Epi-x4 based peptides and derivatives thereof

JP2025186263AActive Publication Date: 2025-12-23UNIV ULM +4
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Patent Information

Application Number
JP2025138725
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2020-02-27
Filing Date
2025-08-22
Publication Date
2025-12-23
Estimated Expiration
2041-02-26

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Abstract

To provide CXCR4 antagonists binding CXCR4 more effectively and with an increased blood stability and pharmacokinetic properties.SOLUTION: Provided are EPI-X4 based peptides and derivatives thereof, peptide derivatives selected from a list of peptide derivatives with a sequence derived from the human serum albumin fragment EPI-X4, which bind to CXCR4 with about 1000-fold stronger efficiency than EPI-X4. The peptide derivatives comprise length variants as well as modifications by length variants, D-amino acids, coupling of fatty acids, cholesterol or polymers, acetyl substitutions of amino groups, aminations of carboxyl groups. Further provided are pharmaceutical compositions of the peptide derivative.SELECTED DRAWING: Figure 1-1
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Description

[Technical Field]

[0001] The present invention relates to peptides that bind to CXC chemokine receptor type 4 and derivatives thereof, therapeutic uses of the peptides, and methods for producing the peptides of the present invention. [Background technology]

[0002] The C-X-C chemokine receptor type 4 (CXCR4) is expressed on many cells of the hematopoietic system, particularly stem cells and tumor cells. CXCR4 is a G protein-coupled receptor (GPCR) whose sole chemokine ligand is stromal cell-derived factor-1 (SDF-1 or CXCL12). CXCR4 is involved in various developmental and physiological processes, including stem cell homing to the liver and bone marrow, organogenesis, and organ and wound healing. Pathophysiologically, CXCR4 is involved in various disease processes, including tumor growth, cancer cell metastasis, and inflammation. Furthermore, CXCR4 is the primary coreceptor for HIV-1 entry into target cells.

[0003] CXCR4's involvement in many processes makes it an attractive target for cancer cell proliferation, differentiation, metastasis, and intervention in inflammatory diseases. To date, only one CXCR4 antagonist has received clinical approval (AMD3100, Hendrix et al., 2000), but only for the mobilization of hematopoietic stem cells in patients with lymphoma and multiple myeloma.

[0004] Peptides derived from the human serum albumin amino acid sequence (EPI-X4 (SEQ ID NO: 1)) have been shown to bind to CXCR4, thereby inhibiting the binding of its natural ligand, CXCL12 (EP 2162462 B1). Peptides derived from EPI-X4 (SEQ ID NO: 1) have been shown to bind to CXCR4 more effectively than the original peptide (EP 3007717 A1). However, effective inhibition of CXCL12 binding requires higher nanomolar concentrations of these peptides, and the half-life of the peptides is limited due to degradation by protease activity. CXCR4 antagonists that bind CXCR4 more effectively and have improved serum stability and pharmacokinetic properties are needed. Summary of the Invention [Means for solving the problem]

[0005] A first aspect of the present invention relates to a peptide consisting of the following amino acid sequence, which is selected from any one of Groups 1 to 11: - Group 7 consists of: d-ILRWSRK-NH2 (SEQ ID NO: 70, JM#173) Md-LRWSRKLPCVS (SEQ ID NO: 45, JM#43) Md-LRWSRKMPCVS (SEQ ID NO: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS (SEQ ID NO: 54, JM#143) ILRWSRK(Pal)LPCVS (SEQ ID NO: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (SEQ ID NO: 56, JM#145) ILRWSRK(Pal)MPCLS (SEQ ID NO: 59, JM#149) IVRWSK(Pal)KVP-NH2 (SEQ ID NO: 63, JM#166) IVRWSKK(Pal)VP-NH2 (SEQ ID NO: 64, JM#167) ILRWSRK(Pal)-NH2 (SEQ ID NO: 67, JM#170) ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 68, JM#171) d-ILRWSRKLP-NH2 (SEQ ID NO: 71, JM#174) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 95, JM#198) ILRWSRK(Glu-Lau)LPCVS (SEQ ID NO: 104, JM#213) ILRWSRK(Glu-Ole)LPCVS (SEQ ID NO: 108, JM#217) ILRWSRK(C16diacid)LPCVS (SEQ ID NO: 117, JM#226) ILRWSRK(Glu-C16diacid)LPCVS (SEQ ID NO: 118, JM#227) ILRWSRK(C18diacid)LPCVS (SEQ ID NO: 119, JM#228) ILRWSRK(Glu-C18diacid)LPCVS (SEQ ID NO: 120, JM#229) ILRWSRK(OEG-OEG-γGlu-C18diacid)LPCVS (SEQ ID NO: 121, JM#230) d-LLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 130, JM#235) d-LLRWSRK(Pal)-NH2 (SEQ ID NO: 131, JM#236) d-ILRWSRK(Pal)-NH2 (SEQ ID NO: 132, JM#237) d-ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 133, JM#238) ILRWSRK(C16diacid)-NH2 (SEQ ID NO: 139, JM#244) ILRWSRK(C18diacid)-NH2 (SEQ ID NO: 140, JM#245) ILRWSRK(Glu-C16diacid)-NH2 (SEQ ID NO: 141, JM#246) ILRWSRK(Glu-C18diacid)-NH2 (SEQ ID NO: 142, JM#247) d-LLRWSRK(C16diacid)-NH2 (SEQ ID NO: 143, JM#248) d-LLRWSRK(C18diacid)-NH2 (SEQ ID NO: 144, JM#249) d-LLRWSRK(Glu-C16diacid)-NH2 (SEQ ID NO: 145, JM#250) d-LLRWSRK(Glu-C18diacid)-NH2 (SEQ ID NO: 146, JM#251) ILRWSRK(Ara)LPCVS (SEQ ID NO: 147, JM#252) ILRWSRK(Glu-Ara)LPCVS (SEQ ID NO: 148, JM#253) ILRWSRK(Ste)-NH2 (SEQ ID NO: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 150, JM#255) d-LLRWSRK(Ste)-NH2 (SEQ ID NO: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 157, JM#260) ILRWSRK(Myr)-NH2 (SEQ ID NO: 159, JM#262) LVRYTKK(Glu-Pal)-NH2 (SEQ ID NO: 161, JM#264) d-LVRYTKK(Glu-Pal)-NH2 (SEQ ID NO: 162, JM#265) ILRWSRK(Pal-Glu)LPSVS (SEQ ID NO: 163) -Group 1 consists of: ILRWSRKMPCLS (SEQ ID NO: 20, JM#18) ILRWSRK(Pal)LPCVS (SEQ ID NO: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 91, JM#194) ILRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 150, JM#255) -Group 2 consists of: ILRWSRK(Pal)L-NH2 (SEQ ID NO: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (SEQ ID NO: 75, JM#178) d-LMRWSRK(Pal)-NH2 (SEQ ID NO: 77, JM#180) ILRWSRK(Ole)LPCVS (SEQ ID NO: 80, JM#183) ILRWSRK(Glu-Lau)LPCVS (SEQ ID NO: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 133, JM#238) d-LLRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 152, JM#257) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (SEQ ID NO: 53, JM#141) IVRWSK(Pal)KVP-NH2 (SEQ ID NO: 63, JM#166) IVRWSKK(Pal)VP-NH2 (SEQ ID NO: 64, JM#167) IVRWSKK(Pal)VPCVS (SEQ ID NO: 66, JM#169) ILRWSRK(Pal)-NH2 (SEQ ID NO: 67, JM#170) ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (SEQ ID NO: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS (SEQ ID NO: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS (SEQ ID NO: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 100, JM#205) ILRWSRK(Myr)LPCVS (SEQ ID NO: 107, JM#216) ILRWSRK(Ste)-NH2 (SEQ ID NO: 149, JM#254) d-LLRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 157, JM#260) ILRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 160, JM#263) -Group 4 consists of: ILRWSRKVPCVS (SEQ ID NO: 10, JM#8) IFRWSRKVPCVS (SEQ ID NO: 12, JM#10) MLRWSRKMPCVS (SEQ ID NO: 29, JM#27) MMRWSRKMPCVS (SEQ ID NO: 36, JM#34) MLRWSRKLPCVS (SEQ ID NO: 41, JM#39) ILRWSRKLPSVS (SEQ ID NO: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS (SEQ ID NO: 52, JM#140) ILRWSRK(Pal)MPCLS (SEQ ID NO: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 92, JM#195) ILRWSRK-AcLPCVS (SEQ ID NO: 97, JM#200) ILRWSRK(Lau)LPCVS (SEQ ID NO: 105, JM#214) d-LLRWSRK(Ste)-NH2 (SEQ ID NO: 151, JM#256) ILRWSRK(Myr)-NH2 (SEQ ID NO: 159, JM#262) -Group 5 consists of: ILRWSKKVPCVS (SEQ ID NO: 3, JM#1) IFRWSKKVPCVS (SEQ ID NO: 4, JM#2) IVRWSRKVPCVS (SEQ ID NO: 5, JM#3) IVRWSHKVPCVS (SEQ ID NO: 6, JM#4) IVRWSKKLPCVS (SEQ ID NO: 7, JM#5) IVRWSKKIPCVS (SEQ ID NO: 8, JM#6) IVRWSKKFPCVS (SEQ ID NO: 9, JM#7) ILRWSHKVPCVS (SEQ ID NO: 11, JM#9) IFRWSHKVPCVS (SEQ ID NO: 13, JM#11) IVRWSKKMPCVS (SEQ ID NO: 14, JM#12) IVRWSKKVPCd-VS (SEQ ID NO: 16, JM#14) ILRWSRKVPCd-VS (SEQ ID NO: 17, JM#15) IIRWSRKMPCVS (SEQ ID NO: 18, JM#16) ILRWSRKVPSVS (SEQ ID NO: 25, JM#23) ILRWSRKMPSVS (SEQ ID NO: 26, JM#24) Ac-SLRWSRKMPCVS (SEQ ID NO: 27, JM#25) d-Ac-SLRWSRKMPCVS (SEQ ID NO: 28, JM#26) d-MLRWSRKMPCVS (SEQ ID NO: 30, JM#28) d-LLRWSRKMPCVS (SEQ ID NO: 31, JM#29) d-FLRWSRKMPCVS (SEQ ID NO: 32, JM#30) GLRWSRKMPCVS (SEQ ID NO: 33, JM#31) Ac-SMRWSRKMPCVS (SEQ ID NO: 34, JM#32) d-Ac-SMRWSRKMPCVS (SEQ ID NO: 35, JM#33) d-MMRWSRKMPCVS (SEQ ID NO: 37, JM#35) d-LMRWSRKMPCVS (SEQ ID NO: 38, JM#36) d-FMRWSRKMPCVS (SEQ ID NO: 39, JM#37) d-GMRWSRKMPCVS (SEQ ID NO: 40, JM#38) d-MLRWSRKLPCVS (SEQ ID NO: 42, JM#40) Id-LRWSRKLPCVS (SEQ ID NO: 43, JM#41) Id-LRWSRKMPCVS (SEQ ID NO: 44, JM#42) Md-LRWSRKLPCVS (SEQ ID NO: 45, JM#43) Md-LRWSRKMPCVS (SEQ ID NO: 46, JM#44) IVRWSKKVP-NH2 (SEQ ID NO: 47, JM#106) IVRWSKK-NH2 (SEQ ID NO: 48, JM#110) ILRWSRKLP-NH2 (SEQ ID NO: 49, JM#114) ILRWSRK-NH2 (SEQ ID NO: 50, JM#118) ILRWSRK(Glu-Pal)LPCVS (SEQ ID NO: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (SEQ ID NO: 56, JM#145) IYRWSRKMPCLS (SEQ ID NO: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (SEQ ID NO: 58, JM#148) IVRWSKKVPSVS (SEQ ID NO: 60, JM#151) IVRWSK(Pal)K-NH2 (SEQ ID NO: 61, JM#164) IVRWSKK(Pal)-NH2 (SEQ ID NO: 62, JM#165) IVRWSK(Pal)KVPCVS (SEQ ID NO: 65, JM#168) d-ILRWSRK-NH2 (SEQ ID NO: 70, JM#173) d-ILRWSRKLP-NH2 (SEQ ID NO: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 72, JM#175) d-LMRWSRK(Pal)MPCVS (SEQ ID NO: 73, JM#176) Md-LRWSRK(Pal)LPCVS (SEQ ID NO: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (SEQ ID NO: 76, JM#179) Md-LRWSRK(Pal)-NH2 (SEQ ID NO: 78, JM#181) ILRWSRK(Ste)LPCVS (SEQ ID NO: 79, JM#182) ILRWSRK(Chl)LPCVS (SEQ ID NO: 81, JM#184) Ac-ILRWSRKLPCVS (SEQ ID NO: 82, JM#185) d-Ac-ILRWSRKLPCVS (SEQ ID NO: 83, JM#186) Ac-MLRWSRKLPCVS (SEQ ID NO: 84, JM#187) d-Ac-MLRWSRKLPCVS (SEQ ID NO: 85, JM#188) VLRWSRKLPCVS (SEQ ID NO: 86, JM#189) d-VLRWSRKLPCVS (SEQ ID NO: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (SEQ ID NO: 99, JM#204) ILRWSRK(Dec)LPCVS (SEQ ID NO: 106, JM#215) d-LLRWSRK(Pal)-NH2 (SEQ ID NO: 131, JM#236) d-ILRWSRK(Pal)-NH2 (SEQ ID NO: 132, JM#237) d-LLRWSRK(Myr)-NH2 (SEQ ID NO: 158, JM#261) ILRWSRK(Pal-Glu)LPSVS (SEQ ID NO: 163) ILRWSRK(Glu-Ste)LPSVS (SEQ ID NO: 164) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 95, JM#198) ILRWSRK(Glu-Ste)LPSVS (SEQ ID NO: 164) -Group 8 consists of: d-LLRWSRKMPCVS (SEQ ID NO: 31, JM#29) ILRWSRK(Pal)L-NH2 (SEQ ID NO: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (SEQ ID NO: 27, JM#25) d-MLRWSRKMPCVS (SEQ ID NO: 30, JM#28) d-Ac-SMRWSRKMPCVS (SEQ ID NO: 35, JM#33) d-MMRWSRKMPCVS (SEQ ID NO: 37, JM#35) d-LMRWSRKMPCVS (SEQ ID NO: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS (SEQ ID NO: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (SEQ ID NO: 75, JM#178) ILRWSRK(Dec)LPCVS (SEQ ID NO: 106, JM#215) d-LLRWSRK(Myr)-NH2 (SEQ ID NO: 158, JM#261) ILRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 160, JM#263) -Group 10 consists of: ILRWSRK(Pal)LPCVS (SEQ ID NO: 55, JM#144) IVRWSK(Pal)KVP-NH2 (SEQ ID NO: 63, JM#166) IVRWSKK(Pal)VP-NH2 (SEQ ID NO: 64, JM#167) ILRWSRK(Pal)-NH2 (SEQ ID NO: 67, JM#170) ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 68, JM#171) ILRWSRK(Pal)L-NH2 (SEQ ID NO: 69, JM#172) d-LMRWSRK(Pal)-NH2 (SEQ ID NO: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (SEQ ID NO: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 91, JM#194) ILRWSRK(Glu-Lau)LPCVS (SEQ ID NO: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 133, JM#238) ILRWSRK(Ste)-NH2 (SEQ ID NO: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 157, JM#260) -Group 11 consists of: ILRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 109, JM#218) ILRW(dC)RKPC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 111, JM#219) IPRW(dC)RKC-NH2, the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 113, JM#220) ILRWSRKLPCVS, where the lysine at position 7 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 115, JM#221) ILRWSKKLPCVS, where the lysine at position 6 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 116, JM#222) IPRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 122, JM#231) ILRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 124, JM#232) IPRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 126, JM#233) ILRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 128, JM#234) IMRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 153, JM#258) IPRW(dC)RKCP-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 155, JM#259) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-My indicates myristic acid under the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol on the preceding amino acid, Ac indicates substitution of an amino group with an acetyl group, Lau indicates lauric acid on the preceding amino acid, Glu-La u indicates lauric acid on the preceding amino acid with a glutamic acid linker, Glu-Ole indicates oleic acid on the preceding amino acid with a glutamic acid linker, C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid with a glutamic acid linker, C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with an OEG-OEG-γ glutamic acid linker, OEG indicates a residue of 8-amino-3,6-dioxaoctanoic acid, Ara indicates a saturated C20 fatty acid on the preceding amino acid, and Glu-Ara indicates a saturated C20 fatty acid on the preceding amino acid with a glutamic acid linker.

[0006] A second aspect of the invention relates to a conjugate in which a peptide according to the invention is linked to a complexing agent.

[0007] A third aspect of the invention relates to a conjugate in which a peptide according to the invention is attached to a polymer.

[0008] A fourth aspect of the present invention relates to a peptide consisting of two identical monomeric peptides according to the present invention, wherein the monomeric peptides are linked via a cysteine ​​bridge formed between the monomeric peptides to form a dimeric peptide.

[0009] A fifth aspect of the present invention relates to a pharmaceutical composition comprising a peptide of the present invention together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticle, cryoprotectant, excipient and / or diluent.

[0010] A sixth aspect of the present invention relates to a peptide of the present invention or a pharmaceutical composition of the present invention for use in medicine.

[0011] A seventh aspect of the present invention relates to the use of the peptide of the present invention or the pharmaceutical composition of the present invention for the preparation of a formulation for oral administration, inhalation administration, intravenous administration, topical administration, intranasal administration, intraperitoneal administration, subcutaneous administration and / or any other injectable administration.

[0012] An eighth aspect of the present invention relates to the treatment of disorders of hematopoiesis, the treatment of wounds, infections caused by viral diseases, in particular HIV-1, HIV-2, SARS-CoV-2, cytomegalovirus, herpes simplex virus (types 1 and 2), varicella-zoster virus, hepatitis A and B virus, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, Rous sarcoma virus, Epstein-Barr virus, etc., bacterial and fungal infections, in particular Pseudomonas, Candida, S. aureus, treatment of infectious processes, treatment of abnormal infectious processes, treatment of inflammation, in particular periodontal disease, arthritis, inflammatory bowel disease, dermatitis and asthma, treatment of growth disorders, diseases of the nervous system, the blood coagulation cascade and the peptide of the invention or the pharmaceutical composition of the invention for use in the treatment of disorders of hematopoiesis, vascular diseases, immune system diseases, improvement of wound and bone healing, treatment of neurological diseases, in particular stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, treatment of warts, hypogammaglobulinemia, immunodeficiency, myelodysplastic syndrome (WHIM-syndrome) and rheumatoid arthritis, treatment of cancer, in particular cancers that express the CXCR4 receptor, such as liver cancer, pancreatic cancer, prostate cancer, breast cancer or other solid tumors, treatment of deficiencies in stem cell mobilization, proliferation and migration, activation of T cells and support of immunoblasts such as CTL / PD-1, treatment of anti-fibrosis, treatment or prevention of scars, treatment of cardiac diseases, treatment of metabolic disorders, in particular diabetes, treatment of lung diseases, in particular pulmonary fibrosis, bronchitis and chronic obstructive pulmonary disease (COPD).

[0013] A ninth aspect of the present invention relates to a peptide of the present invention or a pharmaceutical composition of the present invention for use in the prevention and / or treatment of cancer, a viral disease, a metabolic disorder, a nervous system disease, a disease of the immune system, or a disorder of the blood coagulation cascade and hematopoiesis in a mammal, said mammal being preferably a human.

[0014] A tenth aspect of the present invention relates to a method for producing the peptide of the present invention by solid phase synthesis.

[0015] A further aspect of the present invention relates to a conjugate of a peptide according to the invention bound to cholesterol.

[0016] A further aspect of the present invention relates to a conjugate in which a peptide according to the present invention is linked to a drug.

[0017] A further aspect of the present invention relates to a conjugate of a peptide according to the invention bound to human serum albumin. [Brief explanation of the drawings]

[0018] [Figure 1] Figure 1 shows two diagrams of the X4-HIV-1 assay, in which the infection rate of cells depends on the concentration of different peptide derivatives. [Figure 2] Figure 2 shows two views of an antibody competition assay, where the percentage of bound antibody depends on the concentration of a truncated palmitoylated variant of peptide JM#21 (SEQ ID NO: 23) (A) and a terminally modified truncated palmitoylated variant of peptide JM#21 (SEQ ID NO: 23) (B). [Figure 3] FIG. 3 shows the inhibition of Akt and Erk signaling by CXCL12, and the proportion of phosphorylated Akt and Erk is dependent on the concentration of different peptide derivatives. [Figure 4] FIG. 4 shows the stability of various peptides in whole human plasma. [Figure 5] FIG. 5 is a diagram of an antibody competition assay, in which the percentage of bound antibody depends on the concentration of DOTA-conjugated peptide. [Figure 6] Figure 6 shows two illustrations of the X4-HIV-1 assay, in which the infection rate of cells depends on the concentration of different peptides conjugated to polyethylene glycol (A) or poly(vinyl alcohol) and poly(vinylpyrrolidone) (B). [Figure 7] Figure 7 shows two illustrations of antibody competition assays, where the percentage of bound antibody depends on the concentration of truncated palmitoylated variants of the peptide conjugated to polyethylene glycol (A) or poly(vinyl alcohol) and poly(vinylpyrrolidone) (B). [Figure 8]FIG. 8 shows two diagrams of assays testing the activity of DSPE-conjugated peptides: (A) a diagram of an X4-HIV-1 assay, and (B) a diagram of an antibody competition assay. [Figure 9] FIG. 9 shows the inhibition of CXCL12-induced Ca 2+ -signals by A) JM#21 (SEQ ID NO: 23) and its peptide variants, and B) WSC02 (SEQ ID NO: 2) and its peptide variants. [Figure 10] FIG. 10 shows A) inhibition of CXCL12-induced T cell migration by peptide JM#21 (SEQ ID NO: 23), comparing JM#21 and WSC02 with prior art peptides EPIX4 (SEQ ID NO: 1) and WSC02 (SEQ ID NO: 2), and B) short peptide variants of JM#21 (SEQ ID NO: 23) and WSC02 (SEQ ID NO: 2), and C) peptide variants of fatty acid-binding peptides of JM#21 (SEQ ID NO: 23) and WSC02 (SEQ ID NO: 2). [Figure 11] Figure 11 illustrates the computational model developed for the design of novel peptide derivatives: A) Peptide-protein model in aqueous and membrane environments, B) Tentative binding site investigation, C) Analysis of energy contributions, and D) Intermolecular interactions at the binding site. [Figure 12] FIG. 12 shows the stability of different peptides in human S9 liver fraction. [Figure 13] FIG. 13 shows the in vivo stability of different peptides. [Figure 14] FIG. 14 shows the cellular uptake and distribution of 177Lu-labeled DOTA-conjugated peptide and 177Lu-labeled PentiXather in GHOST-CXCR4+ cells. [Figure 15] FIG. 15 shows the cellular uptake and distribution of 177Lu / 68Ga-labeled DOTA-conjugated peptide and 177Lu / 68Ga-labeled PentiXather in GHOST-CXCR4+ cells. [Figure 16]FIG. 16 shows the intracellular uptake of 177Lu-labeled DOTA-conjugated peptide and 177Lu-labeled PentiXather in Jurkat cells. DETAILED DESCRIPTION OF THE INVENTION

