2] cycloaddition of the azide. This reaction can be used for the selective PEGylation of peptide inhibitors. (Tornoe et al. J.Org.Chem.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).

[1175] Synthesis of peptide inhibitors

[1176] The peptide inhibitors of the present invention can be synthesized using a variety of techniques known to those skilled in the art. In some embodiments, monomeric subunits are synthesized, purified, and dimerized using the techniques described in the accompanying examples. In some embodiments, the present invention provides a method for producing the peptide inhibitor (or its monomeric subunits) of the present invention, comprising the chemical synthesis of a peptide having, consisting of, or primarily consisting of, the amino acid sequence described herein, including but not limited to any of the amino acid sequences of Formula I, II, or any of the amino acid sequences described herein. In other embodiments, the peptide is synthesized recombinantly rather than chemically. In some embodiments, the peptide inhibitor is a dimer, and the method comprises synthesizing two monomeric subunits of the peptide dimer inhibitor and subsequently dimerizing the two monomeric subunits to produce the peptide dimer inhibitor. In various embodiments, dimerization is achieved via any of the various methods described herein. In a specific embodiment, the method for producing the peptide inhibitor (or its monomeric subunits) further comprises cyclizing the peptide inhibitor (or its monomeric subunits) after its synthesis. In a specific embodiment, cyclization is achieved via any of the various methods described herein. In some embodiments, the present invention provides a method for generating the peptide inhibitor (or its monomeric subunit) of the invention, comprising introducing an intramolecular bond, such as a disulfide bond, amide bond, or thioether bond, between two amino acid residues within a peptide, the peptide comprising, consisting of, or substantially consisting of the following: having the amino acid sequence described herein, including but not limited to any of formulas (I)-(IX), or any of the amino acid sequences set forth in the accompanying examples or tables.

[1177] In relevant embodiments, the present invention includes polynucleotides encoding polypeptides having any of the sequences of formulas (I)-(IX) or those set forth in the accompanying examples or tables.

[1178] Additionally, the present invention includes a vector comprising the polynucleotide of the present invention, such as an expression vector.

[1179] processing method

[1180] In some embodiments, the present invention includes a method for inhibiting the binding of IL-23 to IL-23R on cells, comprising contacting IL-23 with the peptide inhibitor of the present invention. In some embodiments, the cells are mammalian cells. In specific embodiments, the method is performed in vitro or in vivo. Inhibition of binding can be determined by a variety of conventional experimental methods and analyses known in the art.

[1181] In some embodiments, the present invention includes a method for inhibiting IL-23 signaling in cells, comprising contacting IL-23 with a peptide inhibitor of the present invention. In some embodiments, the cells are mammalian cells. In specific embodiments, the method is performed in vitro or in vivo. In specific embodiments, inhibition of IL-23 signaling can be determined by measuring changes in the amount of phosphate-STAT3 in the cells.

[1182] In some embodiments, the present invention provides a method for treating a subject suffering from a condition or indication related to IL-21 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), wherein the method comprises administering the peptide inhibitor of the present invention to the subject. In some embodiments, a method is provided for treating a subject suffering from a condition or indication characterized by inappropriate, dysregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the subject an amount of the peptide inhibitor of the present invention sufficient to inhibit (partially or completely) the binding of IL-23 to IL-23R in the subject. In specific embodiments, the inhibition of IL-23 to IL-23R binding occurs in a specific organ or tissue of the subject, such as the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, lymph nodes, mesenteric lymph nodes, or lymphatic ducts.

[1183] In some embodiments, the method of the present invention includes providing the peptide inhibitor of the present invention to a subject in need. In specific embodiments, the subject in need has been diagnosed with or identified as being at risk of developing a disease or condition associated with IL-23 / IL-23R. In specific embodiments, the subject is a mammal.

[1184] In some implementations, the disease or condition is an autoimmune inflammatory disease and related diseases and conditions, such as multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, Crohn's disease, ulcerative colitis, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial vertebral arthritis), psoriatic arthritis, or psoriasis. In the specific implementation plan, the disease or condition is psoriasis (e.g., plaque psoriasis, punctate psoriasis, reversal psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, atopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical stomatitis), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiotherapy or chemotherapy, colitis associated with congenital immune disorders such as leukopenia-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Praque syndrome, and Chediak-Higashi syndrome. (Syndrome), Weil-O'S syndrome, pouchitis following rectocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, virus-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[1185] In some embodiments, the present invention provides a method for treating inflammatory bowel disease (IBD) in a subject of need, comprising administering a peptide inhibitor of the present invention to the subject, wherein the peptide inhibitor comprises or is composed of an amino acid sequence of formula (I). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease. In some embodiments, the peptide inhibitor comprises or is composed of an amino acid sequence of formula (Z) or (Z'). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1186] In some embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (Ia), (Ib), (Ic), or (Id). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1187] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences of formula (IIa), (IIb), or (IIc). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1188] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences of formula (IIIa), (IIIb), (IIIc), or (IIId). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1189] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences: (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1190] In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (Va), (Vb), (Vc), or (Vd). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease. In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), or (VIh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1191] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences of formula (VIIa), (VIIb), (VIIc), or (VIId). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1192] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences: (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), or (VIIIh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1193] In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (IXa), (IXb), (IXc), or (IXd). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1194] In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), (Xg), or (Xh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1195] In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (XIa), (XIb), (XIc), or (XId). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1196] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences: (XIIa), (XIIb), (XIIc), (XIId), (XIIe), (XIIIf), (XIIg), or (XIIh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1197] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences: (XIIIa), (XIIIb), (XIIIc), or (XIIId). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1198] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences of formula (XIVa), (XIVb), (XIVc), (XIVd), (XIVe), (XIVf), (XIVg), or (XIVh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1199] In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (XVa), (XVb), (XVc), or (XVd). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1200] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences of formula (XVIa), (XVIb), (XVIc), (XVId), (XVIe), (XVIIf), (XVIg), or (XVIh). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1201] In other relevant embodiments, the peptide inhibitor comprises or consists of the following amino acid sequences: (XVIIa), (XVIIb), (XVIIc), or (XVIId). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1202] In other relevant embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of formula (Z'), (Z'-A), (Z'-B), (Z'-C), (Z'-D), (Z'-E), (Z'-F), (Z'-G), (Z'-H), (Z'-I), (Z'-J), (Z'-K), (Z'-L), or (Z'-M). In some embodiments, IBD is ulcerative colitis. In some embodiments, IBD is Crohn's disease.