[0019] A first aspect of the present invention relates to a peptide consisting of the following amino acid sequence, which is selected from any one of Groups 1 to 11: - Group 7 consists of: d-ILRWSRK-NH2 (SEQ ID NO: 70, JM#173) Md-LRWSRKLPCVS (SEQ ID NO: 45, JM#43) Md-LRWSRKMPCVS (SEQ ID NO: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS (SEQ ID NO: 54, JM#143) ILRWSRK(Pal)LPCVS (SEQ ID NO: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (SEQ ID NO: 56, JM#145) ILRWSRK(Pal)MPCLS (SEQ ID NO: 59, JM#149) IVRWSK(Pal)KVP-NH2 (SEQ ID NO: 63, JM#166) IVRWSKK(Pal)VP-NH2 (SEQ ID NO: 64, JM#167) ILRWSRK(Pal)-NH2 (SEQ ID NO: 67, JM#170) ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 68, JM#171) d-ILRWSRKLP-NH2 (SEQ ID NO: 71, JM#174) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 95, JM#198) ILRWSRK(Glu-Lau)LPCVS (SEQ ID NO: 104, JM#213) ILRWSRK(Glu-Ole)LPCVS (SEQ ID NO: 108, JM#217) ILRWSRK(C16diacid)LPCVS (SEQ ID NO: 117, JM#226) ILRWSRK(Glu-C16diacid)LPCVS (SEQ ID NO: 118, JM#227) ILRWSRK(C18diacid)LPCVS (SEQ ID NO: 119, JM#228) ILRWSRK(Glu-C18diacid)LPCVS (SEQ ID NO: 120, JM#229) ILRWSRK(OEG-OEG-γGlu-C18diacid)LPCVS (SEQ ID NO: 121, JM#230) d-LLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 130, JM#235) d-LLRWSRK(Pal)-NH2 (SEQ ID NO: 131, JM#236) d-ILRWSRK(Pal)-NH2 (SEQ ID NO: 132, JM#237) d-ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 133, JM#238) ILRWSRK(C16diacid)-NH2 (SEQ ID NO: 139, JM#244) ILRWSRK(C18diacid)-NH2 (SEQ ID NO: 140, JM#245) ILRWSRK(Glu-C16diacid)-NH2 (SEQ ID NO: 141, JM#246) ILRWSRK(Glu-C18diacid)-NH2 (SEQ ID NO: 142, JM#247) d-LLRWSRK(C16diacid)-NH2 (SEQ ID NO: 143, JM#248) d-LLRWSRK(C18diacid)-NH2 (SEQ ID NO: 144, JM#249) d-LLRWSRK(Glu-C16diacid)-NH2 (SEQ ID NO: 145, JM#250) d-LLRWSRK(Glu-C18diacid)-NH2 (SEQ ID NO: 146, JM#251) ILRWSRK(Ara)LPCVS (SEQ ID NO: 147, JM#252) ILRWSRK(Glu-Ara)LPCVS (SEQ ID NO: 148, JM#253) ILRWSRK(Ste)-NH2 (SEQ ID NO: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 150, JM#255) d-LLRWSRK(Ste)-NH2 (SEQ ID NO: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 157, JM#260) ILRWSRK(Myr)-NH2 (SEQ ID NO: 159, JM#262) LVRYTKK(Glu-Pal)-NH2 (SEQ ID NO: 161, JM#264) d-LVRYTKK(Glu-Pal)-NH2 (SEQ ID NO: 162, JM#265) ILRWSRK(Pal-Glu)LPSVS (SEQ ID NO: 163) -Group 1 consists of: ILRWSRKMPCLS (SEQ ID NO: 20, JM#18) ILRWSRK(Pal)LPCVS (SEQ ID NO: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 91, JM#194) ILRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 150, JM#255) -Group 2 consists of: ILRWSRK(Pal)L-NH2 (SEQ ID NO: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (SEQ ID NO: 75, JM#178) d-LMRWSRK(Pal)-NH2 (SEQ ID NO: 77, JM#180) ILRWSRK(Ole)LPCVS (SEQ ID NO: 80, JM#183) ILRWSRK(Glu-Lau)LPCVS (SEQ ID NO: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 133, JM#238) d-LLRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 152, JM#257) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (SEQ ID NO: 53, JM#141) IVRWSK(Pal)KVP-NH2 (SEQ ID NO: 63, JM#166) IVRWSKK(Pal)VP-NH2 (SEQ ID NO: 64, JM#167) IVRWSKK(Pal)VPCVS (SEQ ID NO: 66, JM#169) ILRWSRK(Pal)-NH2 (SEQ ID NO: 67, JM#170) ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (SEQ ID NO: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS (SEQ ID NO: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS (SEQ ID NO: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 100, JM#205) ILRWSRK(Myr)LPCVS (SEQ ID NO: 107, JM#216) ILRWSRK(Ste)-NH2 (SEQ ID NO: 149, JM#254) d-LLRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 157, JM#260) ILRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 160, JM#263) -Group 4 consists of: ILRWSRKVPCVS (SEQ ID NO: 10, JM#8) IFRWSRKVPCVS (SEQ ID NO: 12, JM#10) MLRWSRKMPCVS (SEQ ID NO: 29, JM#27) MMRWSRKMPCVS (SEQ ID NO: 36, JM#34) MLRWSRKLPCVS (SEQ ID NO: 41, JM#39) ILRWSRKLPSVS (SEQ ID NO: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS (SEQ ID NO: 52, JM#140) ILRWSRK(Pal)MPCLS (SEQ ID NO: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 92, JM#195) ILRWSRK-AcLPCVS (SEQ ID NO: 97, JM#200) ILRWSRK(Lau)LPCVS (SEQ ID NO: 105, JM#214) d-LLRWSRK(Ste)-NH2 (SEQ ID NO: 151, JM#256) ILRWSRK(Myr)-NH2 (SEQ ID NO: 159, JM#262) -Group 5 consists of: ILRWSKKVPCVS (SEQ ID NO: 3, JM#1) IFRWSKKVPCVS (SEQ ID NO: 4, JM#2) IVRWSRKVPCVS (SEQ ID NO: 5, JM#3) IVRWSHKVPCVS (SEQ ID NO: 6, JM#4) IVRWSKKLPCVS (SEQ ID NO: 7, JM#5) IVRWSKKIPCVS (SEQ ID NO: 8, JM#6) IVRWSKKFPCVS (SEQ ID NO: 9, JM#7) ILRWSHKVPCVS (SEQ ID NO: 11, JM#9) IFRWSHKVPCVS (SEQ ID NO: 13, JM#11) IVRWSKKMPCVS (SEQ ID NO: 14, JM#12) IVRWSKKVPCd-VS (SEQ ID NO: 16, JM#14) ILRWSRKVPCd-VS (SEQ ID NO: 17, JM#15) IIRWSRKMPCVS (SEQ ID NO: 18, JM#16) ILRWSRKVPSVS (SEQ ID NO: 25, JM#23) ILRWSRKMPSVS (SEQ ID NO: 26, JM#24) Ac-SLRWSRKMPCVS (SEQ ID NO: 27, JM#25) d-Ac-SLRWSRKMPCVS (SEQ ID NO: 28, JM#26) d-MLRWSRKMPCVS (SEQ ID NO: 30, JM#28) d-LLRWSRKMPCVS (SEQ ID NO: 31, JM#29) d-FLRWSRKMPCVS (SEQ ID NO: 32, JM#30) GLRWSRKMPCVS (SEQ ID NO: 33, JM#31) Ac-SMRWSRKMPCVS (SEQ ID NO: 34, JM#32) d-Ac-SMRWSRKMPCVS (SEQ ID NO: 35, JM#33) d-MMRWSRKMPCVS (SEQ ID NO: 37, JM#35) d-LMRWSRKMPCVS (SEQ ID NO: 38, JM#36) d-FMRWSRKMPCVS (SEQ ID NO: 39, JM#37) d-GMRWSRKMPCVS (SEQ ID NO: 40, JM#38) d-MLRWSRKLPCVS (SEQ ID NO: 42, JM#40) Id-LRWSRKLPCVS (SEQ ID NO: 43, JM#41) Id-LRWSRKMPCVS (SEQ ID NO: 44, JM#42) Md-LRWSRKLPCVS (SEQ ID NO: 45, JM#43) Md-LRWSRKMPCVS (SEQ ID NO: 46, JM#44) IVRWSKKVP-NH2 (SEQ ID NO: 47, JM#106) IVRWSKK-NH2 (SEQ ID NO: 48, JM#110) ILRWSRKLP-NH2 (SEQ ID NO: 49, JM#114) ILRWSRK-NH2 (SEQ ID NO: 50, JM#118) ILRWSRK(Glu-Pal)LPCVS (SEQ ID NO: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (SEQ ID NO: 56, JM#145) IYRWSRKMPCLS (SEQ ID NO: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (SEQ ID NO: 58, JM#148) IVRWSKKVPSVS (SEQ ID NO: 60, JM#151) IVRWSK(Pal)K-NH2 (SEQ ID NO: 61, JM#164) IVRWSKK(Pal)-NH2 (SEQ ID NO: 62, JM#165) IVRWSK(Pal)KVPCVS (SEQ ID NO: 65, JM#168) d-ILRWSRK-NH2 (SEQ ID NO: 70, JM#173) d-ILRWSRKLP-NH2 (SEQ ID NO: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 72, JM#175) d-LMRWSRK(Pal)MPCVS (SEQ ID NO: 73, JM#176) Md-LRWSRK(Pal)LPCVS (SEQ ID NO: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (SEQ ID NO: 76, JM#179) Md-LRWSRK(Pal)-NH2 (SEQ ID NO: 78, JM#181) ILRWSRK(Ste)LPCVS (SEQ ID NO: 79, JM#182) ILRWSRK(Chl)LPCVS (SEQ ID NO: 81, JM#184) Ac-ILRWSRKLPCVS (SEQ ID NO: 82, JM#185) d-Ac-ILRWSRKLPCVS (SEQ ID NO: 83, JM#186) Ac-MLRWSRKLPCVS (SEQ ID NO: 84, JM#187) d-Ac-MLRWSRKLPCVS (SEQ ID NO: 85, JM#188) VLRWSRKLPCVS (SEQ ID NO: 86, JM#189) d-VLRWSRKLPCVS (SEQ ID NO: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (SEQ ID NO: 99, JM#204) ILRWSRK(Dec)LPCVS (SEQ ID NO: 106, JM#215) d-LLRWSRK(Pal)-NH2 (SEQ ID NO: 131, JM#236) d-ILRWSRK(Pal)-NH2 (SEQ ID NO: 132, JM#237) d-LLRWSRK(Myr)-NH2 (SEQ ID NO: 158, JM#261) ILRWSRK(Pal-Glu)LPSVS (SEQ ID NO: 163) ILRWSRK(Glu-Ste)LPSVS (SEQ ID NO: 164) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (SEQ ID NO: 95, JM#198) ILRWSRK(Glu-Ste)LPSVS (SEQ ID NO: 164) -Group 8 consists of: d-LLRWSRKMPCVS (SEQ ID NO: 31, JM#29) ILRWSRK(Pal)L-NH2 (SEQ ID NO: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (SEQ ID NO: 27, JM#25) d-MLRWSRKMPCVS (SEQ ID NO: 30, JM#28) d-Ac-SMRWSRKMPCVS (SEQ ID NO: 35, JM#33) d-MMRWSRKMPCVS (SEQ ID NO: 37, JM#35) d-LMRWSRKMPCVS (SEQ ID NO: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS (SEQ ID NO: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (SEQ ID NO: 75, JM#178) ILRWSRK(Dec)LPCVS (SEQ ID NO: 106, JM#215) d-LLRWSRK(Myr)-NH2 (SEQ ID NO: 158, JM#261) ILRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 160, JM#263) -Group 10 consists of: ILRWSRK(Pal)LPCVS (SEQ ID NO: 55, JM#144) IVRWSK(Pal)KVP-NH2 (SEQ ID NO: 63, JM#166) IVRWSKK(Pal)VP-NH2 (SEQ ID NO: 64, JM#167) ILRWSRK(Pal)-NH2 (SEQ ID NO: 67, JM#170) ILRWSRK(Pal)LP-NH2 (SEQ ID NO: 68, JM#171) ILRWSRK(Pal)L-NH2 (SEQ ID NO: 69, JM#172) d-LMRWSRK(Pal)-NH2 (SEQ ID NO: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (SEQ ID NO: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (SEQ ID NO: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 91, JM#194) ILRWSRK(Glu-Lau)LPCVS (SEQ ID NO: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (SEQ ID NO: 133, JM#238) ILRWSRK(Ste)-NH2 (SEQ ID NO: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (SEQ ID NO: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (SEQ ID NO: 157, JM#260) -Group 11 consists of: ILRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 109, JM#218) ILRW(dC)RKPC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 111, JM#219) IPRW(dC)RKC-NH2, the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 113, JM#220) ILRWSRKLPCVS, where the lysine at position 7 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 115, JM#221) ILRWSKKLPCVS, where the lysine at position 6 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 116, JM#222) IPRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 122, JM#231) ILRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 124, JM#232) IPRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 126, JM#233) ILRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 128, JM#234) IMRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 153, JM#258) IPRW(dC)RKCP-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 155, JM#259) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol on the preceding amino acid, Ac indicates substitution of an amino group with an acetyl group, Lau indicates lauric acid on the preceding amino acid, Glu-Lau indicates substitution of a glutamic acid linker Glu-Ole indicates lauric acid on the preceding amino acid with a glutamic acid linker, C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid with a glutamic acid linker, C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with an OEG-OEG-γ glutamic acid linker, OEG indicates a residue of 8-amino-3,6-dioxaoctanoic acid, Ara indicates a saturated C20 fatty acid on the preceding amino acid, and Glu-Ara indicates a saturated C20 fatty acid on the preceding amino acid with a glutamic acid linker.

[0020] The peptide derivatives of the present invention have approximately 100-fold stronger binding efficacy to CXCR4 than previously known peptides. Furthermore, the present invention provides peptides with significantly higher plasma stability than prior art peptides. Furthermore, the present invention provides peptides with significantly longer in vivo circulatory half-lives than currently available peptides. As a result, the present invention provides peptides with enhanced therapeutic potential compared to currently available drugs, since a lower dose is sufficient to provide the desired effect.

[0021] The term derivative refers to full-length fragments of peptide EPI-X4 (SEQ ID NO: 1) including N- and C-terminal truncations, peptides of the invention containing amino acid residue substitutions including D-amino acid residues and modified amino acid residues, and peptides containing N- and C-terminal disulfide bonds and extensions. The terms peptide, peptide derivative, and derivative are used interchangeably. The term peptide also covers cyclized peptides, where the peptides of the invention may be provided in cyclized form.

[0022] Apart from the above modifications, the peptides are preferably coupled to proteins, such as antibodies or human serum albumin (HSA).

[0023] The activity of the peptides was estimated by different assays. First, activity was verified by an HIV-1 inhibition assay (Figure 1). The potency of the inhibitory effect of CXCR4-tropic X4-HIV-1 indirectly reflects the binding affinity of the derivative to CXCR4, because X4-HIV-1 utilizes CXCR4 along with CD4 for cell entry. Cell entry requires the binding of the HIV-1 glycoprotein gp120 to the receptor, which then leads to cell fusion. When CXCR4 is inhibited by receptor ligands, HIV-1 entry is inhibited, resulting in suppression of infection.

[0024] All EPI-X4 derivatives tested dose-dependently and specifically inhibited the infection of reporter cells by X4-HIV-1. Peptides EPI-X4 (SEQ ID NO: 1) and WSC02 (SEQ ID NO: 2) (EP3007717B1) were used as reference peptides. In Figure 1, the results of two assays are shown in diagram form, showing the percentage of infected cells depending on the logarithmic concentration of the different test peptides (Figures 1A and 1B). Using average values ​​estimated over several tests, JM#21 (ID NO: 23) inhibited the infection of reporter cells by EPI-X4 (ID NO: 1, IC 50 =8630nM) and WSC02 (identification ID number: 2, IC50 = 310 nM) was almost 100 times more effective as an inhibitor (IC 50 = 98 nM). It was found that peptide derivatives conjugated to fatty acids, such as palmitic acid (ID No. 75, JM#178; ID No. 77, JM#180; ID No. 91, JM#194; ID No. 92, JM#195; ID No. 93, JM#196; ID No. 94, JM#197), exhibited strongly enhanced anti-HIV-1 activity. The potency of palmitic acid-conjugated JM#21 (ID No. 23) was increased by more than 60-fold compared to WSC02 (ID No. 143 (ID No. 54)). 50 = 5 nM, not shown). 2) C-terminal truncation and amidation of these derivatives further increased the anti-HIV-1 activity (JM#192 (ID number: 89) = 2 nM, not shown; JM#194 (ID number: 91) = 2 nM). Experiments were performed in triplicate. Error bars indicate standard deviation.

[0025] Next, the activity was verified by antibody competition assay (Figure 2). The values ​​determined in the competition assay represent the potency of the compound in competing with an antibody that specifically binds to the binding pocket (ECL2) of CXCR4. These values ​​most likely correlate with the binding affinity of the compound to CXCR4. Figure 2 (A and B) shows the results of the two assays graphically, showing the dependence of the percentage of bound antibody on the concentration of different peptides. The right side of the figure explains the assignment of the curves to the tested peptides. The right side of the legend shows the IC50 values ​​in the competition assay (12G5-assay), the HIV-1 assay, and the individual sequences of the tested peptides. It can be seen that all EPI-X4 derivatives compete for antibody binding. JM#21 (identification ID number: 23) was compared with WSC02 (identification ID number: 2) (IC 50 = 350 nM) and AMD3100 (IC 50 = 690 nM) than effective antibody competition (lower IC 50Using JM#21 (ID number: 23) as a starting point for further development, the present inventors designed derivatives with molecular weights of 1000 Da or less (e.g., JM#118 (ID number: 50)) that have similar affinity to CXCR4 as JM#21 (ID number: 23). Surprisingly, coupling fatty acids to these short derivatives enhanced their binding to CXCR4. EPI-X4 (ID number: 1) (IC 50 Some derivatives bind to the receptor more than 2000 times more effectively (e.g., IC ~2500 nM) compared with 50 (Identification ID: JM#167 (ID: 64) = 2 nM; JM#178 (ID: 75) = 2 nM; JM#191 (ID: 88) = 1 nM) are approximately 300-fold more effective than WSC02 (ID: 2). Three independent experiments were performed for each peptide in each assay. Error bars indicate standard deviation.

[0026] Third, the activity of EPI-X4 derivatives was verified by their effects on CXCL12 / CXCR4-mediated ERK (extracellular signal-regulated kinase) and AKT (serine / threonine protein kinase) signaling (Figure 3). In this assay, CXCR4-expressing cells were stimulated with CXCR4 chemokine ligand CXCL12, subsequently inducing ERK and AKT phosphorylation. Preincubation of cells with a CXCR4 antagonist blocked these pathways. Figure 3 shows the results of the two assays, demonstrating that the percentages of phosphorylated ERK (Figure 3A) and phosphorylated AKT (Figure 3B) depend on the concentration of the different peptides. All EPI-X4 derivatives tested dose-dependently blocked CXCL12-induced signaling. JM#21 (identification ID number: 23) blocked signaling more effectively than WSC02. 10 μM WSC02 (ID No.: 2) reduced AKT signaling by approximately 50%, while JM#21 (ID No.: 23) caused approximately 85% inhibition at the same concentration. JM#21 blocked CXCL12-induced AKT signaling by approximately 50% at 1 μM, which was approximately 10-fold more effective than WSC02 (ID No.: 2). ERK signaling was also effectively blocked by JM#21 (ID No.: 23) (60% reduction at 1 μM), whereas WSC02 (ID No.: 2) reduced Erk phosphorylation by only 20% at the same concentration. JM#21 (ID No.: 23) was also more effective than AMD3100 (approximately 60% reduction in AKT phosphorylation at 10 μM) and EPI-X4 (ID No.: 1) (approximately 40% reduction at 10 μM). Furthermore, JM#18 (ID No.: 20) had a very strong antagonistic effect in this assay. JM#18 (ID No.: 20) blocked CXCL12-induced AKT and ERK signaling by approximately 40% at a concentration of 0.1 μM and by nearly 70% at a concentration of 1 μM (data not shown). Interestingly, palmitic acid coupling enhanced the antagonistic effect. At a concentration of 10 μM, all palmitic acid-coupled derivatives tested 100% inhibited CXCL12-induced AKT and ERK signaling.JM#143 (ID#: 54), a fatty acid-conjugated derivative of JM#21 (ID#: 23), blocked AKT and ERK phosphorylation by nearly 70% at 1 μM, with a 20-25% reduction in signal even at 0.1 μM. Surprisingly, palmitate-conjugated WSC02 (JM#169, ID#: 66) exhibited highly potent antagonistic activity, inhibiting AKT signaling by 85% and ERK signaling by over 70% at 0.1 μM. At 1 μM, AKT signaling was completely blocked, and ERK signaling was almost completely blocked. Two to three independent experiments were performed for each peptide in each assay, in triplicate. Error bars indicate standard deviation.

[0027] Fourth, the stability of the peptide in human plasma and whole human blood was tested (Figure 4). The functional stability of the EPI-X4 (identification ID number: 1) derivative was screened using a CXCR4 antibody-based screening method. The peptide was diluted (>99%) in whole human plasma or blood, and functional activity was measured after either 2 or 8 hours and compared with samples that were not incubated in plasma or blood.

[0028] In Figure 4, peptide stability is shown by the percentage of bound antibody depending on the molar concentration of the peptide. The functional stability of both WSC02 (ID No.: 2) and JM#21 (ID No.: 23) was significantly lower than that of EPI-X4 (ID No.: 1) (t = 17 min) (Figure 4A). After 2 hours, both optimized peptides were completely inactive. The rapid degradation of these variants was also confirmed using mass spectrometry. Furthermore, both truncated variants (JM#114 (ID No.: 49), Figure 4B, and JM#118 (ID No.: 50), Figure 4C) were rapidly inactivated in plasma. Using mass spectrometry, we demonstrated that enzymatic degradation of the EPI-X4 (ID No.: 1) derivative was detected exclusively at the N-terminus. N-terminally modified EPI-X4 (ID number: 1) variants (JM#25 (ID number: 27)-JM#44 (ID number: 46)) showed significantly increased functional plasma stability compared to WSC02 (ID number: 2). On the other hand, anti-CXCR4 activity was either not affected or not strongly affected (IC50 in the following HIV-1 inhibition assay: JM#28 (ID No.: 30) = 246 nM; JM#36 (ID No.: 38) = 206 nM; JM#43 (ID No.: 45) = 810 nM), and activity remained after 2 and even 8 hours of plasma incubation (following remaining activity: JM#28 (ID No.: 30) = 96% after 2 hours, 77% after 8 hours; JM#36 (ID No.: 38) = 85% after 2 hours, 81% after 8 hours; JM#43 (ID No.: 45) = 100% after 2 and 8 hours). Further testing revealed that peptides JM#173 (ID No. 70) and JM#174 (ID No. 71) retained 100% of their initial activity after 8 hours of plasma incubation and were completely stable in human plasma (not shown), a surprising finding given that their corresponding peptides JM#114 (ID No. 49) and JM#118 (ID No. 50), which were not N-terminally modified with d-amino acids, were rapidly inactivated in plasma (Figures 4B and 4C).Due to their strongly reduced size and high stability, JM#173 (identification ID number: 70) and JM#174 (identification ID number: 71) appear to be suitable for enteral administration.

[0029] The present inventors aimed to further enhance plasma stability (and bioavailability), and therefore designed EPI-X4 (ID No.: 1) derivatives conjugated to fatty acids (e.g., palmitic acid). Many of the fatty acid-conjugated derivatives, such as JM#21 (JM#143 (ID No.: 54)-JM#145 (ID No.: 56)), showed significantly improved plasma stability and no loss of activity even after 8 hours of incubation. Surprisingly, the same is true for most truncated and fatty acid-bound variants of JM#21 (ID#: 23), WSC02 (ID#: 2) or similar (e.g., EgJM#170 (ID#: 67), Figure 4D - JM#172 (ID#: 69), Figure 4E and JM#191 (ID#: 88) - JM#193 (ID#: 90) (JM#192 is Figure 4F)). The same is true for variants that were functionally stable in stability assays when combined with N-terminal modifications (e.g., JM#194 (ID#: 91) - JM#197 (ID#: 94)).