[1203] In certain embodiments of methods for treating IBD (e.g., ulcerative colitis or Crohn's disease), the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1204] Ac-[(D)Arg]-[Abu]-QT-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-dK-[Sarc]-NH2(SEQ ID NO:1);

[1205] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu)]-[Sarc]-NH2 (SEQ ID NO: 2);

[1206] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-EN-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:3);

[1207] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)His]-[Sarc]-NH2 (SEQ ID NO: 4);

[1208] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:5);

[1209] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-EN-[(D)Leu)]-[Sarc]-NH2(SEQ ID NO:6);

[1210] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 7);

[1211] Ac-[(D)Arg]-[Abu]-QTWQ-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-[(D)NMeTyr]-NH2(SEQ ID NO:8);

[1212] Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-[(D)NMeTyr]-NH2(SEQ ID NO:9);

[1213] Ac-[(D)Arg]-[Pen]-QTWQ-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-NF-[(D)NMeTyr]-NH2(SEQ ID NO:10);

[1214] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:11);

[1215] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 12);

[1216] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:13);

[1217] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 14);

[1218] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:15);

[1219] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:16);

[1220] Ac-[Abu]-QT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:17);

[1221] Ac-[Abu]-QT-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2(SEQ ID NO:18);

[1222] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NOs: 20, 25);

[1223] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 21);

[1224] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:22);

[1225] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:23);

[1226] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:24);

[1227] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 25);

[1228] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:26);

[1229] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:27);

[1230] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:28);

[1231] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 29);

[1232] Ac-[Pen]-NT-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:30);

[1233] Ac-[Pen]-NT-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:31);

[1234] Ac-[Pen]-NT-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:32);

[1235] Ac-[Pen]-NT-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:33);

[1236] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Et)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:34);

[1237] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4-Me)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:35);

[1238] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Me)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:36);

[1239] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4-OMe)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:37);

[1240] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-i-Pr)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:38);

[1241] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-nPr)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:39);

[1242] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-OMe)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:40);

[1243] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Cl)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:41);

[1244] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(5-OMe)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:42);

[1245] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(3-MePh)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:43);

[1246] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Ph)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:44);

[1247] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Et)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:45);

[1248] Ac-[Pen]-NT-[W(7-(2-FPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:46);

[1249] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Leu]-[(D)NMeTyr]-NH2 (SEQ ID NO: 47);

[1250] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 48);

[1251] Ac-[Pen]-NT-[W(7-(2-OMePh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:49);

[1252] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Ph)]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:50);

[1253] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:51);

[1254] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:52);

[1255] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:53);

[1256] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:54);

[1257] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:55);

[1258] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:56);

[1259] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)NMeTyr]-NH2(SEQ ID NO:57);

[1260] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NF-[(D)NMeTyr]-NH2 (SEQ ID NO: 58);

[1261] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:59);

[1262] Ac-[Pen]-ST-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:60);

[1263] Ac-[Pen]-ST-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ESH-[Sarc]-NH2(SEQ ID NO:61);

[1264] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)NMeTyr]-NH2(SEQ ID NO:62);

[1265] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[(D)Asn]-H-[Sarc]-NH2(SEQ ID NO:63);

[1266] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EGH-[Sarc]-NH2(SEQ ID NO:64);

[1267] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[h(Ser)]-H-[Sarc]-NH2(SEQ ID NO:65);

[1268] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENHP-NH2(SEQ ID NO:66);

[1269] Ac-[Pen]-NT-[W(7-(2-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:67);

[1270] Ac-[Pen]-NT-[W(7-3BiPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:68);

[1271] Ac-[Pen]-NT-[W(7-(phenanthrene-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:69);

[1272] Ac-[Pen]-NT-[W(7-(4-anthracene-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:70);

[1273] Ac-[Pen]-NT-[W(7-(1-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:71);

[1274] Ac-[Pen]-NT-[W(7-(4BiPh))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:72);

[1275] Ac-[Pen]-NT-[W(7-(3,5-t-Bu-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:73);

[1276] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2 (SEQ ID NO:74);

[1277] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2 (SEQ ID NO:75);

[1278] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[2Pal]-NH2(SEQ ID NO:78);

[1279] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[2Pal]-NH2(SEQ ID NO:79);

[1280] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-NH2(SEQ ID NO:80);

[1281] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:81);

[1282] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[(D)NMeTyr]-NH2(SEQ ID NO:82);

[1283] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-ENH-[(D)NMeTyr]-NH2 (SEQ ID NO: 83);

[1284] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-Phe[4-aminomethyl]-[(D)NMeTyr]-NH2(SEQ ID NO:84);

[1285] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-N-[(D)His]-NH2(SEQ ID NO:85);

[1286] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)His]-NH2(SEQ ID NO:86);

[1287] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-[(D)NMeTyr]-NH2(SEQ ID NO:87);

[1288] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENN-[(D)NMeTyr]-NH2(SEQ ID NO:88);

[1289] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NN-[(D)NMeTyr]-NH2 (SEQ ID NO: 89);

[1290] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val]-[(D)NMeTyr]-NH2 (SEQ ID NO: 90);

[1291] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Thr]-[(D)NMeTyr]-NH2(SEQ ID NO:91);

[1292] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-NH2(SEQ ID NO:92);

[1293] Ac-[Abu]-NT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:93);

[1294] Ac-[Abu]-NT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:94);

[1295] Ac-[Abu]-NT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:95);

[1296] Ac-[Abu]-NT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:96);

[1297] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NH-[Sarc]-NH2(SEQ ID NO:97);

[1298] Ac-[Abu]-NT-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2;(SEQ ID NO:98)

[1299] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:99);

[1300] Ac-[(D)Arg]-[Abu]-ST-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:100);

[1301] Ac-[(D)Arg]-[Abu]-NT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:101);

[1302] Ac-[(D)Arg]-[Abu]-NT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[Sarc]-NH2(SEQ ID NO:102);

[1303] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 103);

[1304] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104);

[1305] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 105);

[1306] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106);

[1307] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:107);

[1308] Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:108);

[1309] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:109);

[1310] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:110);

[1311] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:111);

[1312] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:112);

[1313] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:113);

[1314] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[bA]-NH2(SEQ ID NO:114);

[1315] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-[Sarc]-NH2(SEQ ID NO:115);

[1316] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:116);

[1317] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:117);

[1318] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Quin]-[Sarc]-NH2(SEQ ID NO:118);

[1319] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[7-aza-tryptophan]-[Sarc]-NH2(SEQ ID NO:119);

[1320] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)aMeTyr]-NH2 (SEQ ID NO: 120);

[1321] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)aMeTyr]-NH2(SEQ ID NO:121);

[1322] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)aMeTyr]-NH2 (SEQ ID NO: 122);

[1323] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)aMeTyr]-NH2(SEQ ID NO:123);

[1324] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:124);

[1325] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:125);

[1326] Ac-[Pen]-NT-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:126);

[1327] Ac-[Pen]-NT-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:127);