[0030] An alternative stabilization approach was PEGylation of JM#21 (identification ID number: 23). PEGylation had little or no effect on the anti-CXCR4 activity of the variants (IC50 in the HIV-1 inhibition assay for SC024 (20 kDa) = 118 nM, SC029 (telechelic peptide conjugate, 20 kDa) = 98 nM, SC033 (5 kDa) = 716 nM), but strongly increased their functional plasma stability (residual activity after 8 h plasma incubation, same below): SC024 = 30%, SC029 = 38%, SC033 = 72%). Figures 4A–C show three separate experiments. Error bars indicate standard deviation. Figures 4D–F are based on one representative experiment.

[0031] Fifth, this peptide derivative was shown to inhibit calcium signaling. CXCL12 stimulation of CXCR4-expressing B cells induces a strong calcium release. In the presence of a CXCR4 antagonist, this response is attenuated. We observed a reduction in the cytokine-induced calcium signal with 1 μM JM#21 (ID No.: 23), which was much stronger than the reduction observed with the same concentration of WSC02 (ID No.: 2). The fatty acid-binding JM#21 (ID number: 23) variants (JM#143 (ID number: 54), JM#144 (ID number: 55), JM#170 (ID number: 67), JM#192 (ID number: 89), JM#194 (ID number: 91)) (Figure 9A), and the fatty acid-binding WSC02 (ID number: 2) variant (Figure 9B) almost completely blocked calcium signals at a concentration of 1 μM. For each peptide, Figure 9 shows the results of one representative experiment.

[0032] Sixth, all EPI-X4 derivatives tested inhibited CXCL12-induced migration of T cells. JM#21 (ID No.: 23) was more effective than WSC02 (ID No.: 2) and EPI-X4 (ID No.: 1) (Figure 10A). Truncated forms of JM#21 (ID No.: 23) (JM#114 (ID No.: 49), JM#118 (ID No.: 50)) were even more effective than the full-length peptide (Figure 10B). This effect could also be demonstrated for truncated forms of WSC02 (ID No.: 2) (JM#106 (ID No.: 47), JM#110 (ID No.: 48)). The tested fatty acid-linked variants of JM#21 (ID number: 23), especially JM#143 (ID number: 54), had a strongly increased antagonistic effect on CXCL12-induced cell migration (Figure 10C). Three independent experiments were performed for each peptide. Error bars indicate standard deviation. Further testing revealed the high activity of JM#192 (ID number: 89) and JM#194 (ID number: 91) in inhibiting CXCL12-induced migration of T cells (not shown). Furthermore, it was found that binding of peptides to longer fatty acids appears to be beneficial in blocking cancer cell migration. Notably, all tested stearic acid variants were unexpectedly active. For example, the presence of 30 nM of peptide JM#255 (ID number: 150) already resulted in almost complete inhibition of cell migration (not shown).

[0033] Furthermore, we tested the stability of peptides in human S9 liver fractions (in the presence of coenzymes) (Fig. 1). While blood degradation is the primary excretion pathway for most peptide therapeutics, hepatic clearance may play an important role, especially for lipophilic fatty acid conjugates. Therefore, we spiked peptides into human S9 liver fractions to simulate and predict hepatic metabolic clearance. The remaining peptide activity after 2 and 8 hours was measured using an antibody competition assay, and IC values ​​were calculated. 50Values ​​were normalized to the sample without incubation (t=0). The peptides tested included N-terminal modified variants (JM#28 (ID No.: 30), JM#29 (ID No.: 31), JM#36 (ID No.: 38), JM#43 (ID No.: 45), JM#173 (ID No.: 70)) and fatty acid-linked JM#21 (ID No.: 23). The tested derivatives were the variants JM#143 (ID No.: 54) (C16) and JM#198 (ID No.: 95) (C18), as well as truncated fatty acid conjugates (JM#192 (ID No.: 89), JM#194 (ID No.: 91), JM#235 (ID No.: 130), JM#255 (SEQ ID NO: 150), and JM#257 (SEQ ID NO: 152)). All tested derivatives were characterized by relatively high antagonistic activity and excellent stability in human plasma. Both WSC02 (ID No.: 2) and JM#21 (ID No.: 23) were readily inactivated by liver enzymes after 2 hours, as expected (Figure 12A). All stabilized peptides tested retained approximately 60% of their initial activity after 2 hours, except for derivative JM#192 (ID No.: 89), which showed a faster inactivation (Figure 12A). After 8 hours of incubation, all non-fatty acid variants were almost completely inactivated, except for JM#173 (ID No.: 70), which retained approximately 14% of its activity (Figure 12B). Of note, JM#173 (ID No.: 70) was completely resistant to plasma enzymes. Regarding fatty acid conjugates, the stearic acid conjugate JM#198 (ID No.: 95) was more stable than its palmitoylated counterpart JM#143 (ID No.: 54) (Figure 12B). Furthermore, N-terminal modifications appear to have a positive effect on enzyme stability. Variants JM#192 (ID#: 89) and JM#255 (ID#: 150) have unmodified N-termini and degraded more rapidly compared to their N-terminally modified variants (JM#194 (ID#: 91), JM#235 (ID#: 130), and JM#257 (ID#: 152), respectively) (Figure 12B). For each peptide, three independent experiments were performed. Error bars indicate standard deviation.

[0034] Furthermore, the in vivo stability of the peptide was tested (Figure 13). The peptide was injected into the tail vein of mice. Four hours after injection, the mice were sacrificed and blood was collected by cardiac puncture. Plasma was obtained by centrifugation and residual activity was confirmed in an antibody competition assay. As a control, the peptide was added to native plasma (ex vivo). IC 50 The IC value was determined by nonlinear regression assuming an in vivo blood volume of 1.8 ml. Residual activity was calculated as IC 50 (ex vivo) / IC 50(in vivo) × 100. The peptides tested were JM#143 (ID No.: 54), JM#144 (ID No.: 55), JM#192 (ID No.: 89), JM#180 (ID No.: 77), JM#194 (ID No.: 91), JM#235 (ID No.: 130), JM#198 (ID No.: 95), JM#255 (ID No.: 150), JM#257 (ID No.: 152), and JM#204 (ID No.: 99). Surprisingly, the activity of the palmitoylated 7-mer JM#192 (ID No.: 89) was completely lost after 4 hours. In contrast, N-terminal modifications (JM#180 (ID#: 77), JM#194 (ID#: 91), JM#235 (ID#: 130)) appear to protect the peptides from elimination or enzymatic inactivation. For JM#180 (ID#: 77) and JM#194 (ID#: 91), approximately 9% of the conjugates remained active in plasma even 8 hours after injection (not shown). The highest bioavailability after 4 hours was determined for variants lacking the glutamic acid linker, JM#144 (ID#: 55) and JM#180 (ID#: 77) (27% and 29% activity remaining, respectively). The length of the conjugated fatty acid affects in vivo stability and bioavailability. Stearic acid (C18)-conjugated JM#198 (ID No.: 95) remained fully active and available in plasma even 4 hours after injection. In contrast, the activity of the myristoylated (C14) derivative JM#204 (ID No.: 99) was lost after this time. Derivative JM#198 (ID No.: 95) retained 33% of its activity 8 hours after injection and finally lost all activity after 24 hours (not shown). Even though the stearic acid stabilizing properties were not fully transferred to the shorter derivatives JM#255 (ID No.: 150) and JM#257 (ID No.: 152), the C18 conjugate is a superior peptide derivative. JM#198 (ID No.: 95) is characterized by high enzyme resistance, a relatively long circulating half-life, and excellent antagonistic activity. Data are shown from duplicate measurements in two mice. Error bars indicate standard deviation.

[0035] Toxicity studies using zebrafish showed that all the derivatives tested were not toxic to zebrafish embryos at their respective active concentrations.

[0036] Peptides in Group 1 exhibited half-maximal inhibitory concentrations (IC) measured in the X4-HIV-1 inhibition assay. 50 ) is 5 nM or less (to estimate the ability to inhibit X4-HIV-1 infection). The X4-HIV inhibition assay is designed to measure the activity of the peptides of the invention by their efficacy in blocking infection of tissue culture cells by CXCR4-tropic HIV-1 variants.

[0037] Group 2 peptides have IC as measured in the HIV inhibition assay 50 The inhibitory activity is characterized by a concentration of 5 to 10 nM.

[0038] Group 3 peptides have IC as measured in the HIV inhibition assay 50 The inhibitory activity is characterized by a concentration of 10 to 50 nM.

[0039] Peptides in group 4 had IC measured in the HIV inhibition assay 50 The inhibitory activity is characterized by a concentration of 50 to 150 nM.

[0040] Peptides in group 5 have IC as measured in the HIV inhibition assay 50 The inhibitory activity is characterized by a specific activity of 150 nM or more.

[0041] Peptides in group 6 had IC values ​​measured in antibody competition assays 50 These peptides are characterized by IC values ​​of greater than 150 nM when measured in an HIV inhibition assay. 50 It has.

[0042] Group 7 peptides are characterized by a relative activity of 100% measured after 8 hours of plasma incubation. In this study, peptides were incubated in human plasma for a set period of time. Relative activity was estimated by measuring the retention of the ability to block X4-HIV-1 infection over time, or by measuring activity in the 12G5 antibody competition assay over time.

[0043] Peptides in group 8 are characterized by a relative activity of 100% after 2 hours of plasma incubation, but lower (75-99%) after 8 hours of plasma incubation.

[0044] Peptides in group 9 are characterized by a relative activity of 70–99% after 2 h of plasma incubation.

[0045] Peptides in group 10 were IC 50 These peptides are characterized by their activity being 50 nM or less and their relative activity remaining 100% after 8 hours of plasma incubation. This indicates that these peptides maintain high activity over a relatively long period of time.

[0046] Group 11 peptides are cyclized peptides. These peptides are particularly suitable for oral delivery to subjects, such as patients. Cyclization increases the peptide's stability against protease-mediated degradation and shields positively charged amino acid residues.

[0047] As used herein, the term cyclized peptide (or cyclic peptide) refers to a peptide having a cyclic sequence of bonds, which can be through a connection between the amino and carboxyl termini of the peptide, a connection between the amino terminus and a side chain of the peptide, a connection between the carboxyl terminus and a side chain of the peptide, or a connection between two side chains of the peptide.

[0048] The term thioester bond is used synonymously with the term thiolesterol bond.

[0049] We have also synthesized the following linear equivalents of the Group 11 cyclized peptides: ILRWCRKPC-NH2 (Identification ID number: 110, JM#218 straight line) ILRW(dC)RKPC-NH2 (Identification ID number: 112, JM#219 straight line) IPRW(dC)RKC-NH2 (Identification ID number: 114, JM#220 straight line) IPRW(dC)RKP (Identification ID number: 123, JM#231 straight line) ILRW(dC)RKP (Identification ID number: 125, JM#232 straight line) IPRW(dS)RKP (Identification ID number: 127, JM#233 straight line) ILRW(dS)RKP (Identification ID number: 129, JM#234 straight line) IMRWCRKPC-NH2 (ID number: 154, JM#258 straight line) IPRW(dC)RKCP-NH2((Identification ID number: 156, JM#259 straight line)

[0050] The linear equivalents are used as control peptides in assays to characterize the cyclized peptides, such as activity and stability assays.

[0051] Substitution of the N-terminal amino group, introduction of D-amino acids, and certain amino acid substitutions at the N-terminus of the peptide have been shown to inhibit protease activity. These modifications have the advantage of increasing the plasma stability of the peptide, as evidenced by a half-life of 29 hours.

[0052] Coupling of fatty acids, namely palmitic acid, decanoic acid, myristic acid, oleic acid, and stearic acid, to peptides has been shown to confer enhanced activity. Furthermore, coupling of fatty acids can prolong the circulation of a given concentration of peptide in vivo. This is also true for coupling of other fatty acids, such as lauric acid, saturated C16 fatty diacids, saturated C18 fatty diacids, and saturated C20 fatty acids.

[0053] In peptide ID number 121 (JM#230), an OEG-OEG-γGlu linker (2xOEG-γGlu linker) is used to link a fatty acid to the peptide. OEG represents a residue of 8-amino-3,6-dioxaoctanoic acid (i.e., a group of formula -NH-(CH2)2-0-(CH2)2-0-CH2-CO-). The two OEG entities of the linker are conjugated consecutively to the side chains of lysines in the peptide. The fatty acid is linked to the two OEG entities via the γ-glutamic acid entities of the linker.

[0054] Cholesterol has been shown to increase the relative stability and bioavailability of peptides in human plasma.

[0055] A second aspect of the present invention relates to a peptide consisting of the following amino acid sequence, which is selected from any one of Groups 1 to 11: - Group 7 consists of: d-ILRWSRK-NH2 (Identification ID number: 70, JM#173) Md-LRWSRKLPCVS (Identification ID number: 45, JM#43) Md-LRWSRKMPCVS (Identification ID number: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS(Identification ID number: 54, JM#143) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (Identification ID number: 56, JM#145) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) ILRWSRK(Glu-Ste)LPCVS (Identification ID: 95, JM#198) ILRWSRK (Glu-Lau) LPCVS (Identification ID: 104, JM#213) ILRWSRK (Glu-Ole) LPCVS (Identification ID: 108, JM#217) ILRWSRK(C16diacid)LPCVS (Identification ID: 117, JM#226) ILRWSRK (Glu-C16diacid) LPCVS (Identification ID: 118, JM#227) ILRWSRK(C18diacid)LPCVS (Identification ID: 119, JM#228) ILRWSRK (Glu-C18diacid) LPCVS (Identification ID: 120, JM#229) ILRWSRK(OEG-OEG-γGlu-C18diacid) LPCVS (Identification ID: 121, JM#230) d-LLRWSRK(Glu-Pal)-NH2 (Identification ID: 130, JM#235) d-LLRWSRK(Pal)-NH2 (Identification ID: 131, JM#236) d-ILRWSRK(Pal)-NH2 (Identification ID: 132, JM#237) d-ILRWSRK(Glu-Pal)-NH2 (Identification ID: 133, JM#238) ILRWSRK(C16diacid)-NH2 (Identification ID: 139, JM#244) ILRWSRK(C18diacid)-NH2 (Identification ID: 140, JM#245) ILRWSRK(Glu-C16diacid)-NH2 (Identification ID: 141, JM#246) ILRWSRK(Glu-C18diacid)-NH2 (Identification ID: 142, JM#247) d-LLRWSRK(C16diacid)-NH2 (Identification ID: 143, JM#248) d-LLRWSRK(C18diacid)-NH2 (ID number: 144, JM#249) d-LLRWSRK(Glu-C16diacid)-NH2(Identification ID number: 145, JM#250) d-LLRWSRK(Glu-C18diacid)-NH2(Identification ID number: 146, JM#251) ILRWSRK(Ara)LPCVS(ID number: 147, JM#252) ILRWSRK(Glu-Ara)LPCVS(Identification ID number: 148, JM#253) ILRWSRK(Ste)-NH2 (ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (ID number: 150, JM#255) d-LLRWSRK(Ste)-NH2 (ID number: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) ILRWSRK(Myr)-NH2 (Identification ID number: 159, JM#262) LVRYTKK(Glu-Pal)-NH2(Identification ID number: 161, JM#264) d-LVRYTKK(Glu-Pal)-NH2(Identification ID number: 162, JM#265) ILRWSRK(Pal-Glu)LPSVS(Identification ID number: 163) -Group 1 consists of: ILRWSRKMPCLS (ID number: 20, JM#18) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) ILRWSRK(Glu-Ste)-NH2 (ID number: 150, JM#255) -Group 2 consists of: ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRK(Ole)LPCVS(Identification ID number:80, JM#183) ILRWSRK(Glu-Lau)LPCVS(Identification ID number: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 133, JM#238) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (Identification ID number: 53, JM#141) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) IVRWSKK(Pal)VPCVS(Identification ID number: 66, JM#169) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS(Identification ID number: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS(Identification ID number: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (ID number: 100, JM#205) ILRWSRK(Myr)LPCVS(Identification ID number: 107, JM#216) ILRWSRK(Ste)-NH2 (ID number: 149, JM#254) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) ILRWSRK(Glu-Myr)-NH2 (Identification ID number: 160, JM#263) -Group 4 consists of: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (ID number: 36, JM#34) MLRWSRKLPCVS (ID number: 41, JM#39) ILRWSRKLPSVS (ID number: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (ID number: 97, JM#200) ILRWSRK(Lau)LPCVS(Identification ID number: 105, JM#214) d-LLRWSRK(Ste)-NH2 (ID number: 151, JM#256) ILRWSRK(Myr)-NH2 (Identification ID number: 159, JM#262) -Group 5 consists of: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (ID number: 5, JM#3) IVRWSHKVPCVS (Identification ID: 6, JM#4) IVRWSKKLPCVS (ID number: 7, JM#5) IVRWSKKIPCVS (ID number: 8, JM#6) IVRWSKKFPCVS (Identification ID: 9, JM#7) ILRWSHKVPCVS (Identification ID: 11, JM#9) IFRWSHKVPCVS (Identification ID: 13, JM#11) IVRWSKKMPCVS (Identification ID: 14, JM#12) IVRWSKKVPCd-VS (ID number: 16, JM#14) ILRWSRKVPCd-VS (ID number: 17, JM#15) IIRWSRKMPCVS (Identification ID: 18, JM#16) ILRWSRKVPSVS (Identification ID: 25, JM#23) ILRWSRKMPSVS (Identification ID: 26, JM#24) Ac-SLRWSRKMPCVS (ID number: 27, JM#25) d-Ac-SLRWSRKMPCVS (Identification ID: 28, JM#26) d-MLRWSRKMPCVS (Identification ID: 30, JM#28) d-LLRWSRKMPCVS (Identification ID: 31, JM#29) d-FLRWSRKMPCVS (Identification ID: 32, JM#30) GLRWSRKMPCVS (ID number: 33, JM#31) Ac-SMRWSRKMPCVS (Identification ID: 34, JM#32) d-Ac-SMRWSRKMPCVS (Identification ID: 35, JM#33) d-MMRWSRKMPCVS (Identification ID: 37, JM#35) d-LMRWSRKMPCVS (Identification ID: 38, JM#36) d-FMRWSRKMPCVS (Identification ID: 39, JM#37) d-GMRWSRKMPCVS (Identification ID: 40, JM#38) d-MLRWSRKLPCVS (ID number: 42, JM#40) Id-LRWSRKLPCVS (Identification ID: 43, JM#41) Id-LRWSRKMPCVS (Identification ID: 44, JM#42) Md-LRWSRKLPCVS (ID number: 45, JM#43) Md-LRWSRKMPCVS (ID number: 46, JM#44) IVRWSKKVP-NH2 (ID number: 47, JM#106) IVRWSKK-NH2 (ID number: 48, JM#110) ILRWSRKLP-NH2 (ID number: 49, JM#114) ILRWSRK-NH2 (ID number: 50, JM#118) ILRWSRK (Glu-Pal) LPCVS (ID number: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (Identification ID: 56, JM#145) IYRWSRKMPCLS (ID number: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (Identification ID: 58, JM#148) IVRWSKKVPSVS (Identification ID: 60, JM#151) IVRWSK(Pal)K-NH2 (ID Number: 61, JM#164) IVRWSKK(Pal)-NH2 (Identification ID: 62, JM#165) IVRWSK(Pal)KVPCVS (Identification ID: 65, JM#168) d-ILRWSRK-NH2 (ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (Identification ID: 72, JM#175) d-LMRWSRK(Pal)MPCVS (Identification ID: 73, JM#176) Md-LRWSRK(Pal)LPCVS (Identification ID: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (Identification ID: 76, JM#179) Md-LRWSRK(Pal)-NH2 (Identification ID: 78, JM#181) ILRWSRK(Ste)LPCVS (Identification ID: 79, JM#182) ILRWSRK(Chl)LPCVS (Identification ID: 81, JM#184) Ac-ILRWSRKLPCVS (ID number: 82, JM#185) d-Ac-ILRWSRKLPCVS (Identification ID: 83, JM#186) Ac-MLRWSRKLPCVS (Identification ID: 84, JM#187) d-Ac-MLRWSRKLPCVS (Identification ID: 85, JM#188) VLRWSRKLPCVS (ID number: 86, JM#189) d-VLRWSRKLPCVS (ID number: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (Identification ID: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (ID Number: 99, JM#204) ILRWSRK(Dec)LPCVS (Identification ID: 106, JM#215) d-LLRWSRK(Pal)-NH2 (Identification ID: 131, JM#236) d-ILRWSRK(Pal)-NH2 (Identification ID: 132, JM#237) d-LLRWSRK(Myr)-NH2 (Identification ID: 158, JM#261) ILRWSRK(Pal-Glu)LPSVS(Identification ID number: 163) ILRWSRK(Glu-Ste)LPSVS (ID number: 164) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) ILRWSRK(Glu-Ste)LPSVS (ID number: 164) -Group 8 consists of: d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-Ac-SMRWSRKMPCVS (Identification ID number: 35, JM#33) d-MMRWSRKMPCVS (ID number: 37, JM#35) d-LMRWSRKMPCVS (Identification ID number: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) ILRWSRK(Dec)LPCVS(Identification ID number: 106, JM#215) d-LLRWSRK(Myr)-NH2 (Identification ID number: 158, JM#261) ILRWSRK(Glu-Myr)-NH2 (Identification ID number: 160, JM#263) -Group 10 consists of: ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) ILRWSRK(Glu-Lau)LPCVS(Identification ID number: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 133, JM#238) ILRWSRK(Ste)-NH2 (ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (ID number: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) -Group 11 consists of: ILRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 109, JM#218) ILRW(dC)RKPC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 111, JM#219) IPRW(dC)RKC-NH2, the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 113, JM#220) ILRWSRKLPCVS, where the lysine at position 7 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 115, JM#221) ILRWSKKLPCVS, where the lysine at position 6 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 116, JM#222) IPRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 122, JM#231) ILRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 124, JM#232) IPRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 126, JM#233) ILRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 128, JM#234) IMRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 153, JM#258) IPRW(dC)RKCP-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 155, JM#259) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol on the preceding amino acid, Ac indicates substitution of an amino group with an acetyl group, Lau indicates lauric acid on the preceding amino acid, Glu-Lau indicates lauric acid on the preceding amino acid with a glutamic acid linker Glu-Ole indicates lauric acid on the preceding amino acid, Glu-Ole indicates oleic acid on the preceding amino acid with a glutamic acid linker, C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid with a glutamic acid linker, C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with an OEG-OEG-γ glutamic acid linker, OEG indicates a residue of 8-amino-3,6-dioxaoctanoic acid, Ara indicates a saturated C20 fatty acid on the preceding amino acid, and Glu-Ara indicates a saturated C20 fatty acid on the preceding amino acid with a glutamic acid linker, and The peptide is conjugated to a complexing agent.

[0056] That is, the second aspect of the present invention relates to a conjugate in which the peptide according to the present invention is bound to a complexing agent.

[0057] In a preferred embodiment, the peptide is C-terminally conjugated to the complexing agent. C-terminal conjugation of the complexing agent has been shown to have no effect on the activity of the peptide.

[0058] In a preferred embodiment, the complexing agent is a chelating agent such as dodecanetetraacetic acid (DOTA), deferoxamine, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), triazacyclononanephosphinic acid (TRAP), or tris(hydroxypyridinone) (THP).

[0059] In a preferred embodiment, the complexing agent is dodecanetetraacetic acid (DOTA) or deferoxamine. The conjugated peptide is preferably labeled with a radionuclide.

[0060] DOTA is preferably attached to the peptide via a lysine residue. If the peptide does not have an available lysine, DOTA is attached to the peptide via an additional lysine attached to the C-terminal amino acid of the peptide.

[0061] When the peptide is C-terminally linked to DOTA, and the peptide has an amino acid other than lysine as the C-terminal amino acid, DOTA is linked to the peptide via an additional lysine bonded to the C-terminal amino acid of the peptide.When the peptide has lysine as the C-terminal amino acid, DOTA is linked to the C-terminal lysine of the peptide, or DOTA is linked to the peptide via an additional lysine bonded to the C-terminal lysine of the peptide.

[0062] Alternatively, DOTA may be conjugated to the peptide via a cysteine ​​residue. The above statements regarding the conjugation of DOTA via a lysine residue apply equally to the conjugation of DOTA via a cysteine ​​residue.

[0063] Deferoxamine is preferably attached to the peptide via a cysteine ​​residue, or, if the peptide lacks a cysteine, via an additional cysteine ​​attached to the C-terminal amino acid of the peptide.

[0064] When the peptide is C-terminally linked to deferoxamine, and the peptide has an amino acid other than cysteine ​​as the C-terminal amino acid, deferoxamine is linked to the peptide via an additional cysteine ​​linked to the C-terminal amino acid of the peptide. When the peptide has cysteine ​​as the C-terminal amino acid, deferoxamine is linked to the C-terminal cysteine ​​of the peptide, or deferoxamine is linked to the peptide via an additional cysteine ​​linked to the C-terminal cysteine ​​of the peptide.

[0065] Deferoxamine may alternatively be conjugated to the peptide via a lysine residue, and the above statements regarding conjugation of deferoxamine via a cysteine ​​residue equally apply to conjugation of deferoxamine via a lysine residue.

[0066] The above discussion of the conjugation of DOTA with deferoxamine applies equally to the conjugation of peptides with other conjugating agents.

[0067] In a particularly preferred embodiment, the complexing agent is the chelating agent DOTA. In other words, the peptide is conjugated to the chelating agent DOTA, preferably at the C-terminus. DOTA (also known as tetraxetane) is an organic compound with the formula (CH2CH2NCH2CO2H)4. The molecule consists of a central 12-membered tetraaza (i.e., containing four nitrogen atoms) ring. DOTA (dodecane tetraacetic acid) is the abbreviation for this tetracarboxylic acid and its conjugate base. DOTA-bound peptides can be used to bind radionuclides (e.g., 68 Ga and 177These peptides are suitable for labeling with CXCR4 (Identification ID Number: 1). As a result, these peptides are useful for diagnostic and therapeutic approaches. The present EPI-X4 (Identification ID Number: 1) derivatives specific for CXCR4 can be used to combine diagnosis and therapy with the same molecule (radiothorax). Radiothorax using these peptides provides new imaging and treatment options for patients suffering from CXCR4-expressing malignant tumors.

[0068] Figure 5 shows the antibody competition assay (based on one representative experiment per peptide), where the percentage of bound antibody depends on the molar concentration of the indicated peptide. It demonstrates that DOTA-conjugated peptides JM#206 (ID No.: 101) (JM#21 (ID No.: 23) with DOTA) and JM#207 (ID No.: 102) (JM#122 (ID No.: 51) with DOTA) displaced antibody as efficiently as unconjugated JM#21 (ID No.: 23). Similarly, both DOTA-conjugated peptides inhibited HIV-1 infection with similar potency as the unconjugated peptide.

[0069] The present inventors further synthesized the following DOTA-conjugated peptides: peptide ID No. 165 (JM#29 (ID No. 31)) in which DOTA is conjugated via an additional lysine attached to the C-terminal amino acid of the peptide; ID No. 166 (JM#118 (ID No. 50) DOTA is conjugated via the C-terminal lysine of the peptide); ID No. 167 (JM#118 (ID No. 50) DOTA is conjugated via an additional lysine attached to the C-terminal amino acid of the peptide); ID No. 168 (JM#17 3 (ID number: 70) DOTA is attached to the peptide via the C-terminal lysine of the peptide), ID number: 169 (JM#173 (ID number: 70) DOTA is attached to the peptide via an additional lysine attached to the C-terminal amino acid of the peptide), ID number: 170 (JM#235 (ID number: 130) in which DOTA is attached to the peptide via the C-terminal lysine of the peptide), ID number: 171 (JM#235 (ID number: 130) in which DOTA is attached to the peptide via an additional lysine attached to the C-terminal amino acid of the peptide).

[0070] DOTA-binding peptide 177 Lu or 68 It was radiolabeled with Ga (see Examples, Figures 14-16, further below).

[0071] In another particularly preferred embodiment, the complexing agent is the chelating agent deferoxamine. In other words, the peptide is conjugated to the chelating agent deferoxamine, and the peptide is preferably conjugated to deferoxamine at the C-terminus. Deferoxamine is also called desferrioxamine. The deferoxamine-bound peptide can be used to bind radionuclides, e.g. 68 Ga, 177 Lu and 89These peptides are suitable for labeling with Zr. As a result, these peptides are useful for diagnostic and therapeutic applications. The present inventors confirmed the suitability of radiolabeled deferoxamine-conjugated peptides as tumor imaging probes and as probes for peptide distribution analysis, for example, in mouse models. For this purpose, the present inventors synthesized the following deferoxamine-conjugated peptides: C-deferoxamine-conjugated JM#122 (ID No.: 51), C-deferoxamine-conjugated JM#194 (ID No.: 91), C-deferoxamine-conjugated peptide with ID No.: 163, and C-deferoxamine-conjugated peptide with ID No.: 164, where C indicates an additional cysteine ​​attached to the C-terminal amino acid of the peptide, and deferoxamine was conjugated to the peptide via this additional cysteine ​​as (succinimidopropionyldesferoxamine) acetate. The deferoxamine-conjugated peptides were synthesized as follows: 89 It was radiolabeled with Zr.

[0072] As an example, 89 The biodistribution of Zr-radiolabeled C-deferoxamine conjugate JM#122 (ID number: 51) in mice was analyzed. To do so, the labeled conjugate was injected intravenously into the tail vein of immunodeficient mice, and then positron emission tomography (PET) was used to localize and quantify the radioactivity in the body. The results showed that the peptide was absorbed by the kidney within 5 minutes of injection and subsequently released into the bladder.

[0073] Peptide JM#122 (ID No.: 51) was derived from JM#21 (ID No.: 23) by replacing the cysteine ​​at position 10 with serine. Peptide ID No.: 163 was derived from JM#143 (ID No.: 54) by replacing the cysteine ​​at position 10 with serine. Peptide ID No.: 164 was derived from JM#198 (ID No.: 95) by replacing the cysteine ​​at position 10 with serine. The replacement of cysteine ​​with serine facilitated the attachment of deferoxamine to the additional cysteine ​​attached to the C-terminal amino acid of the peptide. Because peptide JM#194 (ID No.: 91) does not have a cysteine, no amino acid substitutions were made prior to attachment of deferoxamine to this peptide.

[0074] A third aspect of the present invention relates to a peptide consisting of the following amino acid sequence, which is selected from any one of Groups 1 to 11: - Group 7 consists of: d-ILRWSRK-NH2 (Identification ID number: 70, JM#173) Md-LRWSRKLPCVS (Identification ID number: 45, JM#43) Md-LRWSRKMPCVS (Identification ID number: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS(Identification ID number: 54, JM#143) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (Identification ID number: 56, JM#145) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) ILRWSRK(Glu-Ste)LPCVS (Identification ID: 95, JM#198) ILRWSRK (Glu-Lau) LPCVS (Identification ID: 104, JM#213) ILRWSRK (Glu-Ole) LPCVS (Identification ID: 108, JM#217) ILRWSRK(C16diacid)LPCVS (Identification ID: 117, JM#226) ILRWSRK (Glu-C16diacid) LPCVS (Identification ID: 118, JM#227) ILRWSRK(C18diacid)LPCVS (Identification ID: 119, JM#228) ILRWSRK (Glu-C18diacid) LPCVS (Identification ID: 120, JM#229) ILRWSRK(OEG-OEG-γGlu-C18diacid) LPCVS (Identification ID: 121, JM#230) d-LLRWSRK(Glu-Pal)-NH2 (Identification ID: 130, JM#235) d-LLRWSRK(Pal)-NH2 (Identification ID: 131, JM#236) d-ILRWSRK(Pal)-NH2 (Identification ID: 132, JM#237) d-ILRWSRK(Glu-Pal)-NH2 (Identification ID: 133, JM#238) ILRWSRK(C16diacid)-NH2 (Identification ID: 139, JM#244) ILRWSRK(C18diacid)-NH2 (Identification ID: 140, JM#245) ILRWSRK(Glu-C16diacid)-NH2 (Identification ID: 141, JM#246) ILRWSRK(Glu-C18diacid)-NH2 (Identification ID: 142, JM#247) d-LLRWSRK(C16diacid)-NH2 (Identification ID: 143, JM#248) d-LLRWSRK(C18diacid)-NH2 (ID number: 144, JM#249) d-LLRWSRK(Glu-C16diacid)-NH2(Identification ID number: 145, JM#250) d-LLRWSRK(Glu-C18diacid)-NH2(Identification ID number: 146, JM#251) ILRWSRK(Ara)LPCVS(ID number: 147, JM#252) ILRWSRK(Glu-Ara)LPCVS(Identification ID number: 148, JM#253) ILRWSRK(Ste)-NH2 (ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (ID number: 150, JM#255) d-LLRWSRK(Ste)-NH2 (ID number: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) ILRWSRK(Myr)-NH2 (Identification ID number: 159, JM#262) LVRYTKK(Glu-Pal)-NH2(Identification ID number: 161, JM#264) d-LVRYTKK(Glu-Pal)-NH2(Identification ID number: 162, JM#265) ILRWSRK(Pal-Glu)LPSVS(Identification ID number: 163) -Group 1 consists of: ILRWSRKMPCLS (ID number: 20, JM#18) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) ILRWSRK(Glu-Ste)-NH2 (ID number: 150, JM#255) -Group 2 consists of: ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRK(Ole)LPCVS(Identification ID number:80, JM#183) ILRWSRK(Glu-Lau)LPCVS(Identification ID number: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 133, JM#238) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (Identification ID number: 53, JM#141) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) IVRWSKK(Pal)VPCVS(Identification ID number: 66, JM#169) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS(Identification ID number: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS(Identification ID number: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (ID number: 100, JM#205) ILRWSRK(Myr)LPCVS(Identification ID number: 107, JM#216) ILRWSRK(Ste)-NH2 (ID number: 149, JM#254) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) ILRWSRK(Glu-Myr)-NH2 (Identification ID number: 160, JM#263) -Group 4 consists of: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (ID number: 36, JM#34) MLRWSRKLPCVS (ID number: 41, JM#39) ILRWSRKLPSVS (ID number: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (ID number: 97, JM#200) ILRWSRK(Lau)LPCVS(Identification ID number: 105, JM#214) d-LLRWSRK(Ste)-NH2 (ID number: 151, JM#256) ILRWSRK(Myr)-NH2 (Identification ID number: 159, JM#262) -Group 5 consists of: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (ID number: 5, JM#3) IVRWSHKVPCVS (Identification ID: 6, JM#4) IVRWSKKLPCVS (ID number: 7, JM#5) IVRWSKKIPCVS (ID number: 8, JM#6) IVRWSKKFPCVS (Identification ID: 9, JM#7) ILRWSHKVPCVS (Identification ID: 11, JM#9) IFRWSHKVPCVS (Identification ID: 13, JM#11) IVRWSKKMPCVS (Identification ID: 14, JM#12) IVRWSKKVPCd-VS (ID number: 16, JM#14) ILRWSRKVPCd-VS (ID number: 17, JM#15) IIRWSRKMPCVS (Identification ID: 18, JM#16) ILRWSRKVPSVS (Identification ID: 25, JM#23) ILRWSRKMPSVS (Identification ID: 26, JM#24) Ac-SLRWSRKMPCVS (ID number: 27, JM#25) d-Ac-SLRWSRKMPCVS (Identification ID: 28, JM#26) d-MLRWSRKMPCVS (Identification ID: 30, JM#28) d-LLRWSRKMPCVS (Identification ID: 31, JM#29) d-FLRWSRKMPCVS (Identification ID: 32, JM#30) GLRWSRKMPCVS (ID number: 33, JM#31) Ac-SMRWSRKMPCVS (Identification ID: 34, JM#32) d-Ac-SMRWSRKMPCVS (Identification ID: 35, JM#33) d-MMRWSRKMPCVS (Identification ID: 37, JM#35) d-LMRWSRKMPCVS (Identification ID: 38, JM#36) d-FMRWSRKMPCVS (Identification ID: 39, JM#37) d-GMRWSRKMPCVS (Identification ID: 40, JM#38) d-MLRWSRKLPCVS (ID number: 42, JM#40) Id-LRWSRKLPCVS (Identification ID: 43, JM#41) Id-LRWSRKMPCVS (Identification ID: 44, JM#42) Md-LRWSRKLPCVS (ID number: 45, JM#43) Md-LRWSRKMPCVS (ID number: 46, JM#44) IVRWSKKVP-NH2 (ID number: 47, JM#106) IVRWSKK-NH2 (ID number: 48, JM#110) ILRWSRKLP-NH2 (ID number: 49, JM#114) ILRWSRK-NH2 (ID number: 50, JM#118) ILRWSRK (Glu-Pal) LPCVS (ID number: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (Identification ID: 56, JM#145) IYRWSRKMPCLS (ID number: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (Identification ID: 58, JM#148) IVRWSKKVPSVS (Identification ID: 60, JM#151) IVRWSK(Pal)K-NH2 (ID Number: 61, JM#164) IVRWSKK(Pal)-NH2 (Identification ID: 62, JM#165) IVRWSK(Pal)KVPCVS (Identification ID: 65, JM#168) d-ILRWSRK-NH2 (ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (Identification ID: 72, JM#175) d-LMRWSRK(Pal)MPCVS (Identification ID: 73, JM#176) Md-LRWSRK(Pal)LPCVS (Identification ID: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (Identification ID: 76, JM#179) Md-LRWSRK(Pal)-NH2 (Identification ID: 78, JM#181) ILRWSRK(Ste)LPCVS (Identification ID: 79, JM#182) ILRWSRK(Chl)LPCVS (Identification ID: 81, JM#184) Ac-ILRWSRKLPCVS (ID number: 82, JM#185) d-Ac-ILRWSRKLPCVS (Identification ID: 83, JM#186) Ac-MLRWSRKLPCVS (Identification ID: 84, JM#187) d-Ac-MLRWSRKLPCVS (Identification ID: 85, JM#188) VLRWSRKLPCVS (ID number: 86, JM#189) d-VLRWSRKLPCVS (ID number: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (Identification ID: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (ID Number: 99, JM#204) ILRWSRK(Dec)LPCVS (Identification ID: 106, JM#215) d-LLRWSRK(Pal)-NH2 (Identification ID: 131, JM#236) d-ILRWSRK(Pal)-NH2 (Identification ID: 132, JM#237) d-LLRWSRK(Myr)-NH2 (Identification ID: 158, JM#261) ILRWSRK(Pal-Glu)LPSVS(Identification ID number: 163) ILRWSRK(Glu-Ste)LPSVS (ID number: 164) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) ILRWSRK(Glu-Ste)LPSVS (ID number: 164) -Group 8 consists of: d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-Ac-SMRWSRKMPCVS (Identification ID number: 35, JM#33) d-MMRWSRKMPCVS (ID number: 37, JM#35) d-LMRWSRKMPCVS (Identification ID number: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) ILRWSRK(Dec)LPCVS(Identification ID number: 106, JM#215) d-LLRWSRK(Myr)-NH2 (Identification ID number: 158, JM#261) ILRWSRK(Glu-Myr)-NH2 (Identification ID number: 160, JM#263) -Group 10 consists of: ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, #194) ILRWSRK(Glu-Lau)LPCVS(Identification ID number: 104, JM#213) d-LLRWSRK(Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 133, JM#238) ILRWSRK(Ste)-NH2 (ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (ID number: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) -Group 11 consists of: ILRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 109, JM#218) ILRW(dC)RKPC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 111, JM#219) IPRW(dC)RKC-NH2, the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 113, JM#220) ILRWSRKLPCVS, where the lysine at position 7 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 115, JM#221) ILRWSKKLPCVS, where the lysine at position 6 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 116, JM#222) IPRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 122, JM#231) ILRW(dC)RKP, in which the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 124, JM#232) IPRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 126, JM#233) ILRW(dS)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 128, JM#234) IMRWCRKPC-NH2, where the 5th cysteine ​​is linked to the 9th cysteine ​​via a disulfide bond to form a cyclic peptide (SEQ ID NO: 153, JM#258) IPRW(dC)RKCP-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 155, JM#259) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol on the preceding amino acid, Ac indicates substitution of an amino group with an acetyl group, Lau indicates lauric acid on the preceding amino acid, Glu-Lau indicates lauric acid on the preceding amino acid with a glutamic acid linker Glu-Ole indicates lauric acid on the preceding amino acid, Glu-Ole indicates oleic acid on the preceding amino acid with a glutamic acid linker, C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid with a glutamic acid linker, C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with an OEG-OEG-γ glutamic acid linker, OEG indicates a residue of 8-amino-3,6-dioxaoctanoic acid, Ara indicates a saturated C20 fatty acid on the preceding amino acid, and Glu-Ara indicates a saturated C20 fatty acid on the preceding amino acid with a glutamic acid linker, and The peptide is conjugated to a polymer.

[0075] That is, the third aspect of the present invention relates to a conjugate in which the peptide according to the present invention is bound to a polymer.

[0076] The polymer is preferably attached to the peptide via a cysteine ​​residue, or if the peptide does not have a cysteine, via an additional cysteine ​​attached to the C-terminal amino acid of the peptide.

[0077] The polymer is preferably bound to the peptide at its C-terminus. If the peptide has an amino acid other than cysteine ​​as its C-terminal amino acid, the polymer is bound to the peptide via an additional cysteine ​​bonded to the C-terminal amino acid of the peptide. If the peptide has cysteine ​​as its C-terminal amino acid, the polymer is bound to the C-terminal cysteine ​​of the peptide, or the polymer is bound to the peptide via an additional cysteine ​​bonded to the C-terminal cysteine ​​of the peptide.

[0078] The polymer may alternatively be attached to the peptide via a lysine residue, and the statements above regarding attachment of the polymer via a cysteine ​​residue apply equally to attachment of the polymer via a lysine residue.

[0079] Polymer-conjugated peptides have been shown to have a relatively high stability in human plasma and a long bioavailability period. Polymers alter the physical and chemical properties of the conjugated peptides, such as hydrophilicity and size, and thus inhibit renal excretion of the peptides. Furthermore, the conjugated polymers encapsulate the peptides, advantageously protecting them from degradation by proteases and antibody activity. The activity of peptides is enhanced by the coupling polymer.

[0080] In a preferred embodiment, the polymer-bound peptide is conjugated to an additional peptide. Dimerization of the polymer-bound peptide further enhances its activity.

[0081] A preferred polymer is polyethylene glycol (PEG), in other words, the peptide is preferably conjugated to PEG.

[0082] A more preferred polymer is poly(vinyl alcohol) (PVA). In other words, the peptide is preferably conjugated to poly(vinyl alcohol). PVA is an alternative to PEG when patients develop anti-PEG antibodies.

[0083] Also preferred is poly(vinylpyrrolidone) (PVP). In other words, the peptide is preferably conjugated to poly(vinylpyrrolidone). PVA provides a further alternative to PEG in cases where patients develop anti-PEG antibodies.

[0084] The coupling polymer has an appropriate molecular weight, e.g., 5-20 kDa. Other molecular weights are possible depending on the application. The 20 kDa variant was found to be more active than the 5 kDa variant in inhibiting HIV-1 infection, while the two variants showed comparable activity in antibody competition.

[0085] In a preferred embodiment, the conjugated polymer can be attached to two copies of the same monomeric peptide. Coupling of different monomeric peptides is also possible. The peptide copies are preferably attached to one end of the polymer. It is also possible for the peptide copies to be attached to different ends of the polymer (telechelic peptide conjugates). A polymer with a peptide copy at one end (SC066) has been shown to have higher activity than a polymer with peptide copies attached to different ends of the polymer (SC029).

[0086] In other words, the polymer of the polymer-binding peptide is preferably bound to a further peptide, which is preferably a copy of the peptide of the present invention. The two peptides are preferably bound at one end of the polymer.

[0087] The effects of polymer-conjugated variants are shown in Figures 6 and 7. The polymer was coupled to peptide JM#21 (ID number: 23). PEG-conjugated peptides SC024 (average molecular weight 20 kDa), SC033 (average molecular weight 5 kDa), SC029 (average molecular weight 20 kDa), and SC066 (average molecular weight 20 kDa) exhibited putative activity by blocking HIV-1 infection, comparable to the state-of-the-art CXCR4 antagonists AMD3100 and JM#21 (ID number: 23) (Figure 6A). Similarly, antibody competition assays showed that the PEG-conjugated derivatives bound to CXCR4 with similar affinity to JM#21 (ID number: 23) and AMD3100 (Figure 7A). A polymer with two peptide copies at one end (SC066) exhibited higher activity than a polymer with peptide copies attached to different ends of the polymer (SC029). In the antibody competition assay, derivative SC066 (two peptide copies at one end of the PEG) showed even higher activity than JM#21 (ID number: 23) and AMD3100. For each peptide and assay, three independent experiments (Figure 6) or two independent experiments (Figure 7) were performed. Error bars indicate standard deviation.

[0088] The activity of the PVP-conjugated peptides SC037 (average molecular weight 20 kDa) and SC060 (two peptides at one end, average molecular weight 20 kDa) and the PVA-conjugated peptides SC042 (average molecular weight 20 kDa) and SC061 (two peptides at one end, average molecular weight 20 kDa) is shown in Figures 8B and 9B. All derivatives had activity comparable to that of JM#21 (identification ID number: 23) and AMD3100, and derivatives SC060 and SC061, which have two copies of the peptide at one end of the PVP and PVA, respectively, showed even higher activity. Three independent experiments were performed for each peptide. Error bars indicate standard deviation.

[0089] In a further preferred embodiment, the PEG-linked peptide is conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). DSPE is a phospholipid that has been shown to increase the relative stability and bioavailability of peptides in human plasma. Because DSPE is conjugated to the peptide via PEG, it has the formula 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]. It is also preferred that DSPE be conjugated (via PEG) to an additional peptide. The additional peptide is preferably a copy of the peptide of the present invention. The two peptides are preferably conjugated at one end of the PEG.

[0090] In Figure 8, the DSPE-conjugated derivatives SC001 (one peptide copy) and SC069 (two peptide copies at one end) were found to have higher activity than cholesterol-conjugated derivatives SC043, JM#21 (ID No.: 23), EPI-X4 (ID No.: 1), WSC02 (ID No.: 2), AMD3100, and albumin fragment Alb409-423, as shown in the HIV inhibition assay (Figure 8A) and antibody competition assay (Figure 8B). The derivative with two peptide copies at one end (SC069) was shown to have higher activity than the derivative with one peptide copy (SC001).

[0091] Regarding the relative stability of the modified peptides in human plasma, we found that cholesterol-conjugated SC043 had the highest stability (relative activity measured after 8 hours of plasma incubation was 100%), followed by PEG-conjugated peptide SC033 (average molecular weight 5 kDa) (relative activity measured after 2 hours of plasma incubation was 87%), PEG-conjugated peptide SC029 (average molecular weight 20 kDa) and SC024 (average molecular weight 20 kDa).

[0092] In SC043, cholesterol is coupled via PEG (average molecular weight 5 kDa) to the cysteine ​​at position 10 of peptide JM#21 (identification ID number: 23). Thus, in a preferred embodiment, the PEG-linked peptide of the present invention is conjugated to cholesterol, and cholesterol is conjugated to the peptide via PEG.