[1328] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[bA]-NH2 (SEQ ID NO: 130);

[1329] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2(SEQ ID NO:131);

[1330] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:132);

[1331] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:133);

[1332] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:134);

[1333] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:135);

[1334] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:136);

[1335] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-acetaminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:137);

[1336] Ac-[Pen]-ET-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:138);

[1337] Ac-[Pen]-ET-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:139);

[1338] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:140);

[1339] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:141);

[1340] Ac-[Pen]-NT-[W(7-(3-formamidophenyl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:142);

[1341] Ac-[Pen]-NT-[W(7-pyrimidin-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:143);

[1342] Ac-[Pen]-NT-[W(7-imidazopyridyl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:144);

[1343] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMe(Lys)]-[Lys(Ac)]-N-[His_3Me]-NH2(SEQ ID NO:145);

[1344] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His_3Me]-NH2(SEQ ID NO:146);

[1345] Ac-[Pen]-NT-[W(7-(4Quin))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:147);

[1346] Ac-[Pen]-NT-[(W(7-(3-pyrazol-1-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:148);

[1347] Ac-[Pen]-NT-[(W(7-(5-Et-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:149);

[1348] Ac-[Pen]-NT-[W(5-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:150);

[1349] Ac-[Pen]-NT-[(W(7-(3-pyrazol-1-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:151);

[1350] Ac-[Pen]-NT-[W(7-indazol-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:152);

[1351] Ac-[Pen]-NT-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:153);

[1352] Ac-[Pen]-NT-[W(5-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:154);

[1353] Ac-[Pen]-NT-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:155);

[1354] Ac-[Pen]-NT-[W(4-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:156);

[1355] Ac-[Pen]-NT-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:157);

[1356] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:158);

[1357] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:159, 285);

[1358] Ac-[Pen]-NT-[W(5-Ca)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:160);

[1359] Ac-[Pen]-NT-[Trp_4aza]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:161);

[1360] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:162);

[1361] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:163);

[1362] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(5Pyal)]-NH2(SEQ ID NO:164);

[1363] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys]-[Lys(Ac)]-N-[(5Pyal)]-NH2(SEQ ID NO:165);

[1364] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(1-Me)His]-NH2(SEQ ID NO:166);

[1365] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(1-Me)His]-NH2(SEQ ID NO:167); or

[1366] Ac-[Pen]-NT-[W(7-Me]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:168);

[1367] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond.

[1368] In certain embodiments of methods for treating IBD (such as ulcerative colitis or Crohn's disease), the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1369] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-NH2(SEQ ID NO:80);

[1370] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104);

[1371] Ac-[Pen]-NT-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:108);

[1372] Ac-[Abu]-QT-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:110);

[1373] Ac-[Abu]-QT-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:112);

[1374] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Quin]-[Sarc]-NH2(SEQ ID NO:118);

[1375] Ac-[Pen]-ST-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:124); or

[1376] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2(SEQ ID NO:125);

[1377] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-Cys thioether bond.

[1378] In certain embodiments of methods for treating IBD (such as ulcerative colitis or Crohn's disease), the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1379] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 105);

[1380] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106);

[1381] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:117);

[1382] Ac-[Pen]-NT-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:126);

[1383] Ac-[Pen]-NT-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:127);

[1384] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:134);

[1385] Ac-[Abu]-QT-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:135);

[1386] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:136);

[1387] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-acetaminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:137); or

[1388] Ac-[Pen]-ET-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:139);

[1389] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond.

[1390] In certain embodiments of methods for treating IBD (such as ulcerative colitis or Crohn's disease), the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1391] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 139);

[1392] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NOs:158, 162, 284);

[1393] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:163);

[1394] Ac-[Pen]-NTW-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:523);

[1395] Ac-[Pen]-NTWQ-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:524);

[1396] Ac-[Abu]-QTWQ-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:525);

[1397] Ac-[Abu]-QTWQ-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:526);

[1398] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:163);

[1399] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-acetaminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:527); or

[1400] Ac-[Pen]-ETW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:528);

[1401] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond.

[1402] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1403] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)Lys]-[(D)NMeTyr]-NH2(SEQ ID NO:201),

[1404] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)His]-[(D)NMeTyr]-NH2(SEQ ID NO:202),

[1405] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Orn]-[(D)NMeTyr]-NH2 (SEQ ID NO: 203),

[1406] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Ser]-[(D)NMeTyr]-NH2 (SEQ ID NO: 204),

[1407] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Phe]-[(D)NMeTyr]-NH2 (SEQ ID NO: 205),

[1408] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)Tyr]-NH2(SEQ ID NO:206),

[1409] Ac-[Pen]-NT-[W(7-Me)]-[(D)Tyr]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 207),

[1410] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENHP-NH2(SEQ ID NO:208),

[1411] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-[(D)Pro]-NH2(SEQ ID NO:209),

[1412] Ac-[Pen]-NT-[W(7-Me)]-[Phe(4-CONH2)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 210),

[1413] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-(D)Phe[4-NH2]-[Sarc]-NH2(SEQ ID NO:211),

[1414] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ENH-NH2(SEQ ID NO:212),

[1415] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-NHN(H)Me (SEQ ID NO: 213),

[1416] Ac-[Pen]-NT-[W(7-Me)]-[Phe(4-NH(Ac))]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO: 214),

[1417] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-[(D)NMeTyr]-NH2 (SEQ ID NO: 215),

[1418] Ac-[Pen]-NT-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2(SEQ ID NO:216),

[1419] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)His]-[(D)NMeTyr]-NH2 (SEQ ID NO: 217),

[1420] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO: 218),

[1421] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO: 219),

[1422] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO: 220),

[1423] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-ENHN(H)Me (SEQ ID NO: 221),

[1424] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-P-NH2(SEQ ID NO:222),

[1425] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-[(D)Pro]-NH2(SEQ ID NO:223),

[1426] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[bAla]-[Sarc]-NH2(SEQ ID NO:224),

[1427] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Val]-[Sarc]-NH2(SEQ ID NO:225),

[1428] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Arg]-[Sarc]-NH2(SEQ ID NO:226),

[1429] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[Hph]-[Sarc]-NH2(SEQ ID NO:227),

[1430] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-Phe[4-NH2]-[Sarc]-NH2(SEQ ID NO:228),

[1431] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-Phe[4-NH2]-[Sarc]-NH2(SEQ ID NO:229),

[1432] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-ENF-[Sarc]-NH2(SEQ ID NO:230),

[1433] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[THP]-[Sarc]-NH2(SEQ ID NO:231),

[1434] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:232),

[1435] Ac-[(D)Arg]-[Cys]-NT-[W(7-Me)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-ENH-[Sarc]-NH2(SEQ ID NO:233),

[1436] Ac-[(D)Arg]-[Cys]-NT-[W(7-Me)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Leu]-[Sarc]-NH2(SEQ ID NO:234),

[1437] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:235),

[1438] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla]-[Sarc]-NH2 (SEQ ID NO: 236),

[1439] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val]-[Sarc]-NH2 (SEQ ID NO: 237),

[1440] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Arg]-[Sarc]-NH2 (SEQ ID NO: 238),

[1441] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Hph]-[Sarc]-NH2 (SEQ ID NO: 239),

[1442] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH2 (SEQ ID NO: 240),

[1443] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH2 (SEQ ID NO: 241),

[1444] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-NH2(SEQ ID NO:242),

[1445] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Phe(4-CF3)]-[Sarc]-NH2 (SEQ ID NO: 243),

[1446] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-Tyr_CHF2-[Sarc]-NH2 (SEQ ID NO: 244),

[1447] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[THP]-P-NH2 (SEQ ID NO:245),

[1448] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO: 246),

[1449] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:247),

[1450] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-[Sarc]-NH2(SEQ ID NO:248),

[1451] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[Phe(2-aminomethyl)]-[Sarc]-NH2(SEQ ID NO:249),

[1452] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Pro(4,4diF)]-NH2(SEQ ID NO:250),

[1453] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[aMePro]-NH2(SEQ ID NO:251),

[1454] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Aib]-NH2(SEQ ID NO:252),

[1455] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[His(3-Me)]-[Sarc]-NH2 (SEQ ID NO: 253),

[1456] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2(SEQ ID NO:261),

[1457] Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2(SEQ ID NO:262),

[1458] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:266),

[1459] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me(SEQ ID NO:267),

[1460] [(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:270),

[1461] Ac-[(D)Arg]-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:271),

[1462] Pr-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-(N-propionylamino)ethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:272),

[1463] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-(N-(4-hydroxy-3-methylphenyl)propionylamino)ethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:273),

[1464] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(5-Me)]-[Sarc]-NH2(SEQ ID NO:276),

[1465] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(5-NH2)]-[Sarc]-NH2(SEQ ID NO:277),

[1466] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-N(H)Me(SEQ ID NO:278),

[1467] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2(SEQ ID NO:279),

[1468] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Gly(N-cyclohexylmethyl)]-NH2(SEQ ID NO:280),

[1469] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Gly(N-isobutyl)]-NH2(SEQ ID NO:281),

[1470] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(3-Me)]-NH2(SEQ ID NO:282),

[1471] Ac-[(D)Arg]-[aMeCys]-NT-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:283),

[1472] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:284),

[1473] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 285, 159),

[1474] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 286),

[1475] Ac-[Pen]-[Gly(allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:287),

[1476] Ac-[Pen]-[Gly(allyl)]-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:288),

[1477] Ac-[Pen]-[Gly(allyl)]-T-(W(4-F)]-[Lys(Ac)]-[Pen]-[Tyr(O-allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2(SEQ ID NO:289),

[1478] Ac-[Pen]-ND-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:290),

[1479] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:291),

[1480] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 299),

[1481] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:308),

[1482] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[(D)Tyr]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 309),

[1483] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 310),

[1484] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2, (SEQ ID NO: 311)

[1485] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:332),

[1486] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-butyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:333),

[1487] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-isobutyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:334),

[1488] Ac-[Pen]-NT-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:335),

[1489] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[a-MeLeu]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 339),

[1490] Ac-[Pen]-LT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[aMeLeu]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:347), or

[1491] Ac-[Abu]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:373),

[1492] Furthermore, the peptide inhibitor is cyclized via a Pen-Pen disulfide bond or via an Abu-C thioether bond.

[1493] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1494] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104),

[1495] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106),

[1496] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 158, 162, 284),

[1497] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NOs: 247, 266),

[1498] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2(SEQ ID NO:261), or

[1499] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me(SEQ ID NO:267),

[1500] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1501] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1502] Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:104),

[1503] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1504] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1505] Ac-[Pen]-NT-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:106),

[1506] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1507] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1508] Ac-[Pen]-NTW-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:158),

[1509] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1510] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1511] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2(SEQ ID NO:247),

[1512] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1513] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1514] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2 (SEQ ID NO:261), wherein the peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1515] In certain embodiments of methods for treating IBD, ulcerative colitis, or Crohn's disease, the peptide inhibitor comprises or is any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof:

[1516] Ac-[(D)Arg]-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me(SEQ ID NO:267),

[1517] The peptide inhibitor is cyclized via Pen-Pen disulfide bonds.

[1518] In some relevant embodiments, the present invention provides a method for selectively inhibiting IL-23 or IL-23R signaling (or IL-23 binding to IL-23R) in a subject of need, comprising administering the peptide inhibitor of the present invention to the subject. In a specific embodiment, the present invention includes a method for selectively inhibiting IL-23 or IL-23R signaling (or IL-23 binding to IL-23R) in the gastrointestinal tract of a subject of need, comprising administering the peptide inhibitor of the present invention to the subject orally. In a specific embodiment, the administered peptide inhibitor is exposed in gastrointestinal tissues (e.g., the small intestine or colon) at a level at least 10, at least 20, at least 50, or at least 100 times greater than the exposure in the blood. In a specific embodiment, the present invention includes a method for selectively inhibiting IL23 or IL23 signaling (or IL23 binding to IL23) in the gastrointestinal tract of a subject of need, comprising administering the peptide inhibitor to the subject, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In another related embodiment, the present invention includes a method for inhibiting gastrointestinal inflammation and / or neutrophil infiltration into the gastrointestinal tract, the method comprising administering the peptide inhibitor of the present invention to a subject in need. In some embodiments, the method of the present invention comprises administering a combination of the peptide inhibitor of the present invention (i.e., a first therapeutic agent) with a second therapeutic agent to a subject in need. In some embodiments, the second therapeutic agent is administered to the subject before and / or simultaneously and / or after administration of the peptide inhibitor. In a specific embodiment, 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 some embodiments, the method comprises administering a third therapeutic agent to the subject. In some embodiments, the second therapeutic agent is an antibody binding to IL-23 or IL-23R.

[1519] Pharmaceutical Composition

[1520] In specific embodiments, a peptide inhibitor or a pharmaceutical composition including a peptide inhibitor is suspended in a sustained-release matrix. As used herein, the sustained-release matrix is ​​a matrix made of a material (typically a polymer) that can be degraded by enzymatic or acid-base hydrolysis or by dissolution. Once in the body, the matrix is ​​acted upon by enzymes and humors. The sustained-release matrix is ​​preferably selected from biocompatible materials such as liposomes, polylactic acid (PLA), polyglycolic acid (glycolic acid polymer), polylactic acid-co-glycolic acid (a copolymer of lactic acid and glycolic acid), polyanhydrides, poly(orthocyanins), polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids (such as phenylalanine, tyrosine, isoleucine), polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicones. One embodiment of the biodegradable matrix is ​​a matrix of one of polylactic acid, polyglycolic acid, or polylactic acid-co-glycolic acid (a copolymer of lactic acid and glycolic acid).