[0093] Polymers were also coupled to peptides JM#29 (ID No.: 31), JM#118 (ID No.: 50), and JM#173 (ID No.: 70). In the case of JM#29 (ID No.: 31), the polymer was attached to the cysteine ​​at position 10 of the peptide. In the cases of JM#118 (ID No.: 50) and JM#173 (ID No.: 70), an additional cysteine ​​was attached to the C-terminal amino acid of the peptide, and the polymer was attached to the peptide via this additional cysteine. The synthesis of the polymer-conjugated peptides was carried out in a manner similar to that of the polymer-conjugated derivative of peptide JM#21 (ID No.: 23). We predict that polymer-conjugated derivatives of peptides JM#29 (ID No.: 31), JM#118 (ID No.: 50), and JM#173 (ID No.: 70) will exhibit activity similar to that observed in the polymer-conjugated derivative of peptide JM#21 (ID No.: 23) (Figures 6-8). Polymer-conjugated derivatives of peptides JM#29 (ID No.: 31), JM#118 (ID No.: 50), and JM#173 (ID No.: 70) have been confirmed to be highly stable in human plasma.

[0094] The DSPE-PEG-conjugated peptides can be used to formulate drug nanocarriers and penetration enhancers. In this case, the peptide portion of the modified peptide appears on the outside of the nanocarrier, and the DSPE portion of the modified peptide appears on the inside of the nanocarrier (micelle formation). The drug may be, for example, an anticancer drug, such as a chemotherapeutic agent like doxorubicin. The nanocarrier is suitable for improving targeting of the drug to the target site. The penetration enhancer is preferably an intestinal permeation enhancer that facilitates oral delivery of macromolecules, such as the DSPE-PEG-conjugated peptides of the present invention. The penetration enhancer may be, for example, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC).

[0095] In a preferred embodiment, the polymer-binding peptide is bound to a chelator. The chelator is preferably bound to the peptide via a lysine residue. The above description regarding the binding of a polymer to a peptide via a lysine residue also applies to the binding of a chelator to a peptide. The resulting conjugate is preferably labeled with a radionuclide via a chelator. This also applies to polymer-binding peptides in which the polymer of the polymer-binding peptide is bound to an additional peptide, as described above. That is, the polymer-binding peptide may be bound to an additional peptide via a polymer, which in turn may be bound to a chelator, in which case the additional peptide is preferably a copy of the peptide of the present invention. The polymer is preferably PEG.

[0096] The chelating agent may also be attached to the polymer-binding peptide via a polymer, for example, in a manner equivalent to attaching a further peptide to the polymer-binding peptide.

[0097] Suitable chelating agents include, for example, dodecanetetraacetic acid (DOTA), deferoxamine, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), triazacyclononanephosphinic acid (TRAP), or tris(hydroxypyridinone) (THP).

[0098] A fourth aspect of the present invention relates to a peptide comprising two identical monomeric peptides according to the present invention, wherein the monomeric peptides are linked to each other via a cysteine ​​bridge formed between the monomeric peptides to form a dimeric peptide. Although dimeric peptides comprising two different monomeric peptides are possible, dimeric peptides comprising two identical monomeric peptides are more effective. The dimeric peptide exhibits increased activity compared to twice the amount of each of the monomeric peptides (both versions have already been disclosed in EP 3007717).

[0099] In a preferred embodiment, the dimeric peptide is conjugated to a complexing agent, such as the chelating agent DOTA. The complexing agent is preferably conjugated to the dimeric peptide via a lysine residue. The above description regarding the conjugation of a polymer to a peptide via a lysine residue also applies to the conjugation of a chelating agent to a dimeric peptide. The above description regarding the peptide conjugated to a complexing agent also applies to the dimeric peptide conjugated to a complexing agent.

[0100] In a preferred embodiment, the dimeric peptide is conjugated to a polymer. The above statements regarding polymer-conjugated peptides apply equally to polymer-conjugated dimeric peptides.

[0101] A fifth aspect of the present invention relates to a pharmaceutical composition comprising a peptide of the present invention together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticles, cryoprotectant, excipient, and / or diluent. The pharmaceutical composition may further comprise binders, disintegrants, lubricants, colorants, sweeteners, flavoring agents, preservatives, and / or the like. The components are selected for use in a particular application. For example, mesoporous nanoparticles are advantageous for sustained release of peptides. Packaging the peptide in mesoporous nanoparticles, such as mesoporous silica nanoparticles, improves the bioavailability of the peptide in vivo.

[0102] Peptides may be packaged in lipid delivery systems such as self-emulsifying drug delivery systems (SEDDS). Peptides have ideal properties for lipid delivery systems because they are very small and either positively charged or already lipophilic, which lends itself to packaging.

[0103] The peptides of the invention may be formulated with a penetration enhancer, preferably an intestinal penetration enhancer, to facilitate oral delivery of the peptides of the invention. The penetration enhancer may be, for example, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC).

[0104] The fatty acid-binding peptide derivatives of the present invention can be formulated with free fatty acids to provide nanocarriers (micelle formation). These nanocarriers can then be loaded with, for example, drugs and penetration enhancers. The drugs can be, for example, anticancer drugs, such as chemotherapeutic agents, such as doxorubicin. The nanocarriers are suitable for improving the targeting of drugs to target sites. The penetration enhancer can be, for example, SNAC.

[0105] A sixth aspect of the present invention relates to a peptide of the present invention or a pharmaceutical composition of the present invention for use in medicine.

[0106] A seventh aspect of the present invention relates to the use of a peptide of the present invention or a pharmaceutical composition of the present invention for the preparation of a formulation for oral, inhaled, intravenous, topical, intranasal, intraperitoneal, subcutaneous and / or any other injectable form. The pharmaceutical composition can be administered, for example, in the form of a liquid formulation, including solutions, suspensions and emulsions, as well as in the form of pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations and powders.

[0107] In a preferred embodiment, the pharmaceutical composition is prepared as a lyophilized formulation in a buffered solution.

[0108] In a preferred embodiment, the pharmaceutical composition is prepared as a formulation for oral administration, in which case the peptide may be formulated with a penetration enhancer, as described above.

[0109] An eighth aspect of the present invention relates to a peptide of the present invention or a pharmaceutical composition of the present invention for use in the treatment of disorders of hematopoiesis, in particular for supporting stem cell mobilization, proliferation and migration; a peptide of the present invention or a pharmaceutical composition of the present invention for use in the treatment of wounds, in particular wounds caused by burns; viral diseases, in particular infections caused by HIV-1, HIV-2, SARS-CoV-2, cytomegalovirus, herpes simplex virus (types 1 and 2), varicella-zoster virus, hepatitis A and B virus, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, Rous sarcoma virus, Epstein-Bar virus; in the treatment of infections caused by bacteria and fungi, in particular Pseudomonas, Candida, S. aerus, treatment of infectious processes, treatment of abnormal infectious processes; treatment of inflammation (in particular periodontal disease); treatment of growth disorders, diseases of the nervous system, disorders of the blood coagulation cascade and hematopoiesis, vascular diseases, diseases of the immune system, wound and bone healing. improvement of inflammatory bowel disease, use in the treatment of nervous system diseases, in particular stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, treatment in the treatment of warts, hypogammaglobulinemia, immunodeficiency, myelodysplastic syndrome (WHIM-syndrome) and rheumatoid arthritis, treatment of cancer, in particular cancers that exhibit the CXCR4 receptor, preferably liver, pancreatic, prostate, breast or other solid cancers, treatment of stem cell mobilization, proliferation and migration defects, activation of T cells and support of immunoblasts, preferably cytotoxic T lymphocytes bearing programmed death receptor 1 (CTL / PD-1), anti-fibrotic treatment, treatment or prevention of scars, treatment of heart diseases, in particular heart failure; treatment of metabolic disorders, in particular diabetes, treatment of lung diseases, in particular pulmonary fibrosis, bronchitis, chronic obstructive pulmonary disease (COPD).

[0110] Experimental data support the efficacy of the claimed peptide derivatives against the above-mentioned diseases. In the example of JM#21 (ID No.: 23), this peptide was shown to antagonize the in vitro and in vivo growth and migration of acute myeloid leukemia (AML) cells, primary patient material, and Waldenström's macroglobulinemia (WM) cells harboring different WHIM-like CXCR4 mutations. This was accompanied by essential changes that suppressed oncogenic MAP kinase signaling in AML and WM cells. Regarding AML cells, JM#21 (ID No.: 23) was shown to efficiently block the CXCR4 12G5 epitope in a dose-dependent manner, inhibit AML cell migration along a CXCL12 gradient, reduce CXCL12-induced ERK phosphorylation in AML cells, and reduce the engraftment potential of CXCR4 AML primary patient samples in NSG mice, but had no inhibitory effect on the engraftment potential of CD34+ normal cells. In the context of WM cells, JM#21 (identification ID number: 23) was shown to dose-dependently block the CXCR4 12G5 epitope in WM cells with and without different CXCR4 mutations, impair migration along a CXCL12 gradient in WM cells with or without the S338X mutation, and dose-dependently reduce CXCL12-induced ERK phosphorylation in CXCR4-mutated WM cells.

[0111] A ninth aspect of the present invention relates to a peptide of the present invention or a pharmaceutical composition of the present invention for use in the prevention and / or treatment of cancer, viral diseases, metabolic disorders, nervous system disorders, immune system disorders, or disorders of the blood coagulation cascade and hematopoiesis in a mammal, wherein the mammal is preferably a human. The terms "prevention" and "treatment" include the step of administering to the mammal a pharmaceutically effective amount of a peptide of the present invention or a pharmaceutical composition of the present invention, or a salt or hydrate thereof, effective to treat the above conditions.

[0112] The peptides of the present invention or pharmaceutical compositions of the present invention are preferably used for the prevention and / or treatment of CXCR4-expressing cancers. The CXCR4-expressing cancers are preferably CXCR4-expressing liver cancer, pancreatic cancer, prostate cancer, or breast cancer, or other CXCR4-expressing solid tumors. Preferred CXCR4-expressing cancers are also CXCR4-expressing cancers of the hematopoietic system, such as AML, WM, and B-cell lymphoma.

[0113] The peptide of the present invention or the pharmaceutical composition of the present invention is preferably for use in the treatment of inflammation, including the treatment of inflammatory diseases such as atopic dermatitis, allergic asthma, colitis and arthritis.

[0114] The peptide of the invention or the pharmaceutical composition of the invention is preferably for use in the treatment of HIV-1 or HIV-2 infection.

[0115] The peptide of the present invention or the pharmaceutical composition of the present invention is preferably used for treating infection with SARS-CoV-2. In infection with SARS-CoV-2, CXCR4-positive cells are suggested to be involved in the progression of severe disease in the lungs.

[0116] A tenth aspect of the present invention relates to a method for preparing the peptides of the present invention by solid phase synthesis. When this is not possible, for example in the case of polymer-coupled peptides, other methods are chosen for the preparation of their derivatives. In a preferred embodiment, monomeric peptides are provided and coupled under oxidative reaction conditions that allow the SH bonds to be oxidized to obtain -SS- bonds.

[0117] The peptides of the present invention may be coupled to cholesterol. Thus, a further aspect of the present invention relates to conjugates in which the peptides of the present invention are bound to cholesterol. Cholesterol has been shown to increase the relative stability of peptides in human plasma as well as their bioavailability. Cholesterol is preferably bound to the peptide via a lysine or cysteine ​​residue. The above statements regarding the binding of polymers to peptides via cysteine ​​or lysine residues also apply to the binding of cholesterol to peptides.

[0118] When cholesterol is bound to a peptide via a cysteine ​​residue, it is bound to the peptide via a linker. The linker is selected to have an appropriate length. Preferably, the linker is PEG. The PEG is selected to have an appropriate molecular weight, for example, 5 to 20 kDa. As an example, the present inventors coupled cholesterol via PEG to the cysteine ​​residues of peptides JM#21 (ID No.: 23) and JM#29 (ID No.: 31). The present inventors also coupled cholesterol via PEG to an additional cysteine ​​attached to the C-terminal amino acid of peptides JM#118 (ID No.: 50) and JM#173 (ID No.: 70).

[0119] When cholesterol is bound to a peptide via a lysine residue, cholesterol is either bound directly to the peptide or via a linker. The linker is selected to have an appropriate length. The linker is preferably a glutamic acid linker. As an example, the present inventors synthesized and analyzed peptide JM#184 (identification ID number: 81) (JM#21 (identification ID number: 23) in which cholesterol is directly bound to the lysine at position 7 of the peptide).

[0120] The peptides of the present invention may be conjugated to saturated and / or unsaturated fatty acids. The saturated and / or unsaturated fatty acids are preferably conjugated to the peptide via a lysine residue. The above description regarding the conjugation of a polymer to a peptide via a lysine residue also applies to the conjugation of a saturated and / or unsaturated fatty acid to a peptide. The saturated and / or unsaturated fatty acid is conjugated to the peptide directly or via a linker. The linker is selected to have an appropriate length. The linker is preferably a glutamic acid linker.

[0121] The peptides of the present invention may be conjugated to a drug. Accordingly, a further aspect of the present invention relates to a conjugate in which the peptides of the present invention are conjugated to a drug. This conjugate has two active agents, namely, the peptide and the drug. The drug is preferably conjugated to the peptide via a lysine residue or a cysteine ​​residue. The above description regarding the conjugation of the polymer to the peptide via a cysteine ​​or lysine residue also applies to the conjugation of the drug to the peptide. The drug may be, for example, an anti-cancer drug, such as a chemotherapeutic agent. The peptide is suitable for improving the targeting of the anti-cancer drug to cancer. The drug may be, for example, an antibody, such as an HIV-1 antibody or a receptor-targeting antibody.

[0122] As mentioned above, the peptide of the present invention is preferably coupled to a protein. The protein to be conjugated to the peptide is, for example, an antibody or human serum albumin (HSA). Therefore, a further aspect of the present invention relates to a conjugate in which the peptide of the present invention is conjugated to a protein.

[0123] In a preferred embodiment, the peptides of the present invention are conjugated to human serum albumin. The peptides are preferably conjugated to albumin via the disulfide ribbing method. For this purpose, peptides such as JM#21 (identification ID number: 23) are preferably conjugated to albumin via an allyl linker. The allyl linker can be linked to disulfide bridges in albumin without disrupting the integrity of the protein. The only cysteine ​​in albumin, cysteine ​​34 (Cys34), is preferably protected prior to reaction to maintain accessibility to Cys34-binding drugs, such as aldoxorubicin. Albumin has a long circulating half-life and accumulates in solid tumor tissues and at sites of inflammation, which are also target sites for the peptides of the present invention. Therefore, albumin-binding peptides are highly stable in human plasma and provide a platform for targeting tumors or sites of inflammation. The therapeutic effect of albumin-binding peptides may be achieved via CXCR4. Additional therapeutic effects may be achieved via agents additionally bound to albumin (eg, via Cys34).

[0124] The peptides of the present invention may also be conjugated to a scaffold protein other than human serum albumin, such as avidin.

[0125] In a preferred embodiment, the peptide of the present invention is conjugated to an antibody.The antibody is preferably a monoclonal antibody with a plasma circulation half-life comparable to that of albumin.By using a branched linker, a heterodimer with a peptide that targets other therapeutically important receptors (such as thaumatostatin receptor, CCR2, CXCR7) can be fused to the antibody, thereby creating a bispecific antibody construct that simultaneously targets CXCR4 and other interaction partners.

[0126] In a particularly preferred embodiment, the peptides of the present invention are conjugated to broadly neutralizing HIV-1 antibodies (bNAbs), thereby creating bispecific EPI-X4-bNAb constructs suitable for HIV-1 therapy and prevention. Broadly neutralizing HIV-1 antibodies neutralize multiple HIV-1 viral strains.

[0127] In a preferred embodiment, the peptides of the present invention are conjugated to a maleimide linker. The maleimide linker is preferably conjugated to the peptide via a cysteine ​​residue. The above description regarding the attachment of a polymer to a peptide via a cysteine ​​residue also applies to the attachment of a maleimide linker to a peptide. Examples of maleimide linkers are mal-dPEG(3)-mal and mal-PEG-mal (see below). The maleimide linker can interact with Cys34 on human serum albumin. Peptides attached to maleimide linkers, such as JM#173 (Identification Number: 70), are expected to react with albumin in vivo (the peptide is attached to Cys34 on albumin via the maleimide linker), and are therefore highly stable in human plasma but not lipophilic (similar to fatty acid-linked peptide versions). As an example, we used peptides JM#21 (ID No.: 23) and JM#29 (ID No.: 31) to attach bis-1,13-(3-maleimidopropionyl)amido)-4,7,10-trioxatridecane (mal-DPEG(3)-mal) or α,ω-bismaleimide polyethylene glycol (PEG-MW 2.000 Da) (mal-PEG-mal) via the peptide cysteine. We further used peptide JM#173 (ID No.: 70) to design a conjugate, JM#173-C-mal-PEG-mal, in which the maleimide linker mal-PEG-mal is attached to an additional cysteine ​​linked to the C-terminal amino acid of JM#173 (ID No.: 70).

[0128] In a preferred embodiment, the peptides of the present invention are conjugated to human serum albumin via a maleimide linker, where the peptides of the present invention are conjugated to Cys34 on albumin via a maleimide linker, and the conjugation is performed in vitro.

[0129] Everything further described above in relation to the peptides of the invention, particularly the preferred embodiments, uses, medical applications and methods, also applies to peptides conjugated with cholesterol, unsaturated fatty acids, drugs, proteins or maleimide linkers.

[0130] The present inventors further synthesized the following peptides: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (ID number: 19, JM#17) ILRWSRKMPCMS (ID number: 22, JM#20) ILRWSRKLPCVS (ID number: 23, JM#21) ILRWSRKFPCVS (Identification ID number: 24, JM#22) ILRWSRKMPCFS (ID number: 21, JM#19)

[0131] Peptides with identification numbers s. 15, 19, 22, 23, and 24 had IC values ​​of 5 nM or less as measured in the X4-HIV-1 inhibition assay. 50 It was found that the compound has an inhibitory activity characterized by:

[0132] Peptide ID number 21 had an IC 50 It was found that the inhibitory activity was characterized by a concentration of 5 to 10 nM.

[0133] Everything that has been said in relation to the peptides of the invention, in particular the preferred embodiments, uses, medical applications and methods, also applies to the peptides with identification ID numbers 15, 19, 22, 23, 24 and 21.

[0134] The present inventors have further synthesized the following peptides, which form part of the present disclosure: d-ILRWSRKEYEK(Pal)EYE (ID number: 134, JM#239) d-ILRWSRK(Pal)EK(Pal)(ID number: 135, JM#240) ILRW(dC)RK(Pal)PC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (ID number: 136, JM#241) d-ILRW(dC)RKPC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (ID number: 137, JM#242) d-ILRW(dC)RK(Pal)PC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (ID number: 138, JM#243)

[0135] The activity of peptide ID number s. 134-138 was found to be insufficient.

[0136] Disclosed is a method for treating a CXCR4-related medical condition in a mammal, the method comprising administering a peptide of the present invention or a pharmaceutical composition of the present invention to the mammal, preferably a human. CXCR4-related pathologies include disorders of hematopoiesis, particularly stem cell recruitment, proliferation, and migration; wounds, particularly burn wounds; viral diseases, particularly infections with HIV-1, HIV-2, SARS-CoV-2, cytomegalovirus, herpes simplex virus (types 1 and 2), varicella-zoster virus, hepatitis A and B virus, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, rass sarcoma virus, and Epstein-Barr virus; bacterial and fungal infections (particularly Pseudomonas, Candida, and S. aerus), infectious processes, infections (particularly Pseudomonas, Candida, and S. aerus), infectious processes, abnormal infectious processes, inflammation, particularly periodontal disease, and growth disorders. It is used to treat nervous system diseases, disorders of the blood coagulation cascade and hematopoiesis, vascular diseases, diseases of the immune system, wound and bone healing, nervous system diseases, especially stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, warts, hypogammaglobulinemia, immunodeficiency, myelodysplastic syndrome (WHIM-syndrome), and rheumatoid arthritis, cancer, especially cancers that express the CXCR4 receptor, preferably liver, pancreas, prostate, breast, or other solid tumors; stem cell recruitment, proliferation, and migration; T cell activation; and lack of support for immunoblasts, preferably cytotoxic T lymphocytes bearing programmed death receptor 1 (CTL / PD-1). It is also used to treat fibrosis, scarring, heart disease, especially heart failure, metabolic diseases, especially diabetes, lung diseases, especially pulmonary fibrosis, bronchitis, and chronic obstructive pulmonary disease (COPD).

[0137] Also disclosed are methods for preventing and / or treating cancer, viral diseases, metabolic disorders, nervous system disorders, immune system disorders, or disorders of the blood coagulation cascade and hematopoiesis in a mammal, comprising administering a peptide of the present invention or a pharmaceutical composition of the present invention to the mammal, wherein the mammal is preferably a human. The cancer is preferably a CXCR4-expressing cancer. The CXCR4-expressing cancer is preferably CXCR4-expressing liver cancer, pancreatic cancer, prostate cancer, or breast cancer, or another CXCR4-expressing solid tumor. Preferred CXCR4-expressing cancers are also CXCR4-expressing cancers of the hematopoietic system, such as AML, WM, and B-cell lymphoma. Immune system diseases are preferably inflammatory diseases such as atopic dermatitis, allergic asthma, colitis, and arthritis. Viral diseases are preferably infections caused by HIV-1, HIV-2, or SARS-CoV-2.

[0138] Experimental Method HIV-1 Inhibition Assay. CXCR4-tropic NL4-3 virus stocks were generated by transient transfection of 293T cells with proviral DNA as described (Munch et al., 2007). The following day, the transfection mixture was removed and fresh medium containing 2.5% FCS was added. Two days after transfection, the supernatant was harvested and centrifugation was performed to remove cell debris. Aliquots were stored at -80°C. For infection of TZM-bl cells in the presence of inhibitors, 1 x 10 CXCR4-tropic NL4-3 virus was added in 70 μl DMEM containing 2.5% FCS. 5 Cells were seeded at a density of 1000 cells / ml. Compounds were diluted in PBS and added in 10 μl. After 15 minutes, cells were inoculated with 20 μl of diluted virus. Infection rates were measured 3 days later using the Gal-Screen system (Applied Biosystems).

[0139] Antibody Competition Assay. Compound-antibody binding competition was performed on SupT1 cells. To do so, cells were washed with PBS containing 1% FCS and then seeded at 50,000 cells per well in a 96-well plate. The buffer was removed, and the plate was pre-cooled to 4°C. Compounds were diluted in PBS, and antibodies (clone 12G5, APC-labeled) were diluted in PBS containing 1% FCS. Antibodies were used at concentrations close to their determined Kd. Then, 15 μl of compound was added to the cells, followed immediately by 15 μl of antibody. The plate was incubated at 4°C in the dark for 2 hours. Cells were then washed twice with PBS containing 1% FCS and fixed with 2% PFA. Antibody binding was analyzed by flow cytometry (FACS CytoFLEX; Beckman Coulter®).

[0140] Stability Assay. Whole blood was collected from healthy donors into EDTA tubes and either used directly or centrifuged at 2,500 x g for 15 minutes to obtain plasma. Plasma from six donors was pooled and stored in aliquots at -80°C. Compounds were diluted 200-fold in human plasma or whole blood to a final concentration of 20 μM. Samples at time t=0 were collected immediately and stored at -80°C. The plasma / compound or blood / compound mixture was transferred to 37°C and shaken at 350 rpm. Samples were collected at predetermined time points and stored at -80°C. To measure the functional activity of plasma / peptide samples, the mixtures were thawed and diluted with ice-cold PBS. 12G5-APC antibody competition was performed as described previously. For blood / peptide functional stability, samples were thawed and centrifuged at 14,000 rpm to remove cells and debris. The supernatant was diluted with PBS and used for the 12G5-antibody competition assay. After a 2-hour incubation, cells were washed and 50 μl of 1-step-Fix / Lyse solution (Thermo Fisher #00-5333-54) was added for 15 minutes at room temperature, after which cells were washed again and analyzed for bound antibody.

[0141] Stability assay in human S9 liver fraction. Pooled human liver S9 fractions were obtained from Thermo Fisher Scientific at a total protein concentration of 20 mg / ml. Fractions were stored in 25 μl aliquots at -80°C. For stability experiments, they were diluted with Tris buffer to a final concentration of 0.5 mg / ml. Cofactors (or buffer) were added immediately before the start of the experiment (NADPH: 1 mM, UDPGA: 0.5 mM, GSH: 2.5 mM, PAPS: 0.05 mg / ml, Sigma-Aldrich). The reaction was initiated by adding peptide or compound to a concentration of 20 μM and gently mixing at 37°C. Enzyme stability measurements were performed as described for plasma.

[0142] In vivo stability assay. 100 μl of a 700 μg / ml peptide stock solution in 0.9% NaCl was intravenously injected into the tail vein of C57BL / 6NCrl (BL6) mice. Mice were killed by cervical dislocation 4 hours after injection. Mouse plasma was obtained by cardiac puncture. Blood was diluted 19:1 with 0.16 M NaEDTA and centrifuged at 2000 × g for 20 minutes at 4°C to obtain plasma. Plasma was stored at -80°C until residual peptide activity in the plasma was measured in a 12G5 antibody competition assay. Peptide activity in plasma was compared with that of the peptide-spiked plasma sample.

[0143] ERK / AKT signaling assay. CXCL12-induced ERK and AKT phosphorylation was measured in SupT1 cells. To this end, 100,000 cells were seeded per well in 100 μl of medium supplemented with 1% FCS in a 96-well plate. Cells were incubated at 37°C for 2 hours, followed by the addition of 5 μl of compound. After 15 minutes of incubation at 37°C, cells were stimulated with 5 μl of CXCL12 diluted in PBS to a final concentration of 100 ng / ml. After an additional 2 minutes of incubation, the reaction was stopped by adding 20 μl of 10% PFA. The PFA was removed, and cells were fixed for 15 minutes at 4°C before being permeabilized with 100 μl of ice-cold methanol. After 15 min at 4°C, the methanol was removed, the cells were washed, and 30 μl of primary antibodies (phospho-p44 / 42 MAPK (Erk1) (Tyr204) / (Erk2) (D1H6G) mouse mAb #5726; phosphor-Akt (Ser473) (193H12) rabbit mAb #4058 Cell Signaling) were added for 1 h at 4°C. After removing the antibodies and washing the cells, secondary antibodies were added for 30 min. The cells were then washed and analyzed by flow cytometry.

[0144] Migration assays were performed using 96-well transwell assay plates (Corning Incorporated, Kennebunk, ME, USA) equipped with 5 μm polycarbonate filters. First, the lower chamber was filled with 235 μl of assay buffer (RPMI supplemented with 0.1% BSA) containing or not containing 100 ng / ml CXCL12 and serial dilutions of CXCR4 inhibitor compounds (in assay buffer). Next, 75 μL (0.5 × 10 cells) of Jurkat cells (in assay buffer) were added to the upper chamber, with or without compounds. After 4 hours at 37°C (5% CO), 100 μL of the lower chamber was transferred to a new 96-well plate and analyzed using the Cell-Titer-Glo® assay (Promega, Madison, WI, USA). The percentage of migrated cells was calculated as described by Balabanian et al. (2005). To obtain relative migration rates, the percentage of migrated cells was normalized to the CXCL12-only control.

[0145] Ca++ signaling For calcium measurements, 1 × 106 BCR-ABL-transfected mouse bone marrow cells were incubated with 5 μg / mL Indo-1 (Molecular Probes) and 0.5 μg / mL pluronic F-127 (Molecular Probes) in Iscove's medium supplemented with 1% FCS (Pan Biotech) for 45 min at 37°C. The cells were then washed by centrifugation, and the cell pellet was resuspended in Iscove's medium containing 1% FCS and treated with EPI-X4 derivatives (1 μM or 0.5 μM) for 10 min at room temperature. The cells were pre-warmed for 5 min at 37°C. Calcium flux was assessed by FACS analysis on a BD LSR Fortessa. After a 30-s baseline recording, CXCR4-dependent calcium signaling was determined by stimulation with 100 ng / mL mouse SDF-1a (PeproTech).

[0146] Molecular Modeling The first step in the design of enhanced EPI-X4 (Identification ID No.: 1) derivatives was to determine how the peptide binds to CXCR4. Using this knowledge, we were able to improve ligand efficiency by designing short peptides that are potentially more active than EPI-X4 (Identification ID No.: 1). Therefore, our computational approach consisted of the following steps:

[0147] Construction of a CXCR4 model based on the reported crystal structure (2.50 Å, PDB code: 3ODU), which also includes the highly flexible N-terminal region (available in the literature from NMR studies, PDB code 2K04).

[0148] b. Docking calculations and homology modeling for initial exploration of the EPI-X4 binding site in CXCR4.

[0149] c. For each binding site, we constructed a CXCR4-EPI-X4 model in explicit solvent and lipid membrane (an example is shown in Figure 11A). The model consisted of 257 POPC lipids, approximately 40,000 TIP3P water molecules, 50 mM KCl, and the CXCR4-EPI-X4 complex.

[0150] We performed atomistic molecular dynamics (MD) simulations of each model to analyze factors such as ligand flexibility, interaction interface area, solvent accessibility, and hydrogen bond interactions in different binding modes. Analysis of all these parameters revealed that D was the preferred binding motif. In D, the N-terminus of EPI-X4 is inserted into CXCR4, and the C-terminus of the peptide is exposed to the solvent (Figure 11B).

[0151] Based on the e.MD simulations, we performed an energetic analysis of the electrostatic and van der Waals contributions to the interaction energy in each binding motif, as well as the contributions of individual residues of EPI-X4 to the interaction energy (Figure 11C).

[0152] We also performed extensive coarse-grained (CG) MD simulations to investigate the self-assembly of the CXCR4-EPI-X4 complex from the unbound state using non-equilibrium dynamics. These CG simulations further confirmed that D is the most favored mode, as predicted by atomistic MD (Figure 11D).

[0153] Using information about how EPI-X4 (ID No. 1) binds to CXCR4 and the individual contribution of each residue of the peptide to binding, we designed truncated peptide derivatives with neutral C-termini that we predicted would be more efficient than EPI-X4 (ID No. 1). In this way, a set of peptides was identified and their experimental activity was evaluated.

[0154] Toxicity in Zebrafish. To test toxic effects in zebrafish, chorion-free fish embryos (24 hours post-fertilization) were exposed to compounds for 24 hours and then assayed under a stereomicroscope. Each assay was performed in duplicate with 3 x 10 embryos (in 100 μl) per concentration (total n = 60). The highest concentration of peptide solvent was used as a negative control. The pleurocidin antimicrobial peptide NRC-03 (GRRKRKWLRRIGKGVKIIGGAALDHL-NH2) (ID number: 103) was used at a concentration of 6 μM as a positive control for acute toxicity.

[0155] Polymer-bound peptide synthesis. Materials: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol) 2000 Da] (ammonium salt) (Cat. No. PG2-DSML-2k) and cholesterol-poly(ethylene glycol) maleimide 5000 Da (PG2-CSML-5k) were purchased from Nanocs Inc. (New York, USA). Methoxypoly(ethylene glycol) 20 kDa maleimide (Cat. No. PJK-231) and dimaleimidepoly(ethylene glycol) 20 kDa (Cat. No. PSB-305) were purchased from Creative PEGWorks (North Carolina, USA). All other chemicals were purchased from commercial vendors (Sigma-Aldrich, Acros, TCI). Deuterated solvents were supplied by Urisotop. Dichloromethane (CH2Cl2), acetonitrile (MeCN), tetrahydrofuran (THF), and toluene (PhMe) were obtained from an MBraun SPS-800 solvent purification system. Ultrapure water was dispensed from a MilliQ Direct 8 (Millipore) [18.2 MΩ·cm].

[0156] 1 H-NMR Spectroscopy. Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz on a Varian Mercury 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to residual solvent.

[0157] SDS-PAGE analysis was performed in an electrophoresis tank using NuPAGE® bis-tris 4-12% precast gels (Invitrogen). Samples were prepared in NuPAGE® LDS sample buffer (4x). Sample volume was typically 10 μL. NuPAGE® MOPS SDS running buffer (20x) was used as the running buffer. The applied voltage for electrophoresis was 150 V, and the electrophoresis time was 1 hour. The SDS-PAGE gel was stained with Coomassie blue stain for 30 minutes and then washed with distilled water for 1 hour.

[0158] Preparative Reversed-Phase High-Performance Liquid Chromatography (Prep RP-HPLC) 18 RP-HPLC was performed using a DiscoveryBIO Wide Pore Column (10 μm, 150 × 10 mm) with 5% acetonitrile containing 0.01% TFA as solvent A and 100% acetonitrile containing 0.01% TFA as solvent B. The solvents used were HPLC grade. The gradient used was 30–60% solvent B over 25 min. The analysis was performed with a flow rate of 2 mL / min and UV detection at 280 nm.

[0159] Azeotropic distillation of PEG compounds: Poly(ethylene glycol) (PEG) (0.05-0.1 g) was placed in a 50 mL Schlenk flask fitted with a rubber septum and a magnetic stir bar and heated. Anhydrous toluene (5 mL) was injected into the flask using a clean glass syringe and needle. The flask was gently warmed to dissolve the PEG in the toluene. The stoppered side arm of the Schlenk flask was connected to a vacuum oil pump fitted with an ice trap. The stopper on the side arm was slowly opened and a vacuum was applied, and the toluene was observed to slowly effervescent. The flask was gently rotated to avoid splashing the mixture. Any moisture that formed on the exterior of the flask was wiped off until all the solvent had been removed from the flask. The flask was left under vacuum for an additional 30 minutes at room temperature.

[0160] Reagent synthesis [ka]

[0161] Synthesis of 4-(3-(p-tolylthio)-2-(p-tolylthio)methyl)propanoyl)benzoic acid. 4-(3-(p-tolylthio)-2-((p-tolylthio)methyl)propanoyl)benzoic acid 1, Prepared as previously described 1 (1.6g, 72.7%). 1H-NMR(CDCl3): 2.38(s, 6H), 3.16-3.31(m, 4H), 3.85(q, 1H), 7.15(d, 4H), 7.18(d, 4H), 7.64(d, 2H), 8.07(d, 2H)

[0162] Synthesis of bisulfide PEG 20 kDa. Toluene-dried methoxypoly(ethylene glycol)amine (mPEG-NH2, 20,000 g / mol, 100 mg, 1 equiv, 5.1 μmol) and 4-dimethylaminopyridine (0.06 mg, 0.1 equiv, 0.5 μmol) were dissolved in anhydrous dichloromethane (3 mL) under an argon atmosphere. A mixture of 4-(3-(p-tolylthio)-2-((p-tolylthio)methyl)propanoyl)benzoic acid 1 (8.73 mg, 4 equiv, 20 μmol) and N,N'-diisopropylcarbodiimide (3.12 μL, 4 equiv, 200 μmol) in anhydrous dichloromethane (2 mL) was added dropwise to the initial PEG solution under an argon atmosphere. After this, the dichloromethane was removed from the filtrate by rotoevaporation, and the viscous crude product residue was redissolved in acetone with gentle warming. The flask was then placed in a dry ice bath to precipitate the product, which was isolated by centrifugation to dryness, resulting in the PEG bis-sulfide. 2 Obtained as a white solid product (0.101 g, 98.2%). 1 H NMR: (CDCl3, 400MHz) δ2.49(s, 6H), 3.38(s, 3H), 3.44-3.84(m, PEG+4H), 4.34CHCO(qn, 1H), 7.36, 7.69(q, 4H), 7.64, 7.81(q, 4H).

[0163] Sulfide oxidation and synthesis of bis-sulfone PEG 20kDa. Bis-sulfide PEG 20kDa 2(50 mg, 1 equiv., 2.5 μmol) and potassium peroxymonosulfate Oxone® (3.08 mg, 4 equiv., 10 μmol) were dissolved in 50% aqueous methanol (3 mL). The reaction mixture was stirred overnight at room temperature. After this time, the volatiles were removed by rotary evaporation, and purification was carried out by acetone / dry ice precipitation as previously described. The resulting solid was dried in a desiccator to obtain bis-sulfone PEG-120 as a white fluffy solid. Got 3 (24mg, 48%). 1 H-NMR (CDCl): 2.38 (s, 6H), 3.16-3.31 (m, 4H), 3.85 (q, 1H), 7.15 (d, 4H), 7.18 (d, 4H), 7.64 (d, 2H), 8.07 (d, 2H). [ka]

[0164] Synthesis of NHS-activated bis-sulfide 4. 4-(2,2-bis[(p-tolylsulfonyl)methyl]acetyl)benzoic acid was prepared under an argon atmosphere. 1 A mixture of N-hydroxysuccinimide (0.5 g, 1 equiv., 1.15 mmol), N-hydroxysuccinimide (0.139 g, 1.05 equiv., 1.21 mmol), and anhydrous dichloromethane (5 mL) was cooled in an ice bath. Next, neat 1,3-diisopropylcarbodiimide (188 μL, 1.05 equiv., 1.21 mmol) was added dropwise. After 3 h, the reaction mixture was passed through a non-absorbent cotton wool filter. The homogeneous filtrate was diluted with dichloromethane, washed twice with water, and dried over magnesium sulfate. Gravity filtration followed by removal of volatiles under vacuum afforded the desired active NHS ester. 4 is Obtained as a solid product (0.39 g, 78% yield). 1 H-NMR (CDCl3): 2.35 (s, 6H), 2.94 (s, 4), 3.16-3.25 (dd, 4H), 3.80 (q, 1H), 7.05 (d, 4H), 7.10 (d, 4H), 7.60 (d, 2H), 8.05 (d, 2H). [ka]

[0165] Synthesis of DSPE-PEG-bis-sulfide 2 kDa. Toluene-dried 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol) 2 kDa] (ammonium salt) 5 (DSPE-PEG-NH2, 2000 g / mol, 50 mg, 1 equiv, 25 μmol), NHS-activated bis-sulfide 4 (53.4 mg, 4 equiv, 100 μmol), and 4-dimethylaminopyridine (0.3 mg, 0.1 equiv, 2.5 μmol) were dissolved in anhydrous dichloromethane (5 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 48 h. After this time, dichloromethane was removed from the filtrate by rotary evaporation, and the viscous crude residue was redissolved in acetone with gentle warming. The flask was then placed in a dry ice bath to precipitate the product, which was then centrifuged and dried in vacuo to give DSPE-PEG bis-sulfide. 6 Obtained as a white solid (26.5 mg, 42.4%). 1 HNMR: (CDCl3, 400MHz) δ2.35(s, 6H), 3.39-3.84(m, PEG), 4.27(br, 1H), 7.05(d, 4H), 7.10(d, 4H), 7.60(d, 2H), 8.05(d, 2H)

[0166] Conversion to bis-sulfone DSPE-PEG 2kDa by sulfide oxidation. Bis-sulfide DSPE-PEG 2kDa 5 (26.5 mg, 1 equiv., 8.28 μmol) and potassium peroxymonosulfate Oxone® (10.2 mg, 4 equiv., 33.1 μmol) were dissolved in 50% aqueous methanol (3 mL). The reaction mixture was stirred overnight at room temperature. After this time, the volatiles were removed by rotary evaporation, and purification was carried out by acetone / dry ice precipitation as previously described. The resulting solid was dried in a desiccator to give bis-sulfone DSPEPEG as a white solid. I got a 6 (16.3 mg, 56.2%). 1H-NMR (CDCl): 2.49 (s, 6H), 3.38-3.80 (m, PEG), 4.27 (m, 2H), 7.36 (d, 4H), 7.63 (d, 2H), 7.70 (d, 4H), 7.80 (d, 2H). [ka]

[0167] Synthesis of bis-sulfide PVP 20 kDa. Amine-terminated polyvinylpyrrolidone (PVP-NH2, 23800 g / mol, 100 mg, 1 equiv, 4.2 μmol) and NHS-activated bis-sulfide (8.97 mg, 4 equiv, 16.8 μmol) were dissolved in anhydrous dimethylformamide (DMF, 2 mL) under an argon atmosphere. After stirring the reaction mixture at room temperature for 48 h, the product was precipitated in ethyl ether and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and lyophilized to yield bis-sulfide PVP as a white solid (66.5 mg, 66.5%). 1 HNMR: (CDCl3, 400MHz) 1.72 (br, 2H, PVP), 2.06 (br, 2H, PVP), ), 2.39 (br, 2H, PVP) , 3.20(br, 2H, PVP), 3.73(br, 1H, PVP), 7.04(d, 4H), 7.08(d, 4H), 7.5-7.6(br, 4H)

[0168] Generation of bis-sulfone PVP 20 kDa by sulfide oxidation. Bis-sulfide PVP 20 kDa (66.5 mg, 1 equiv., 2.74 μmol) and potassium peroxymonosulfate Oxone® (5.07 mg, 4 equiv., 11 μmol) were dissolved in 50% aqueous methanol (3 mL). The reaction mixture was stirred overnight at room temperature. After this time, volatiles were removed by rotary evaporation, and purification was achieved by DMF / ethyl ether precipitation as previously described. The resulting solid was dried in a desiccator to yield bis-sulfone PVP as a white solid (31.85 mg, 47.7%). 1HNMR: (CDCl3, 400MHz) 1.72 (br, 2H, PVP), 2.06 (br, 2H, PVP), ), 2.39 (br, 2H, PVP+6Hfrombis-sulfone), 3.20 (br, 2H, PVP+6Hfrombis-sulfone), 3.20(br, 2H, PVP), 3.73(br, 1H, PVP), 7.36(d, 4H), 7.63(d, 2H), 7.70(d, 4H), 7.81(d, 2H) [ka]

[0169] Synthesis of bis-sulfide PVA 20 kDa. Amine-terminated poly(vinyl alcohol) (PVA-NH2, 19800 g / mol, 100 mg, 1 equiv, 4.2 μmol) was dissolved in DMSO (1 mL) and heated to 60 °C until completely dissolved. The solution was cooled to room temperature, and NHS-activated bis-sulfide (8.97 mg, 4 equiv, 16.8 μmol) in DMSO (1 mL) was added under an argon atmosphere. The reaction mixture was stirred at room temperature for 48 h. After this time, the product was precipitated in heptane and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and lyophilized to yield PVA bis-sulfide as a white solid (78.2 mg, 91.7%). 1 HNMR: (DMSO-d6, 400MHz) δ1.36 (br, 2H, PVA), 3.81 (br, 1H, PVA), 7.04-7.10 (br, 8H), 7.5-7.6 (br, 4H)

[0170] Synthesis of bis-sulfone PVA 20 kDa by sulfide oxidation. Bis-sulfide PVA 20 kDa (78.2 mg, 1 equiv., 3.85 μmol) and potassium peroxymonosulfate Oxone® (4.74 mg, 4 equiv., 15.4 μmol) were dissolved in 50% aqueous methanol (3 mL). The reaction mixture was stirred overnight at room temperature. After this time, the volatiles were removed by rotary evaporation and purified by DMSO / heptane precipitation as previously described. The resulting solid was dried in a desiccator to yield bis-sulfone PVA as a white solid (54.6 mg, 69.5%). 1 HNMR: (DMSO-d6, 400MHz) δ1.36(br, 2H, PVA), 3.81(br, 1H, PVA), 7.34(d, 4H), 7.62(d, 2H), 7.70(d, 4H), 7.80(d, 2H) [ka]

[0171] Synthesis of maleimide PVP 20 kDa. Amine-terminated polyvinylpyrrolidone (PVP-NH2, 23800 g / mol, 50 mg, 1 equiv, 2.1 μmol) and maleimide-PEG2-succinimide ester (3.57 mg, 4 equiv, 0.8 μmol) were dissolved in anhydrous dimethylformamide (DMF, 2 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 48 h. After this time, the product was precipitated in ethyl ether and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and lyophilized to yield PVP maleimide as a white solid (23.6 mg, 47.2%). 1 HNMR: (CDCl3, 400MHz) 1.72 (br, 2H, PVP), 1.99 (br, 2H, PVP), ), 2.38 (br, 2H, PVP), 3.20 (br, 2H, PVP), 3.73 (br, 1H, PVP), 8.02 (s, 2H). [ka]

[0172] Synthesis of maleimide PVA 20 kDa. Amine-terminated polyvinyl alcohol (PVA-NH2, 19800 g / mol, 100 mg, 1 equiv, 5.05 μmol) was dissolved in anhydrous DMSO (2 mL) and heated to 60 °C. After complete dissolution, maleimide-PEG2-succinimidyl ester (8.59 mg, 4 equiv, 0.2 μmol) was added, and the mixture was stirred at room temperature for 48 h. After this time, the product was precipitated in heptane and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and lyophilized to yield PVA maleimide as a white solid (88.7 mg, 86.8%). 1 HNMR: (DMSO-d6, 400MHz) δ1.36 (br, 2H, PVA), 3.81 (br, 1H, PVA), 6.99 (s, 2H, maleimide), 8.0 (br, 2H, -NH)

[0173] Peptide bioconjugation General procedure for maleimide monoconjugation. Native peptide (1 mg, 1 equivalent, 0.714 μmol) was dissolved in 0.5 mL of phosphate-buffered saline, pH 7.4 (10 mM phosphate, 150 mM sodium chloride). To this peptide solution, 1 equivalent of each maleimide conjugation reagent dissolved in 0.5 mL of PBS buffer was added to achieve a final peptide concentration of 1 mg / mL. This mixture was incubated at room temperature for 4 hours. After this time, the bioconjugate was separated from the native peptide by preparative RP-HPLC or gel filtration. Collected fractions were analyzed by UV-Vis spectroscopy at 280 nm to determine the presence and conjugation of the peptide, respectively. After lyophilization, the peptide conjugate was typically obtained as a solid. [Table 1]

[0174] General procedure for maleimide diconjugation. The native peptide (10 mg, 1 equiv., 7.14 μmol) was dissolved in 5 mL of phosphate-buffered saline, pH 7.4 (10 mM phosphate, 150 mM sodium chloride). To this peptide solution, dimaleimide PEG 20 kDa (81.4 mg, 0.5 equiv., 3.57 μmol) dissolved in 5 mL of PBS buffer was added. The mixture was incubated at room temperature for 4 h. After this, the bioconjugate was separated from the native peptide by LH20 gel filtration using ACN / MQ water as the eluent. Collected fractions were analyzed by UV-Vis spectroscopy at 280 nm to determine the presence of peptide and conjugate, respectively. After lyophilization, the peptide conjugate was obtained as a solid.

[0175] General procedure for bis-sulfone conjugation: 1 equivalent of the respective bis-alkylating reagent was added to 10 equivalents of excess native peptide in 1 mL of 50 mM sodium phosphate buffer, pH 7.8, containing 20 mM EDTA. For PVA conjugation, the reagent was first dissolved in 100 μL of DMSO and heated to 60 °C to dissolve. This mixture was then incubated at room temperature for 48 hours. After this time, the bioconjugate was separated from the native peptide by gel filtration. Collected fractions were analyzed by UV-Vis spectroscopy at 280 nm to determine the presence and binding of the peptide, respectively. After lyophilization, the peptide conjugate was typically obtained as a solid. Peptide content was characterized by UV absorbance, SDS-PAGE, and / or RP-HPLC. [Table 2] [Example]

[0176] Radiolabeling of DOTA-binding peptides and evaluation of radiolabeled conjugates DOTA-conjugated peptides In this example, the following DOTA-labeled peptides were used: DOTA-K-JM#21 (ID number: 101, JM#206) (JM#21 (ID number: 23) in which DOTA was conjugated to the peptide via an additional lysine attached to the C-terminal amino acid of the peptide), DOTA-K-JM#122 (ID No.: 102, JM#207) (JM#122 (ID No.: 51) in which DOTA is attached via an additional lysine attached to the C-terminal amino acid of the peptide), DOTA-K-JM#29 (ID number: 165) (JM#29 (ID number: 31) in which DOTA is attached to the peptide via an additional lysine attached to the C-terminal amino acid of the peptide), DOTA-JM#118 (ID number: 166) (JM#118 (ID number: 50) to which DOTA was bound via the C-terminal lysine of the peptide), DOTA-K-JM#173 (Identification ID Number: 169) (JM#173 (Identification ID Number: 70) with DOTA attached to the peptide via an additional lysine attached to the C-terminal amino acid of the peptide), and DOTA-K-JM#235 (ID number: 171) (JM#235 (ID number: 130) with DOTA conjugated via an additional lysine attached to the C-terminal amino acid of the peptide).