[1521] In some embodiments, the present invention includes a pharmaceutical composition comprising one or more peptide inhibitors of the present invention and a pharmaceutically acceptable carrier, diluent, or excipient. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation aid. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenolic sorbic acid, and their analogues. It may also be necessary to include isotonic agents, such as sugars, sodium chloride, and their analogues.

[1522] In some embodiments, the composition is administered orally, non-enterically, intracisionally, intravaginally, intraperitoneally, rectally, topically (e.g., by powder, ointment, drops, suppositories, or percutaneous patches), by inhalation (e.g., intranasal spray), by eye (e.g., intraocular), or buccally. As used herein, the term "non-enteric" refers to administration methods including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intra-articular injections and infusions. Thus, in some embodiments, the composition is formulated for delivery via any of these routes of administration.

[1523] In some embodiments, pharmaceutical compositions for non-enteric injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders, which are intended to be immediately reconstituted into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethyl cellulose and suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Appropriate flowability can be maintained, for example, by using coating substances (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Prolonged absorption in injectable pharmaceutical forms can be achieved by including delayed absorption agents (such as aluminum monostearate and gelatin).

[1524] Injectable accumulation forms include those prepared by forming microencapsulation matrices with peptide inhibitors in one or more biodegradable polymers such as polylactide-polyglycolic acid, poly(orthoester), poly(anhydride), and (poly)diols (such as PEG). The release rate of the peptide inhibitor can be controlled depending on the peptide-to-polymer ratio and the properties of the specific polymer used. Accumulated injectable formulations are also prepared by encapsulating the peptide inhibitor in liposomes or microemulsions compatible with body tissues.

[1525] Injectable formulations can be sterilized, for example, by filtration via a bacterial trapping filter or by incorporating a sterilizing agent into a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media just before use.

[1526] Topical application includes application to the skin or mucous membranes, including the surfaces of the lungs and eyes. Compositions for topical pulmonary application, including those for inhalation and nasal administration, may involve solutions and suspensions in aqueous and non-aqueous formulations and may be prepared as pressurized or non-pressurized dry powders. In non-pressurized powder compositions, the active ingredient may be in a finely pulverized form and may be mixed with a pharmaceutically acceptable inert carrier comprising particles of a larger size, for example, up to 100 micrometers in diameter. Suitable inert carriers include sugars, such as lactose.

[1527] Alternatively, the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and, in effect, the overall composition ensure that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surfactant, such as a liquid or solid nonionic surfactant, or may be a solid anionic surfactant. A solid anionic surfactant in the form of a sodium salt is preferred.

[1528] Another form of topical application is application to the eye. The peptide inhibitor of the present invention can be delivered in a pharmaceutically acceptable ophthalmic medium form, such that the peptide inhibitor maintains contact with the ocular surface for a duration sufficient to allow the peptide inhibitor to penetrate the cornea and internal areas of the eye, such as the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous fluid, cornea, iris / eyelashes, lens, choroid / retina, and sclera. Pharmaceutically acceptable ophthalmic mediators may be, for example, ointments, vegetable oils, or encapsulating materials. Alternatively, the peptide inhibitor of the present invention can be injected directly into the vitreous body and aqueous humor.

[1529] Compositions for rectal or vaginal administration are preferably suppositories prepared by mixing the peptide inhibitor of the invention with a suitable non-irritating excipient or carrier (such as cocoa oil, polyethylene glycol); or suppository waxes that are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

[1530] The peptide inhibitors of the present invention can also be administered in liposomes or other lipid carriers. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Lipid systems are formed from monolayers or multilayers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. In addition to the peptide inhibitors of the present invention, the compositions of the present invention in liposome form may also contain stabilizers, preservatives, excipients, and the like. In some embodiments, lipids include phospholipids, including phosphatidylcholine (lecithin) and serine, both natural and synthetic. Methods for forming liposomes are known in the art.

[1531] Pharmaceutical compositions of the present invention suitable for non-enteral administration may include sterile aqueous solutions and / or suspensions of peptide inhibitors isotonic with the recipient's blood, typically using sodium chloride, glycerol, glucose, mannitol, sorbitol and analogues.

[1532] In some aspects, the present invention provides a pharmaceutical composition for oral delivery. The compositions and peptide inhibitors of the present invention can be prepared for oral administration according to any of the methods, techniques, and / or delivery media described herein. Furthermore, those skilled in the art will understand that the peptide inhibitors of the present invention can be modified or integrated into systems or delivery media not disclosed herein, but are well known in the art and compatible for oral delivery of peptides.

[1533] In some embodiments, the formulation for oral administration may include adjuvants (e.g., resorcinol) and / or nonionic surfactants (such as polyethylene glycol ether and n-hexadecimal polyethylene ether) to artificially increase intestinal wall permeability, and / or enzyme inhibitors (e.g., pancreatic trypsin inhibitors, diisopropyl fluorophosphate (DFF), or aprotinin) to inhibit enzymatic degradation. In some embodiments, the peptide inhibitor in a solid dosage form for oral administration may be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, or raffinose. Maltitol, polydextrose, starch, agar, alginate, chitin, polyglucosamine, pectin, gum arabic, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. These dosage forms may also contain other types of additives, such as inactive diluents; lubricants, such as magnesium stearate and parabens; preservatives, such as sorbic acid, ascorbic acid, and α-tocopherol; antioxidants, such as cysteine; disintegrants; binders; thickeners; buffers; pH adjusters; sweeteners; flavorings, or aromas.

[1534] In specific embodiments, oral dosage forms or unit doses compatible with the peptide inhibitor of the present invention may include mixtures of peptide inhibitors with non-pharmaceutical components or excipients, as well as other non-reusable materials that may be considered as ingredients or encapsulations. Oral compositions may include at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, oral dosage forms comprising an effective amount of the peptide inhibitor are provided, wherein the dosage form includes at least one of: pills, tablets, capsules, gels, pastes, decoctions, syrups, ointments, and suppositories. In some cases, an oral dosage form is provided that is designed and configured to achieve delayed release of the peptide inhibitor in the small intestine and / or colon of a subject.

[1535] In some embodiments, oral pharmaceutical compositions comprising the peptide inhibitors of the present invention include an enteric coating designed to delay the release of the peptide inhibitors in the small intestine. In at least some embodiments, pharmaceutical compositions are provided in delayed-release pharmaceutical formulations comprising the peptide inhibitors of the present invention and protease inhibitors such as aprotinins. In some cases, pharmaceutical compositions of the present invention comprise an enteric coating soluble in gastric juice at a pH of about 5.0 or higher. In at least one embodiment, a pharmaceutical composition is provided comprising an enteric coating comprising polymers having dissociable carboxylic acid groups, such as cellulose derivatives including hydroxypropyl methyl phthalate, cellulose acetate phthalate, and cellulose trimellitate, and similar derivatives of cellulose and other carbohydrate polymers.

[1536] In some embodiments, pharmaceutical compositions including the peptide inhibitors of the present invention are provided in an enteric-coated form, the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner within the lower gastrointestinal system of a subject and to avoid systemic side effects. In addition to enteric coating, the peptide inhibitors of the present invention can be encapsulated, coated, conjugated, or otherwise associated with any compatible oral drug delivery system or component. For example, in some embodiments, the peptide inhibitors of the present invention are provided in a lipid carrier system comprising at least one of polymeric hydrogels, nanoparticles, microspheres, microcells, and other lipid systems.

[1537] To overcome peptide degradation in the small intestine, some embodiments of the present invention include a hydrogel polymer carrier system containing the peptide inhibitor of the present invention, thereby protecting the peptide inhibitor from proteolytic degradation in the small intestine and / or colon. The peptide inhibitor of the present invention can be further formulated for use in harmony with a carrier system designed to increase peptide solubility kinetics and enhance intestinal absorption of the peptide. These methods include using liposomes, microcells, and nanoparticles to increase the gastrointestinal permeability of the peptide.

[1538] Various bioreactive systems can also be combined with one or more peptide inhibitors of the present invention to provide agents for oral delivery. In some embodiments, the peptide inhibitors of the present invention are combined with bioreactive systems such as hydrogels and mucosal adhesive polymers having hydrogen-bonded groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, etc.). Polyglucosamine and alginate are used in combination to provide a therapeutic agent for oral administration. Other embodiments include methods for optimizing or prolonging the drug retention time of the peptide inhibitors disclosed herein, wherein the surface of the peptide inhibitor is modified to include mucosal adhesive properties via hydrogen bonding, polymers having linked mucins and / or hydrophobic interactions. These modified peptide molecules can exhibit increased drug retention time in the subject according to the desired characteristics of the invention. Furthermore, targeted mucosal adhesive systems can specifically bind to receptors on the surface of intestinal epithelial cells and M cells, thereby further increasing the absorption of particles containing peptide inhibitors.

[1539] Other embodiments include a method for oral delivery of the peptide inhibitor of the present invention, wherein the peptide inhibitor is provided to a subject in combination with a permeability enhancer, such a permeability enhancer facilitating peptide delivery on the intestinal mucosa by increasing paracellular or intercellular permeability. Various permeability enhancers and methods for oral delivery of therapeutic agents are described in Brayden, DJ, Mrsny, RJ, 2011. Oral peptide delivery: prioritizing the leading technologies. Ther. Delivery 2(12), 1567-1573.

[1540] In some embodiments, the pharmaceutical compositions and formulations of the present invention include the peptide inhibitors of the present invention and one or more permeation enhancers. Examples of absorption enhancers may include, for example, bile salts, fatty acids, surfactants (anionic, cationic and non-anionic), chelating agents, zonal OT, esters, cyclodextrins, dextran sulfate, hydrazones, crown ethers, EDTA, sucrose esters, and phosphatidylcholine. Although absorption enhancers are not typically carriers themselves, they are also widely associated with other carriers to improve oral bioavailability by delivering peptides and proteins across the intestinal mucosa. Such substances may be added to formulations in excipient form or incorporated to form nonspecific interactions with the desired peptide inhibitor.

[1541] Dietary components and / or other naturally occurring substances that have been shown to enhance the osmotic pressure of tightly bound substances and are generally considered safe (GRAS) include, for example, triglycerides, acylcarnitines, bile salts, and medium- and long-chain fatty acids. Sodium salts of medium- and long-chain fatty acids (MCFAs) are also suggested as osmotic enhancers. The most widely studied MCFAS is sodium decanoate, a salt of decanoic acid, which comprises 2% to 3% fatty acids in the milk fat fraction. To date, sodium decanoate has primarily been used as a suppository formulation (Doktacillin). TM The excipients in the oil were used to improve rectal absorption of ampicillin. Another dietary MCFAS, sodium caprylate (8-carbon), showed lower permeability in vitro compared to sodium decanoate. Sodium caprylate and peptide drugs were formulated with other excipients in the oil as blends to produce oily suspensions (OS) with improved permeability (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014).

[1542] For example, in some embodiments, a permeation enhancer is combined with a peptide inhibitor, wherein the permeation enhancer comprises at least one of medium- and long-chain fatty acids, long-chain fatty acids, bile salts, amphiphilic surfactants, and chelating agents. In some embodiments, medium- and long-chain fatty acid salts promote absorption by increasing paracellular permeability of the intestinal epithelium. In some embodiments, a permeation enhancer comprising sodium N-[hydroxybenzoyl]amino]octanoate is used to form a weaker non-covalent association with the peptide inhibitor of the present invention, wherein the permeation enhancer facilitates membrane transport and further dissociates upon reaching the bloodstream. In some embodiments, the peptide inhibitor of the present invention is conjugated to oligoarginine, thereby increasing the cellular permeability of the peptide to various cell types. Furthermore, in at least one embodiment, a non-covalent bond is provided between the peptide inhibitor of the present invention and a permeation enhancer selected from the group consisting of cyclodextrins (CDs) and dendritic polymers, wherein the permeation enhancer reduces peptide aggregation and increases the stability and solubility of the peptide inhibitor molecule.

[1543] In some embodiments, the pharmaceutical composition or formulation includes the peptide inhibitor and transient permeability enhancer (TPE) of the present invention. The permeability enhancer and TPE can be used to increase oral bioavailability or peptide inhibitors. An example of a usable TPE is an oily suspension formulation dispersing a powder containing sodium caprylate and a therapeutic agent (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014).

[1544] In some embodiments, the pharmaceutical composition and formulation may include the peptide inhibitor of the present invention and one or more absorption enhancers, enzyme inhibitors or mucosal adhesive polymers.

[1545] In a specific embodiment, the peptide inhibitor of the present invention is formulated in a formulation medium, such as an emulsion, liposome, microsphere or nanoparticle.