[0177] Radiolabeling 177 Lu-labeled versions of DOTA-conjugated peptides were prepared by incubating 3 nmol of the peptide with different activity [ 177After incubation with [Lu]LuCl3 (150-450 MBq), the peptides were prepared in ammonium acetate buffer (0.4 M, pH 5.2). Cysteine-containing peptides were incubated at 75°C for 30 min, and cysteine-free peptides were incubated at 95°C for 30 min. 10% ethanol (except Penixather) was added to the reaction mixture to prevent radiolysis. DTT (10 mM) was also added to prevent dimer formation of cysteine-containing peptides. For quality control, 5 μl of this solution was added to 50 μl of Ca-DTPA solution and analyzed by RP-HPLC. After determining the radiochemical purity (>95%), the reaction mixture was diluted with 1% human serum albumin (HSA) to the desired activity concentration and used directly for evaluation.

[0178] 68 Three nmol of peptides were added to the 1000-kDa ... 68 Ga-labeled versions of DOTA-conjugated peptides were prepared in sodium acetate buffer (0.2 M, pH 4-4.5) after incubation with [Ga]GaCl3 (10-200 MBq) at 95 °C for 15 min. For quality control, 5 μl of this solution was added to 50 μl of Ca-DTPA solution and analyzed by RP-HPLC. After determining the radiochemical purity (>95%), the reaction mixture was diluted with 1% human serum albumin (HSA) to the desired activity concentration and used directly for evaluation.

[0179] stability 177 Lu / 68 The stability of Ga-labeled DOTA-conjugated peptides in ammonium acetate buffer (0.4 M, pH 5.2) and sodium acetate buffer (0.2 M, pH 4-4.5) was investigated at different time points ( 177 Lu-complex uses 0, 1, 2, 4, 24h, 68 The radiochemical purity of each radiolabeled conjugate was determined at 0, 1, and 2 h (for Ga-complex) and assessed by measuring at room temperature. For this purpose, aliquots of the labeling solution were stored at room temperature. RP-HPLC injections were performed sequentially at the desired time points.

[0180] By measuring the radiochemical purity, 177The radiolytic instability of [Lu]Lu-labeled DOTA-conjugated peptides was followed over time (Table 3). Results are the mean ± standard deviation from at least two separate experiments. The most stable at room temperature was [ 177 Lu]Lu-DOTA-JM#118 80±2%, [ 177 Lu]Lu-DOTA-K-JM#235 80±10%, [ 177 For [Lu]Lu-DOTA-K-JM#207, 78±1% of the radiolabeled conjugate remained after 24 hours. [Table 3]

[0181] lipophilic 177 Lu / 68 The hydrophilicity / lipophilicity of Ga-labeled conjugates was determined by the "shake flask" method. 10 μL of 1 pmol of Ga-labeled conjugate was added to a presaturated solution containing 500 μL of n-octanol and 500 μL of phosphate-buffered saline (PBS), pH 7.4. 177 Lu / 68 Ga-labeled conjugate was added. The solution was vortexed for 1 hour to reach equilibrium, then centrifuged (3000 rpm) for 10 minutes. 100 μl samples were removed from each phase and measured in a γ-counter. The partition coefficient was calculated as the average logarithm of the ratio of radioactivity between the organic and PBS phases (n = 3). Results are the mean ± standard deviation from at least two separate experiments. 177 As a reference molecule, Lu / , known as a CXCR4-directed endoscopic therapeutic drug, 68 Ga-labeled PentiXather was used.

[0182] Lipophilicity is an important physicochemical property of potential radiotracers, and is involved in their biodistribution, excretion, pharmacokinetics, and plasma protein binding. 177 Lu]Lu-Pentixather(log DO / PBSpH7.4 -1.53±0.08) compared to [ 177 Lu]Lu-DOTA-K-JM#122 has the lowest log DO / PBSpH7.4 Value -3.23±0.23, [177 Lu]Lu-DOTA-K-JM#235 is the most lipophilic substance (log DO / PBSpH7.4 0.29±0.10). 177 The Lu-labeled conjugate was found to be moderately lipophilic (Table 4). 68 For Ga-complexes, [ 68 Ga]Ga-Pentixather(log DO / PBSpH7.4 -2.17±0.07) is [ 68 Ga]Ga-DOTA-K-JM#173(log DO / PBSpH7.4 -2.67±0.36) was more lipophilic (Table 4). [Table 4]

[0183] Cellular uptake and distribution Ghost-CXCR4 cells (1x10) seeded in a 24-well plate 5 cells / well) 177 Lu / 68 The receptor binding and internalization rates of Ga-labeled conjugates were investigated. Radiolabeled conjugates (1 nM) were added, and cells were incubated at 37°C for different time points (15, 30, and 60 min). The incubation was interrupted by removing the medium and washing the cells twice with ice-cold PBS. Membrane-bound radiolabeled conjugates were obtained by washing the cells twice with ice-cold glycine buffer, pH 2.8, followed by collection of the internalized fraction with 1 M NaOH. Activity in each fraction was measured using a γ-counter. Nonspecific binding was measured in the presence of a 100,000-fold excess of AMD3100 (blocking agent). The results, expressed as a percentage of applied radioactivity, are shown in Figures 14 and 15, both of which show cellular uptake at 60 min.

[0184] [ 177 Lu]Lu-DOTA-K-JM#173 is all other 177 Compared with the Lu-labeled conjugate, it showed the highest overall cellular uptake (Figure 14). More specifically, 177Lu]Lu-DOTA-K-JM#173 binds primarily to the cell membrane and is more lipophilic [ 177 Lu]Lu-DOTA-K-JM#235 is primarily internalized (Figure 14). 177 Lu]Lu-DOTA-K-JM#173 is the reference molecule in this assay. 177 Lu]Lu-Pentixather was shown to be superior.

[0185] 177 Based on the results obtained above for the Lu-labeled conjugates, the best performing molecule (JM#173-K-DOTA (identification ID number: 169)) was selected and evaluated in vitro using Ga-68. 68 Ga]Ga-DOTA-K-JM#173 is [ 68 It showed higher intracellular uptake compared to Ga]Ga-Pentixather (Figure 15). 68 It was confirmed that 8.25±0.5% of Ga]Ga-DOTA-K-JM#173 bound to the cell membrane (FIG. 15), and 2.82±0.3% was encapsulated.

[0186] Next, an in vitro assay was performed using Jurkat cells (suspension) with CXCR4 expression similar to that of GHOST-CXCR4. Jurkat cells (4 x 10) were cultured in assay medium containing 5% BSA. 5 cells / sample) in the presence or absence of AMD3100 (100 μM) and 1 nM [ 177 Lu]Lu-Pentixather and [ 177 The cells were incubated with [Lu]Lu-DOTA-K-JM#173 at 37°C for different time points (15, 30, and 60 minutes). The samples were then centrifuged, the supernatant removed, and the pellet washed twice with 300 μL of cold PBS. Finally, the supernatant and pellet were counted in a gamma counter to determine total cellular uptake. This finding was not corroborated by findings obtained with GHOST-CXCR4+ cells. In this study, the compound [ 177 Lu]Lu-Pentixather and [ 177We found that both Lu]Lu-DOTA-K-JM#173 showed very similar cellular uptake in Jurkat cells (Fig. 16).

[0187] Small Animal SPECT / CT and PET / CT Imaging SPECT / CT:[ 177 Lu]Lu-Pentixather systemic distribution [ 177 Lu]Lu-DOTA-K-JM#173 and [ 177 Healthy Balb / c mice were treated with 15-20MBq (100pmol) of [Lu]Lu-DOTA-K-JM#235. 177 Lu-labeled complexes were injected via the tail vein, and SPECT / CT images were acquired 4 hours post-injection (pi). For image acquisition, mice were euthanized by CO2 inhalation 4 hours later, calibrated with appropriate dose calibrators, and scanned in a supine, cranial position using a SPECT / CT system (NanoSPECT / CT™ Bioscan Inc.) dedicated to small animal imaging. Images were reconstructed using a proprietary HiSPECT iterative reconstruction method and fused with CT images using proprietary InVivoScope (Bioscan) software.

[0188] PET / CT:[ 68 Ga]Ga-Pentixather and [ 68 PET / CT imaging was performed to measure and compare the whole-body distribution of [Ga]Ga-DOTA-K-JM#173. Healthy Balb / c mice were administered 5-6 MBq (200 pmol). 68 The Ga-labeled complex was injected via the tail vein, and PET / CT images were acquired. After 1 hour, animals were euthanized by CO2 inhalation, calibrated with appropriate dose calibrators, and imaged head-on in a supine position using a dedicated small animal imaging PET / CT system (Molecubes). Images were reconstructed using Molecubes software and fused with CT images using Vivo Quant.

[0189] 177 Lu]Lu-DOTA-K-JM#173 and [ 68To get a first impression of the in vivo properties of [Ga]Ga-DOTA-K-JM#173, we performed small animal nanoSPECT / CT and PET / CT imaging with Pentaxather as a reference. The highly lipophilic compound [ 177 Lu]Lu-DOTA-K-JM#235 was also evaluated by SPECT / CT imaging to determine its distribution pattern. 177 Lu]Lu-DOTA-K-JM#173(logD pH7.4 =-2.72±0.22) accumulates mainly in the kidney and is highly lipophilic [ 177 Lu]Lu-DOTA-K-JM#235(logD pH7.4 The reference compound Penixather (logD = 0.29 ± 0.102) was observed to accumulate predominantly in the liver, with some background activity, demonstrating distinct pharmacokinetic behavior. pH7.4 =-1.53±0.08), along with higher background activity, 177 Lu]Lu-DOTA-K-JM#235 showed similar liver uptake.

[0190] conclusion Radiolabeled DOTA-conjugated peptides were evaluated in terms of lipophilicity, stability, and cellular uptake in GHOST-CXCR4+ cells. 177 Lu]Lu-DOTA-K-JM#173 and its diagnostic counterpart[ 68 [Ga]Ga-DOTA-K-JM#173 was synthesized using other conjugates and references [ 177 Compared with [Lu]Lu-Pentixather, it showed the highest cellular uptake into GHOST-CXCR4+ cells and can therefore be said to be the most promising radiolabeled DOTA-conjugated peptide.

[0191] moreover,[ 177 Lu]Lu-DOTA-K-JM#173 and [ 68In vitro, [Ga]Ga-DOTA-K-JM#173 was not specifically taken up by any organ. However, this lack of uptake by other organs may be due to the specificity of these compounds for human CXCR4. On the other hand, the accumulation in the kidney is due to excretion in urine. 177 Renal accumulation is considered desirable, rather than hepatic accumulation as in the case of [Lu]Lu-Pentixather. Renal uptake of radioactivity can be reduced by using nephroprotectants, which reduces off-target radiotoxicity. However, hepatic absorption cannot be reduced, which is a major drawback in imaging diagnosis and treatment. From this point of view, [ 177 Lu]Lu-DOTA-K-JM#173 appears to be a suitable radiopharmaceutical.

[0192] Additionally, the following provisions are disclosed: 1. A peptide consisting of the following amino acid sequence, selected from any one of Groups 1 to 11: - Group 7 consists of: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (ID number: 19, JM#17) ILRWSRKMPCLS (ID number: 20, JM#18) ILRWSRKMPCMS (ID number: 22, JM#20) ILRWSRKLPCVS (ID number: 23, JM#21) ILRWSRKFPCVS (Identification ID number: 24, JM#22) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) -Group 2 consists of: ILRWSRKMPCFS (ID number: 21, JM#19) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRK(Ole)LPCVS(Identification ID number:80, JM#183) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (Identification ID number: 53, JM#141) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) IVRWSKK(Pal)VPCVS(Identification ID number: 66, JM#169) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS(Identification ID number: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS(Identification ID number: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (ID number: 100, JM#205) -Group 4 consists of: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (ID number: 36, JM#34) MLRWSRKLPCVS (ID number: 41, JM#39) ILRWSRKLPSVS (ID number: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (ID number: 97, JM#200) -Group 5 consists of: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (ID number: 6, JM#4) IVRWSKKLPCVS (ID number: 7, JM#5) IVRWSKKIPCVS (Identification ID number: 8, JM#6) IVRWSKKFPCVS (ID number: 9, JM#7) ILRWSHKVPCVS (Identification ID number: 11, JM#9) IFRWSHKVPCVS (Identification ID number: 13, JM#11) IVRWSKKMPCVS (Identification ID number: 14, JM#12) IVRWSKKVPCd-VS (Identification ID number: 16, JM#14) ILRWSRKVPCd-VS (Identification ID number: 17, JM#15) IIRWSRKMPCVS (ID number: 18, JM#16) ILRWSRKVPSVS (Identification ID number: 25, JM#23) ILRWSRKMPSVS (Identification ID number: 26, JM#24) Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-Ac-SLRWSRKMPCVS (Identification ID number: 28, JM#26) d-MLRWSRKMPCVS (Identification ID: 30, JM#28) d-LLRWSRKMPCVS (Identification ID: 31, JM#29) d-FLRWSRKMPCVS (Identification ID: 32, JM#30) GLRWSRKMPCVS (ID number: 33, JM#31) Ac-SMRWSRKMPCVS (Identification ID: 34, JM#32) d-Ac-SMRWSRKMPCVS (Identification ID: 35, JM#33) d-MMRWSRKMPCVS (Identification ID: 37, JM#35) d-LMRWSRKMPCVS (Identification ID: 38, JM#36) d-FMRWSRKMPCVS (Identification ID: 39, JM#37) d-GMRWSRKMPCVS (Identification ID: 40, JM#38) d-MLRWSRKLPCVS (ID number: 42, JM#40) Id-LRWSRKLPCVS (Identification ID: 43, JM#41) Id-LRWSRKMPCVS (Identification ID: 44, JM#42) Md-LRWSRKLPCVS (ID number: 45, JM#43) Md-LRWSRKMPCVS (ID number: 46, JM#44) IVRWSKKVP-NH2 (ID number: 47, JM#106) IVRWSKK-NH2 (ID number: 48, JM#110) ILRWSRKLP-NH2 (ID number: 49, JM#114) ILRWSRK-NH2 (ID number: 50, JM#118) ILRWSRK (Glu-Pal) LPCVS (ID number: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (Identification ID: 56, JM#145) IYRWSRKMPCLS (ID number: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (Identification ID: 58, JM#148) IVRWSKKVPSVS (Identification ID: 60, JM#151) IVRWSK(Pal)K-NH2 (ID Number: 61, JM#164) IVRWSKK(Pal)-NH2 (Identification ID: 62, JM#165) IVRWSK(Pal)KVPCVS (Identification ID: 65, JM#168) d-ILRWSRK-NH2 (ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (Identification ID: 72, JM#175) d-LMRWSRK(Pal)MPCVS (Identification ID: 73, JM#176) Md-LRWSRK(Pal)LPCVS (Identification ID: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (Identification ID: 76, JM#179) Md-LRWSRK(Pal)-NH2 (Identification ID: 78, JM#181) ILRWSRK(Ste)LPCVS (Identification ID: 79, JM#182) ILRWSRK(Chl)LPCVS (Identification ID: 81, JM#184) Ac-ILRWSRKLPCVS (ID number: 82, JM#185) d-Ac-ILRWSRKLPCVS (Identification ID: 83, JM#186) Ac-MLRWSRKLPCVS (Identification ID: 84, JM#187) d-Ac-MLRWSRKLPCVS (Identification ID: 85, JM#188) VLRWSRKLPCVS (ID number: 86, JM#189) d-VLRWSRKLPCVS (ID number: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (Identification ID number: 99, JM#204) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) - Group 7 consists of: Md-LRWSRKLPCVS (Identification ID number: 45, JM#43) Md-LRWSRKMPCVS (Identification ID number: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS(Identification ID number: 54, JM#143) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (Identification ID number: 56, JM#145) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) d-ILRWSRK-NH2 (Identification ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID number: 71, JM#174) -Group 8 consists of: d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-Ac-SMRWSRKMPCVS (Identification ID number: 35, JM#33) d-MMRWSRKMPCVS (ID number: 37, JM#35) d-LMRWSRKMPCVS (Identification ID number: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) -Group 10 consists of: ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol, and Ac indicates that the amino group has been replaced with an acetyl group. 2. A peptide consisting of the following amino acid sequence, selected from any one of Groups 1 to 11: - Group 7 consists of: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (ID number: 19, JM#17) ILRWSRKMPCLS (ID number: 20, JM#18) ILRWSRKMPCMS (ID number: 22, JM#20) ILRWSRKLPCVS (ID number: 23, JM#21) ILRWSRKFPCVS (Identification ID number: 24, JM#22) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) -Group 2 consists of: ILRWSRKMPCFS (ID number: 21, JM#19) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRK(Ole)LPCVS(Identification ID number:80, JM#183) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (Identification ID number: 53, JM#141) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) IVRWSKK(Pal)VPCVS(Identification ID number: 66, JM#169) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS(Identification ID number: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS(Identification ID number: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (ID number: 100, JM#205) -Group 4 consists of: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (ID number: 36, JM#34) MLRWSRKLPCVS (ID number: 41, JM#39) ILRWSRKLPSVS (ID number: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (ID number: 97, JM#200) -Group 5 consists of: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (ID number: 6, JM#4) IVRWSKKLPCVS (ID number: 7, JM#5) IVRWSKKIPCVS (Identification ID number: 8, JM#6) IVRWSKKFPCVS (ID number: 9, JM#7) ILRWSHKVPCVS (Identification ID number: 11, JM#9) IFRWSHKVPCVS (Identification ID number: 13, JM#11) IVRWSKKMPCVS (Identification ID number: 14, JM#12) IVRWSKKVPCd-VS (Identification ID number: 16, JM#14) ILRWSRKVPCd-VS (Identification ID number: 17, JM#15) IIRWSRKMPCVS (ID number: 18, JM#16) ILRWSRKVPSVS (Identification ID number: 25, JM#23) ILRWSRKMPSVS (Identification ID number: 26, JM#24) Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-Ac-SLRWSRKMPCVS (Identification ID number: 28, JM#26) d-MLRWSRKMPCVS (Identification ID: 30, JM#28) d-LLRWSRKMPCVS (Identification ID: 31, JM#29) d-FLRWSRKMPCVS (Identification ID: 32, JM#30) GLRWSRKMPCVS (ID number: 33, JM#31) Ac-SMRWSRKMPCVS (Identification ID: 34, JM#32) d-Ac-SMRWSRKMPCVS (Identification ID: 35, JM#33) d-MMRWSRKMPCVS (Identification ID: 37, JM#35) d-LMRWSRKMPCVS (Identification ID: 38, JM#36) d-FMRWSRKMPCVS (Identification ID: 39, JM#37) d-GMRWSRKMPCVS (Identification ID: 40, JM#38) d-MLRWSRKLPCVS (ID number: 42, JM#40) Id-LRWSRKLPCVS (Identification ID: 43, JM#41) Id-LRWSRKMPCVS (Identification ID: 44, JM#42) Md-LRWSRKLPCVS (ID number: 45, JM#43) Md-LRWSRKMPCVS (ID number: 46, JM#44) IVRWSKKVP-NH2 (ID number: 47, JM#106) IVRWSKK-NH2 (ID number: 48, JM#110) ILRWSRKLP-NH2 (ID number: 49, JM#114) ILRWSRK-NH2 (ID number: 50, JM#118) ILRWSRK (Glu-Pal) LPCVS (ID number: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (Identification ID: 56, JM#145) IYRWSRKMPCLS (ID number: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (Identification ID: 58, JM#148) IVRWSKKVPSVS (Identification ID: 60, JM#151) IVRWSK(Pal)K-NH2 (ID Number: 61, JM#164) IVRWSKK(Pal)-NH2 (Identification ID: 62, JM#165) IVRWSK(Pal)KVPCVS (Identification ID: 65, JM#168) d-ILRWSRK-NH2 (ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (Identification ID: 72, JM#175) d-LMRWSRK(Pal)MPCVS (Identification ID: 73, JM#176) Md-LRWSRK(Pal)LPCVS (Identification ID: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (Identification ID: 76, JM#179) Md-LRWSRK(Pal)-NH2 (Identification ID: 78, JM#181) ILRWSRK(Ste)LPCVS (Identification ID: 79, JM#182) ILRWSRK(Chl)LPCVS (Identification ID: 81, JM#184) Ac-ILRWSRKLPCVS (ID number: 82, JM#185) d-Ac-ILRWSRKLPCVS (Identification ID: 83, JM#186) Ac-MLRWSRKLPCVS (Identification ID: 84, JM#187) d-Ac-MLRWSRKLPCVS (Identification ID: 85, JM#188) VLRWSRKLPCVS (ID number: 86, JM#189) d-VLRWSRKLPCVS (ID number: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (Identification ID number: 99, JM#204) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) - Group 7 consists of: Md-LRWSRKLPCVS (Identification ID number: 45, JM#43) Md-LRWSRKMPCVS (Identification ID number: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS(Identification ID number: 54, JM#143) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (Identification ID number: 56, JM#145) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) d-ILRWSRK-NH2 (Identification ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID number: 71, JM#174) -Group 8 consists of: d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-Ac-SMRWSRKMPCVS (Identification ID number: 35, JM#33) d-MMRWSRKMPCVS (ID number: 37, JM#35) d-LMRWSRKMPCVS (Identification ID number: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) -Group 10 consists of: ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol, and Ac indicates replacement of an amino group with an acetyl group, and The peptide is C-terminally linked to a conjugation agent. 3. A peptide consisting of the following amino acid sequence, selected from any one of Groups 1 to 11: - Group 7 consists of: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (ID number: 19, JM#17) ILRWSRKMPCLS (ID number: 20, JM#18) ILRWSRKMPCMS (ID number: 22, JM#20) ILRWSRKLPCVS (ID number: 23, JM#21) ILRWSRKFPCVS (Identification ID number: 24, JM#22) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) -Group 2 consists of: ILRWSRKMPCFS (ID number: 21, JM#19) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRK(Ole)LPCVS(Identification ID number:80, JM#183) -Group 3 consists of: d-LLRWSRK(Pal)MPCVS (Identification ID number: 53, JM#141) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) IVRWSKK(Pal)VPCVS(Identification ID number: 66, JM#169) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) ILRWSRKK(Glu-Ste)LPCVS(Identification ID number: 96, JM#199) ILRWSRK(Glu-Dec)LPCVS(Identification ID number: 98, JM#203) ILRWSRK(Glu-Ste)LPCVS (ID number: 100, JM#205) -Group 4 consists of: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (ID number: 36, JM#34) MLRWSRKLPCVS (ID number: 41, JM#39) ILRWSRKLPSVS (ID number: 51, JM#122) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (ID number: 97, JM#200) -Group 5 consists of: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (ID number: 6, JM#4) IVRWSKKLPCVS (ID number: 7, JM#5) IVRWSKKIPCVS (Identification ID number: 8, JM#6) IVRWSKKFPCVS (ID number: 9, JM#7) ILRWSHKVPCVS (Identification ID number: 11, JM#9) IFRWSHKVPCVS (Identification ID number: 13, JM#11) IVRWSKKMPCVS (Identification ID number: 14, JM#12) IVRWSKKVPCd-VS (Identification ID number: 16, JM#14) ILRWSRKVPCd-VS (Identification ID number: 17, JM#15) IIRWSRKMPCVS (ID number: 18, JM#16) ILRWSRKVPSVS (Identification ID number: 25, JM#23) ILRWSRKMPSVS (Identification ID number: 26, JM#24) Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-Ac-SLRWSRKMPCVS (Identification ID: 28, JM#26) d-MLRWSRKMPCVS (Identification ID: 30, JM#28) d-LLRWSRKMPCVS (Identification ID: 31, JM#29) d-FLRWSRKMPCVS (Identification ID: 32, JM#30) GLRWSRKMPCVS (ID number: 33, JM#31) Ac-SMRWSRKMPCVS (Identification ID: 34, JM#32) d-Ac-SMRWSRKMPCVS (Identification ID: 35, JM#33) d-MMRWSRKMPCVS (Identification ID: 37, JM#35) d-LMRWSRKMPCVS (Identification ID: 38, JM#36) d-FMRWSRKMPCVS (Identification ID: 39, JM#37) d-GMRWSRKMPCVS (Identification ID: 40, JM#38) d-MLRWSRKLPCVS (ID number: 42, JM#40) Id-LRWSRKLPCVS (Identification ID: 43, JM#41) Id-LRWSRKMPCVS (Identification ID: 44, JM#42) Md-LRWSRKLPCVS (ID number: 45, JM#43) Md-LRWSRKMPCVS (ID number: 46, JM#44) IVRWSKKVP-NH2 (ID number: 47, JM#106) IVRWSKK-NH2 (ID number: 48, JM#110) ILRWSRKLP-NH2 (ID number: 49, JM#114) ILRWSRK-NH2 (ID number: 50, JM#118) ILRWSRK (Glu-Pal) LPCVS (ID number: 54, JM#143) ILRWSRKLPCK(Glu-Pal)S (Identification ID: 56, JM#145) IYRWSRKMPCLS (ID number: 57, JM#146) ILRWSRK(Glu-Pal)MPCLS (Identification ID: 58, JM#148) IVRWSKKVPSVS (Identification ID: 60, JM#151) IVRWSK(Pal)K-NH2 (ID Number: 61, JM#164) IVRWSKK(Pal)-NH2 (Identification ID: 62, JM#165) IVRWSK(Pal)KVPCVS (Identification ID: 65, JM#168) d-ILRWSRK-NH2 (ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) d-ILRWSRK(Pal)LP-NH (Identification ID: 72, JM#175) d-LMRWSRK(Pal)MPCVS (Identification ID: 73, JM#176) Md-LRWSRK(Pal)LPCVS (Identification ID: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (Identification ID: 76, JM#179) Md-LRWSRK(Pal)-NH2 (Identification ID: 78, JM#181) ILRWSRK(Ste)LPCVS (Identification ID: 79, JM#182) ILRWSRK(Chl)LPCVS (Identification ID: 81, JM#184) Ac-ILRWSRKLPCVS (ID number: 82, JM#185) d-Ac-ILRWSRKLPCVS (Identification ID: 83, JM#186) Ac-MLRWSRKLPCVS (Identification ID: 84, JM#187) d-Ac-MLRWSRKLPCVS (Identification ID: 85, JM#188) VLRWSRKLPCVS (ID number: 86, JM#189) d-VLRWSRKLPCVS (ID number: 87, JM#190) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (Identification ID number: 99, JM#204) -Group 6 consists of: d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) d-MLRWSRK(Glu-Pal)-NH2 (Identification ID number: 93, JM#19 6) d-MLRWSRKK(Glu-Pal)-NH2 (Identification ID number: 94, JM#197) ILRWSRK(Glu-Ste)LPCVS (ID number: 95, JM#198) - Group 7 consists of: Md-LRWSRKLPCVS (Identification ID number: 45, JM#43) Md-LRWSRKMPCVS (Identification ID number: 46, JM#44) ILRWSRK(Glu-Pal)LPCVS(Identification ID number: 54, JM#143) ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) ILRWSRKLPCK(Glu-Pal)S (Identification ID number: 56, JM#145) ILRWSRK(Pal)MPCLS(Identification ID number: 59, JM#149) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) d-ILRWSRK-NH2 (Identification ID number: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID number: 71, JM#174) -Group 8 consists of: d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) -Group 9 consists of: Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-Ac-SMRWSRKMPCVS (Identification ID number: 35, JM#33) d-MMRWSRKMPCVS (ID number: 37, JM#35) d-LMRWSRKMPCVS (Identification ID number: 38, JM#36) d-LLRWSRK(Glu-Pal)MPCVS(Identification ID number: 52, JM#140) d-LMRWSRK(Pal)MP-NH2 (Identification ID number: 75, JM#178) -Group 10 consists of: ILRWSRK(Pal)LPCVS(Identification ID number: 55, JM#144) IVRWSK(Pal)KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK(Pal)VP-NH2(Identification ID number:64, JM#167) ILRWSRK(Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK(Pal)LP-NH2 (Identification ID number: 68, JM#171) ILRWSRK(Pal)L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK(Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRKK(Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRK(Glu-Pal)-NH2 (Identification ID number: 89, JM#192) ILRWSRKLK(Glu-Pal)-NH2 (Identification ID number: 90, JM#193) d-LMRWSRK(Glu-Pal)-NH2 (Identification ID number: 91, JM#194) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol, and Ac indicates the replacement of an amino group with an acetyl group; The peptide is conjugated to a polymer. 4. The peptide according to 3, wherein the peptide is linked to PEG. 5. The peptide according to 4, wherein the peptide is conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine. 6. The peptide according to 3, wherein the peptide is conjugated to poly(vinyl alcohol). 7. The peptide according to 3, wherein the peptide is poly(vinylpyrrolidone). 8. A peptide consisting of two identical monomer peptides according to any one of the preceding items, wherein the monomer peptides are linked to each other via a cysteine ​​bridge formed between the monomer peptides to form a dimeric peptide. 9. A peptide or pharmaceutical composition according to any of the preceding paragraphs for use in medicine. 10. A pharmaceutical composition comprising a peptide according to any of the preceding paragraphs together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticle, cryoprotectant, excipient and / or diluent. 11. Use of a peptide or pharmaceutical composition according to any of the preceding clauses for the preparation of a formulation for oral administration, inhalation, intravenous administration, topical administration, intranasal administration, intraperitoneal administration, subcutaneous administration and / or other injectable forms. 12. The use according to 11, wherein the peptide or the pharmaceutical composition is used for preparing a lyophilized formulation of a buffered formulation. 13. Treatment of disorders of hematopoiesis, especially support of stem cell mobilization, proliferation and migration; treatment of wounds, especially treatment of burn wounds; treatment of viral diseases, especially treatment of infections with HIV-1, HIV-2, cytomegalovirus, herpes simplex virus (types 1 and 2), varicella-zoster virus, hepatitis A and B virus, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, rabies virus, sarcoma virus, and Epstein-Barr virus; treatment of bacterial and fungal infections, especially infections with Pseudomonas, Candida, and S. aerus; treatment of infectious processes, abnormal infectious processes; treatment of inflammation, especially periodontal disease; treatment of growth disorders; diseases of the nervous system; disorders of the blood coagulation cascade and hematopoiesis , for use in the treatment of diseases of the vascular system, diseases of the immune system, for improving wound and bone healing, for use in the treatment of diseases of the nervous system, in particular stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, for the treatment of warts, hypogammaglobulinemia, immunodeficiency, myelocatechus syndrome and rheumatoid arthritis, for use in the treatment of cancer, in particular cancers that exhibit CXCR receptors, preferably liver, pancreatic, prostate, breast or other solid cancers, for the treatment of defects in stem cell mobilization, proliferation and migration, for the activation of T cells and the support of immunoblasts, preferably cytotoxic T lymphocytes bearing programmed death receptor 1, for antifibrotic treatment, for the treatment or prevention of scars, for the treatment of heart diseases, in particular heart failure, for the treatment of metabolic diseases, in particular diabetes. 14. Methods for preventing and / or treating cancer, viral diseases, metabolic disorders, nervous system diseases, immune system diseases, and blood coagulation cascade and hematopoietic disorders in mammals, including humans. 15. A method for producing the peptide according to any one of the preceding paragraphs by solid phase synthesis.