[1546] Other embodiments of the invention provide a method of treating a subject with the peptide inhibitor of the invention, the peptide inhibitor having an extended half-life. In one aspect, the invention provides a peptide inhibitor having a half-life sufficient for daily (qd) or twice-daily (bid) administration of a therapeutically effective amount in vitro or in vivo for at least several hours to one day (e.g., when administered to a human subject). In some embodiments, the peptide inhibitor has a half-life of three days or longer, sufficient for weekly (qw) administration of a therapeutically effective amount. In some embodiments, the peptide inhibitor has a half-life of eight days or longer, sufficient for bi-weekly (biw) or monthly administration of a therapeutically effective amount. In some embodiments, the peptide inhibitor is derivatized or modified to have a longer half-life compared to underivatized or unmodified peptide inhibitors. In some embodiments, the peptide inhibitor contains one or more chemical modifications to extend the serum half-life.

[1547] When used in at least one of the therapeutic or delivery systems described herein, the peptide inhibitors of the present invention may be used in pure form or, when such forms are present, in a pharmaceutically acceptable salt form.

[1548] The total daily dosage of the peptide inhibitors and compositions of the present invention can be determined by the attending physician within the bounds of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a number of factors, including a) the condition being treated and its severity; b) the activity of the specific compound used; c) the specific composition used; the patient's age, weight, general health condition, sex, and diet; d) the time of administration, route of administration, and excretion rate of the specific peptide inhibitor used; e) the duration of treatment; f) the drugs used in combination with or concurrently with the specific peptide inhibitor used; and similar factors well known in the medical field.

[1549] In a specific implementation, the total daily dose of the peptide inhibitor of the present invention to be administered to a human or other mammalian host in a single or multiple doses may be, for example, 0.0001 to 300 mg / kg body weight per day or 1 to 300 mg / kg body weight per day.

[1550] Non-invasive testing for intestinal inflammation

[1551] The peptide inhibitor of the present invention can be used to detect, assess, and diagnose intestinal inflammation via microPET imaging, wherein the peptide inhibitor is labeled with a chelating group or a detectable label as part of a non-invasive diagnostic procedure. In some embodiments, the peptide inhibitor is conjugated with a bifunctional chelating agent. In some embodiments, the peptide inhibitor is radiolabeled. The labeled peptide inhibitor is then administered to the subject orally or rectally. In some embodiments, the labeled peptide inhibitor is contained in drinking water. Following ingestion of the peptide inhibitor, inflammation in the entire intestinal and gastrointestinal tract of the subject can be observed using microPET imaging.

[1552] Example

[1553] Synthesis of substituted tryptophan

[1554] Synthesis of 7-methyltryptophan

[1555] 7-Methyltryptophan was purchased from a commercial source. Alternatively, the compound can be synthesized according to one of the methods described below.

[1556] Synthesis of 7-ethyltryptophan

[1557] 7-Ethyltryptophan was synthesized according to the method described in Scheme 1:

[1558] Option 1

[1559]

[1560] Synthesis of 7-isopropyltryptophan

[1561] 7-Isopropyltryptophan was synthesized according to the method described in Scheme 2:

[1562] Option 2

[1563]

[1564] Procedure for 7-isopropyl compounds:

[1565] Suzuki's coincidence

[1566] A sealed solution of (S)-3-(7-bromo-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propionate (5.0 g, 12.6 mmol) in n-propanol was mixed with potassium isopentenyl trifluoroate (2.2 g, 15.1 mmol) and purged with nitrogen. Triethylamine (3.5 mL, 25.5 mmol) was added to the mixture, followed by the addition of catalyst [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II), combined with dichloromethane (0.72 g, 0.88 mmol), purged with nitrogen for 10 min, and heated to 100 °C overnight. The solution was concentrated to a residue, which was dissolved in ethyl acetate (150 mL) and washed with water and brine. The organic layer was concentrated, and the crude material was purified by rapid column chromatography (3.2 g, 71%) to give a thick, bubbly solid.

[1567] Transfer hydrogenation :

[1568] Methyl (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(7-(prop-1-en-2-yl)-1H-indol-3-yl)propionate (3.1 g, 8.6 mmol) was added to a solution of ethanol (40 mL) with 10% Pd / C (100 mg, 50% wet catalyst), followed by the addition of ammonium formate (1.6 g, 25.3 mmol), and the resulting mixture was heated to 65–70 °C for 2 hours. The reaction mixture was concentrated, water was added to the residue, and the residue was extracted to ethyl acetate (2 × 100 mL). The organic layer was washed with water and brine and concentrated. The resulting product (3.1 g, quantified) was used as is in the next reaction.

[1569] hydrolysis :

[1570] Lithium hydroxide (1.26 g, 30.0 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-isopropyl-1H-indol-3-yl)propionate (3.6 g, 10.0 mmol) in THF / MeOH / water (4:1:1), and the solution was stirred overnight. The solution was concentrated to remove the solvent, diluted with water, and acidified with 10% aqueous citric acid. The aqueous layer containing the product was extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated to give the desired product (2.8 g, 94%) as a thick oil. The crude product was used in the next step without further purification.

[1571] Boc to protect :

[1572] Trifluoroacetic acid (6 mL) was added to a cold solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-isopropyl-1H-indole-3-yl)propionic acid (2.8 g, 8.0 mmol) in dichloromethane (12 mL), and the solution was stirred at room temperature for 5 hours. The solution was evaporated to dryness, then dissolved in dichloromethane (10 mL), treated with HCl / ether, and concentrated. The crude hydrochloride was suspended in MTBE (25 mL), stirred for 30 minutes, and filtered to give (S)-2-amino-3-(7-isopropyl-1H-indole-3-yl)propionate (1.3 g, 68%) as a grayish-white solid (hygroscopic).

[1573] Fmoc protection :

[1574] Sodium bicarbonate (1.55 g, 18.4 mmol) was added to a solution of (S)-2-amino-3-(7-isopropyl-1H-indol-3-yl)propionate (1.3 g, 4.6 mmol) in THF / water (33 mL: 10 mL), followed by fractional addition of N-(9-piperylmethoxycarbonyloxy)succinimide (1.55 g, 4.6 mmol). The resulting mixture was stirred overnight and concentrated to remove THF. The residue was diluted with water, acidified with 2N HCl, and extracted with ethyl acetate (2 × 75 mL). The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated to give a product as a bubbly, low-melting-point solid (1.85 g, 86%).

[1575] Synthesis of 7-phenyl-substituted tryptophan

[1576] 7-Phenyl-substituted tryptophan can be synthesized according to the method described in Scheme 3:

[1577] Scheme 3.7-Phenyl-substituted tryptophan

[1578]

[1579] Suzuki coupling with arylboronic acid

[1580] Methyl (S)-3-(7-bromo-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propionate (4.0 g, 10.0 mmol) was purged with nitrogen for 10 min in anhydrous toluene (30 mL). K₂CO₃ (2.0 g, 15.0 mmol) was added to 10 mL of water, followed by phenylboronic acid (1.47 g, 12.0 mmol), and the reaction mixture was purged with nitrogen for 10 min. Pd(dppf)Cl₂·DCM (0.58 g, 0.71 mmol), ethanol (10 mL), and THF (20 mL) were added, and the reaction mixture was heated to 100 °C for 8 h with stirring. The reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM (200 mL). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography of 60 to 120 mesh to obtain a multi-bubbly solid product (3.6 g, 90%).

[1581] hydrolysis :

[1582] Lithium hydroxide (1.15 g, 27.3 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-phenyl-1H-indol-3-yl)propionate (3.6 g, 9.1 mmol) in THF / MeOH / water (4:1:1), and the solution was stirred overnight. The solution was concentrated to remove the solvent, diluted with sufficient water, and acidified with 10% citric acid. The aqueous layer containing the product was extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated to give the desired product (3.3 g, 95%).

[1583] Boc to protect :

[1584] Trifluoroacetic acid (6.6 mL) was added to a cooled solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-phenyl-1H-indol-3-yl)propionic acid (3.3 g, 8.6 mmol) in dichloromethane (13 mL), and the solution was stirred at room temperature for 6 hours. The solution was evaporated to dryness, then dissolved in dichloromethane (10 mL), treated with HCl / ether, and concentrated. The crude hydrochloride was suspended in MTBE (25 mL), stirred for 30 minutes, and filtered to give (S)-2-amino-3-(7-phenyl-1H-indol-3-yl)propionate (1.8 g, 66%).

[1585] Fmoc protection :

[1586] Sodium bicarbonate (1.92 g, 22.8 mmol) was added to a solution of (S)-2-amino-3-(7-phenyl-1H-indol-3-yl)propionate (1.8 g, 5.7 mmol) in THF / water (45 mL: 13 mL), followed by fractional addition of N-(9-piperylmethoxycarbonyloxy)succinimide (1.92 g, 5.7 mmol). The resulting mixture was stirred overnight and concentrated to remove THF. The residue was diluted with sufficient water, acidified with 2N HCl, and extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with water and brine, dried over Na₂SO₄, concentrated, and the residue was suspended in 20% MTBE / hexane to give the desired product (2.6 g, 92%).

[1587] Synthesis of 7-heteroaryl-substituted tryptophan

[1588] The 7-heteroaryl-substituted tryptophan can be synthesized according to the method described in Scheme 4:

[1589] Scheme 4.7 - Heteroaryl-substituted tryptophan

[1590]

[1591] Where R is a heteroaryl group, which is unsubstituted or substituted with a halogen, alkyl, cyano, haloalkyl, hydroxyl, or alkoxy group.

[1592] The specific representative R group is selected from thienyl, pyridyl, piperidinyl and morpholinyl.

[1593] Synthesis of 7-thienyl (thiophenyl)-substituted tryptophan

[1594] 7-Thienyl (thiophenyl)-substituted tryptophan can be synthesized according to the method described in Scheme 5:

[1595] Scheme 5.7-Thiophenyl-substituted tryptophan

[1596]

[1597] The Suzuki-Miyaura cross-coupling reaction was carried out using a modified method described by Frese et al. (ChemCatChem 2016, 8, 1799-1803). Na₂PdCl₄ and the Buchwald ligand SPhos were used as the Pd source. This system is known to catalyze challenging acceptor combinations with excellent results, even at low temperatures. In this case, 7-bromoTrp and boric acid were subjected to Suzuki-Miyaura cross-coupling to give the desired product, which was subsequently protected with Fmoc-OSu.

[1598] L-7-(thiophen-3-yl)-tryptophan: 7-bromo-L-tryptophan (0.283 g, 1 mmol), thiophen-3-acid (0.383 g, 3.00 mmol, 3 equivalents), and K₂CO₃ (10 equivalents) were placed in a flask and purged with N₂. Degassed water:1-butanol (9:1, 30 mL) was added via syringe, and the reaction mixture was stirred at 95 °C. To initiate the reaction, SPhos (6.2 mg, 15 mole%) and Na₂Cl₄Pd (15.2 mg, 5 mole%) were transferred to the mixture at 40 °C after prior heating of the Pd salt and ligands for 10 min.

[1599] After completion, the aqueous solution of the reactants was diluted with H2O (20 mL), and the solution was acidified to pH 1.0 by dropwise addition of 1 M HCl. The precipitated palladium black was removed by filtration (Whatman, 20 μm pore size), and the filtrate was lyophilized. Finally, the crude product was purified by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) using a C18 column (5 μm, 250 × 50 mm) at a flow rate of 50 mL / min. Separation was achieved using a linear gradient of buffer B in buffer A (buffer A: 0.05% TFA aqueous solution; buffer B: 0.043% TFA, 90% acetonitrile in water). Analysis was monitored using a C18 column (3 μm, 50 × 2 mm) at a flow rate of 1 mL / min. The fraction containing the purified product was then lyophilized. Yield: 104 mg (36% yield). MS (ESI) m / z 287.08 [M+H]+ (C 15 H 15 O2NS calculated value: 287.12.

[1600] Fmoc-L-7-(thiophen-3-yl)-tryptophan: The amino acid L-7-(thiophen-3-yl)-tryptophan (31.5 mg, 0.11 mmol) was dissolved in water and sodium bicarbonate (2 equivalents) with stirring. The resulting solution was cooled to 5 °C and Fmoc-OSu (44.53 mg, 1.05 equivalents) was slowly added as a solution in dioxane. The resulting mixture was stirred at 0 °C for 1 hour and then allowed to warm overnight to room temperature. Water was then added and the aqueous layer was extracted twice with EtOAc. The organic layer was back-extracted twice with a saturated sodium bicarbonate solution. The combined aqueous layers were acidified to pH 1.0 with 10% HCl and subsequently extracted three times with EtOAc. The combined organic layers were dried (sodium sulfate) and concentrated under vacuum. The resulting residue was purified by rapid chromatography (SiO2) using (toluene, ethyl acetate, (1:1), 1% acetic acid). Yield: 50 mg (89% yield). MS(ESI)m / z 509.10[M+H]+(C 15 H 15 O2NS calculated value: 508.59.

[1601] Synthesis of tryptophan with 7-substitution

[1602] The 7-substituted tryptophan can be synthesized according to the method described in Scheme 3:

[1603] Added 7-substituted tryptophan

[1604]

[1605] Example 1: Synthesis of peptide monomers

[1606] The peptide monomers of this invention were synthesized using Merrifield solid-phase synthesis technology on a Protein Technology's Symphony multiple channel synthesizer. Peptides were assembled us...

Claims

1. A peptide represented by the following formula: Or its pharmaceutically acceptable salt.

2. The peptide according to claim 1, wherein the peptide is: 。 3. The peptide of claim 1, wherein the peptide is a pharmaceutically acceptable salt of the peptide represented by the following formula: 。

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