[0193] References Described in Hendrix CW, Flexner C, MacFarland RT, Giandomenico C, Fuchs EJ, Redpath E, Bridger G, Henson GW, 2000, Antimicrob Agents Chemother 44:1667-1673. Described in Munch J, Rajan D, Schindler M, Specht A, Rucker E, Novembre, FJ, Nerrienet, E, Muller-Trutwin, MC, Peeters, M, Hahn, BH and Kirchhoff, F, 2007, J Virol 81:13852-13864. Described in Balabanian K, Levoye A, Klemm L, Lagane B, Hermine O, Harriague J, Baleux F, Arenzana-Seisdedos F, Bachelerie F, 2008 J Clin Invest 118:1074-1084.

Claims

1. A peptide consisting of the following amino acid sequence, selected from any one of Groups 1 to 11: - Group 7 composition: d-ILRWSRK-NH2 (Identification ID number: 70, JM#173) Md-LRWSRKLPCVS (Identification ID number: 45, JM#43) Md-LRWSRKMPCVS (Identification ID number: 46, JM#44) ILRWSRK (Glu-Pal) LPCVS (Identification ID number: 54, JM#143) ILRWSRK (Pal) LPCVS (Identification ID number: 55, JM#144) ILRWSRKLPCK (Glu-Pal) S (Identification ID number: 56, JM#145) ILRWSRK (Pal) MPCLS (ID number: 59, JM#149) IVRWSK (Pal) KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK (Pal) VP-NH2 (Identification ID number: 64, JM#167) ILRWSRK (Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK (Pal) LP-NH2 (Identification ID number: 68, JM#171) d-ILRWSRKLP-NH2 (Identification ID number: 71, JM#174) IRWSRK (Glu-Ste) LPCVS (Identification ID number: 95, JM#198) ILRWSRK (Glu-Lau) LPCVS (Identification ID number: 104, JM#213) ILRWSRK (Glu-Ole) LPCVS (Identification ID number: 108, JM#217) ILRWSRK (C16diacid) LPCVS (Identification ID number: 117, JM#226) ILRWSRK (Glu-C16diacid) LPCVS (Identification ID number: 118, JM#227) IRWSRK (C18 diacid) LPCVS (ID number: 119, JM#228) ILRWSRK (Glu-C18diacid) LPCVS (Identification ID number: 120, JM#229) ILRWSRK (OEG-OEG-γGlu-C18diacid) LPCVS (Identification ID number: 121, JM#230) d-LLRWSRK (Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-LLRWSRK (Pal)-NH2 (Identification ID number: 131, JM#236) d-ILRWSRK (Pal)-NH2 (Identification ID number: 132, JM#237) d-ILRWSRK (Glu-Pal)-NH2 (Identification ID number: 133, JM#238) ILRWSRK (C16diacid)-NH2 (Identification ID number: 139, JM#244) IRWSRK (C18 diacid)-NH2 (ID number: 140, JM#245) ILRWSRK (Glu-C16diacid)-NH2 (Identification ID number: 141, JM#246) IRWSRK (Glu-C18 diacid)-NH2 (ID number: 142, JM#247) d-LLRWSRK (C16diacid)-NH2 (Identification ID number: 143, JM#248) d-LLRWSRK(C18diacid)-NH2 (ID number: 144, JM#249) d-LLRWSRK (Glu-C16diacid)-NH2 (Identification ID number: 145, JM#250) d-LLRWSRK (Glu-C18diacid)-NH2 (Identification ID number: 146, JM#251) IRWSRK (Ara) LPCVS (Identification ID number: 147, JM#252) ILRWSRK (Glu-Ara) LPCVS (Identification ID number: 148, JM#253) IRWSRK (Ste)-NH2 (Identification ID number: 149, JM#254) IRWSRK (Glu-Ste)-NH2 (ID number: 150, JM#255) d-LLRWSRK(Ste)-NH2 (ID number: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) d-LLRWSRK (Glu-Myr)-NH2 (Identification ID number: 157, JM#260) ILRWSRK (Myr)-NH2 (Identification ID number: 159, JM#262) LVRYTKK (Glu-Pal)-NH2 (Identification ID number: 161, JM#264) d-LVRYTKK (Glu-Pal)-NH2 (Identification ID number: 162, JM#265) ILRWSRK (Pal-Glu) LPSVS (Identification ID number: 163) - Group 1 consists of: ILRWSRKMPCLS (Identification number: 20, JM#18) ILRWSRK (Pal) LPCVS (Identification ID number: 55, JM#144) ILRWSRK (Glu-Pal)-NH2 (Identification ID number: 89, JM#192) d-LMRWSRK (Glu-Pal)-NH2 (Identification ID number: 91, JM#194) IRWSRK (Glu-Ste)-NH2 (ID number: 150, JM#255) - Group 2 consists of: ILRWSRK (Pal) L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK (Pal) MP-NH2 (Identification ID number: 75, JM#178) d-LMRWSRK (Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRK (Ole) LPCVS (Identification ID number: 80, JM#183) ILRWSRK (Glu-Lau) LPCVS (Identification ID number: 104, JM#213) d-LLRWSRK (Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-ILRWSRK (Glu-Pal)-NH2 (Identification ID number: 133, JM#238) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) - Group 3 composition: d-LLRWSRK (Pal) MPCVS (Identification ID number: 53, JM#141) IVRWSK (Pal) KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK (Pal) VP-NH2 (Identification ID number: 64, JM#167) IVRWSKK (Pal) VPCVS (Identification ID number: 66, JM#169) ILRWSRK (Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK (Pal) LP-NH2 (Identification ID number: 68, JM#171) ILRWSRKK (Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRKLK (Glu-Pal)-NH2 (Identification ID number: 90, JM#193) ILRWSRKK (Glu-Ste) LPCVS (Identification ID number: 96, JM#199) ILRWSRK (Glu-Dec) LPCVS (Identification ID number: 98, JM#203) IRWSRK (Glu-Ste) LPCVS (Identification ID number: 100, JM#205) ILRWSRK (Myr) LPCVS (Identification ID number: 107, JM#216) IRWSRK (Ste)-NH2 (Identification ID number: 149, JM#254) d-LLRWSRK (Glu-Myr)-NH2 (Identification ID number: 157, JM#260) ILRWSRK (Glu-Myr)-NH2 (Identification ID number: 160, JM#263) Group 4 consists of: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (ID number: 36, JM#34) MLRWSRKLPCVS (Identification ID number: 41, JM#39) ILRWSRKLPSVS (Identification ID number: 51, JM#122) d-LLRWSRK (Glu-Pal) MPCVS (Identification ID number: 52, JM#140) ILRWSRK (Pal) MPCLS (ID number: 59, JM#149) d-LMRWSRKK (Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (ID number: 97, JM#200) ILRWSRK (Lau) LPCVS (Identification ID number: 105, JM#214) d-LLRWSRK(Ste)-NH2 (ID number: 151, JM#256) ILRWSRK (Myr)-NH2 (Identification ID number: 159, JM#262) - Group 5 composition: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (ID number: 6, JM#4) IVRWSKKLPCVS (Identification ID number: 7, JM#5) IVRWSKKIPCVS (Identification ID number: 8, JM#6) IVRWSKKFPCVS (Identification ID number: 9, JM#7) ILRWSHKVPCVS (Identification ID number: 11, JM#9) IFRWSHKVPCVS (Identification ID number: 13, JM#11) IVRWSKKMPCVS (Identification ID number: 14, JM#12) IVRWSKKVPCd-VS (Identification ID number: 16, JM#14) ILRWSRKVPCd-VS (Identification ID number: 17, JM#15) IIRWSRKMPCVS (ID number: 18, JM#16) ILRWSRKVPSVS (Identification ID number: 25, JM#23) ILRWSRKMPSVS (Identification ID number: 26, JM#24) Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-Ac-SLRWSRKMPCVS (Identification ID number: 28, JM#26) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) d-FLRWSRKMPCVS (Identification ID number: 32, JM#30) GLRWSRKMPCVS (Identification ID number: 33, JM#31) Ac-SMRWSRKMPCVS (Identification ID number: 34, JM#32) d-Ac-SMRWSRKMPCVS (Identification ID: 35, JM#33) d-MMRRWSRRKMPCVS (Identification ID: 37, JM#35) d-LMRWSRKMPCVS (Identification ID: 38, JM#36) d-FMRWSRKMPCVS (Identification ID: 39, JM#37) d-GMRWSRKMPCVS (Identification ID: 40, JM#38) d-MLRWSRKLPCVS (Identification ID: 42, JM#40) Id-LRWSRKLPCVS (Identification ID: 43, JM#41) Id-LRWSRKMPCVS (Identification ID: 44, JM#42) Md-LRWSRKLPCVS (Identification ID: 45, JM#43) Md-LRWSRKMPCVS (Identification ID: 46, JM#44) IVRWSKKVP-NH2 (Identification ID: 47, JM#106) IVRWSKK-NH2 (Identification ID: 48, JM#110) ILRWSRKLP-NH2 (Identification ID: 49, JM#114) ILRWSRK-NH2 (Identification ID: 50, JM#118) ILRWSRK (Glu-Pal) LPCVS (Identification ID: 54, JM#143) ILRWSRKLPCK (Glu-Pal)S (Identification ID: 56, JM#145) IYRWSRKMPCLS (Identification ID: 57, JM#146) ILRWSRK (Glu-Pal) MPLS (Identification ID: 58, JM#148) IVRWSKKVPVS (Identification ID: 60, JM#151) IVRWSK (Pal)K-NH2 (Identification ID: 61, JM#164) IVRWSKK (Pal)-NH2 (Identification ID: 62, JM#165) IVRWSK (Pal) KVPCVS (Identification ID: 65, JM#168) d-ILRWSRK-NH2 (Identification ID: 70, JM#173) d-ILRWSRKLP-NH2 (Identification ID: 71, JM#174) d-ILRWSRK(Pal)LP-NH2 (Identification ID: 72, JM#175) d-LMRWSRK(Pal)MPCVS (Identification ID: 73, JM#176) Md-LRWSRK(Pal)LPCVS (Identification ID: 74, JM#177) Md-LRWSRK(Pal)LP-NH2 (Identification ID: 76, JM#179) Md-LRWSRK(Pal)-NH2 (Identification ID: 78, JM#181) ILRWSRK(Ste) LPCVS (Identification ID: 79, JM#182) ILRWSRK (Chl) LPCVS (Identification ID number: 81, JM#184) Ac-ILRWSRKLPCVS (Identification ID number: 82, JM#185) d-Ac-I LRWSRKLPCVS (Identification ID number: 83, JM#186) Ac-MLRWSRKLPCVS (Identification ID number: 84, J#187) d-Ac-MLRWSRKLPCVS (Identification ID number: 85, JM#188) VLRWSRKLPCVS (Identification ID number: 86, JM#189) d-VLRWSRKLPCVS (Identification ID number: 87, JM#190) d-MLRWSRK (Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK (Glu-Pal)-NH2 (Identification ID number: 94, JM#197) IRWSRK (Glu-Ste) LPCVS (Identification ID number: 95, JM#198) ILRWSRK (Glu-Myr) LPCVS (Identification ID number: 99, JM#204) ILRWSRK (Dec) LPCVS (Identification ID number: 106, JM#215) d-LLRWSRK (Pal)-NH2 (Identification ID number: 131, JM#236) d-ILRWSRK (Pal)-NH2 (Identification ID number: 132, JM#237) d-LLRWSRK (Myr)-NH2 (Identification ID number: 158, JM#261) ILRWSRK (Pal-Glu) LPSVS (Identification ID number: 163) ILRWSRK (Glu-Ste) LPSVS (Identification ID number: 164) Group 6 consists of: d-LMRWSRKK (Glu-Pal)-NH2 (Identification ID number: 92, JM#195) d-MLRWSRK (Glu-Pal)-NH2 (Identification ID number: 93, JM#196) d-MLRWSRKK (Glu-Pal)-NH2 (Identification ID number: 94, JM#197) IRWSRK (Glu-Ste) LPCVS (Identification ID number: 95, JM#198) ILRWSRK (Glu-Ste) LPSVS (Identification ID number: 164) - The composition of Group 8 is as follows: d-LLRWSRKMPCVS (Identification ID number: 31, JM#29) ILRWSRK (Pal) L-NH2 (Identification ID number: 69, JM#172) ILRWSRK (Glu-Pal)-NH2 (Identification ID number: 89, JM#192) Group 9 consists of: Ac-SLRWSRKMPCVS (Identification ID number: 27, JM#25) d-MLRWSRKMPCVS (Identification ID number: 30, JM#28) d-Ac-SMRWSRKMPCVS (Identification ID number: 35, JM#33) d-MMRWSRKMPCVS (ID number: 37, JM#35) d-LMRWSRKMPCVS (Identification ID number: 38, JM#36) d-LLRWSRK (Glu-Pal) MPCVS (Identification ID number: 52, JM#140) d-LMRWSRK (Pal) MP-NH2 (Identification ID number: 75, JM#178) ILRWSRK (Dec) LPCVS (Identification ID number: 106, JM#215) d-LLRWSRK (Myr)-NH2 (Identification ID number: 158, JM#261) ILRWSRK (Glu-Myr)-NH2 (Identification ID number: 160, JM#263) Group 10 consists of: ILRWSRK (Pal) LPCVS (Identification ID number: 55, JM#144) IVRWSK (Pal) KVP-NH2 (Identification ID number: 63, JM#166) IVRWSKK (Pal) VP-NH2 (Identification ID number: 64, JM#167) ILRWSRK (Pal)-NH2 (Identification ID number: 67, JM#170) ILRWSRK (Pal) LP-NH2 (Identification ID number: 68, JM#171) ILRWSRK (Pal) L-NH2 (Identification ID number: 69, JM#172) d-LMRWSRK (Pal)-NH2 (Identification ID number: 77, JM#180) ILRWSRKK (Glu-Pal)-NH2 (Identification ID number: 88, JM#191) ILRWSRK (Glu-Pal)-NH2 (Identification ID number: 89, JM#192) ILRWSRKLK (Glu-Pal)-NH2 (Identification ID number: 90, JM#193) d-LMRWSRK (Glu-Pal)-NH2 (Identification ID number: 91, JM#194) ILRWSRK (Glu-Lau) LPCVS (Identification ID number: 104, JM#213) d-LLRWSRK (Glu-Pal)-NH2 (Identification ID number: 130, JM#235) d-ILRWSRK (Glu-Pal)-NH2 (Identification ID number: 133, JM#238) IRWSRK (Ste)-NH2 (Identification ID number: 149, JM#254) IRWSRK (Glu-Ste)-NH2 (ID number: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (ID number: 152, JM#257) d-LLRWSRK (Glu-Myr)-NH2 (Identification ID number: 157, JM#260) Group 11 consists of: ILRWCRKPC-NH2, where the cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 109, JM#218) ILRW(d-C)RKPC-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 111, JM#219) IPRW(d-C)RKC-NH2, the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 113, JM#220) ILRWSRKLPCVS, wherein the lysine at position 7 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 115, JM#221) ILRWSKKLPCVS, wherein the lysine at position 6 is linked to the carboxyl terminus via a peptide bond to form a cyclic peptide (SEQ ID NO: 116, JM#222) IPRW(d-C)RKP, the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 122, JM#231) ILRW(d-C)RKP, the d-cysteine ​​at position 5 is linked to the proline at position 8 via a thioester bond to form a cyclic peptide (SEQ ID NO: 124, JM#232) IPRW(d-S)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 126, JM#233). ILRW(d-S)RKP, where the d-serine at position 5 is linked to the proline at position 8 via an ester bond to form a cyclic peptide (SEQ ID NO: 128, JM#234) IMRWCRKPC-NH2, where the cysteine ​​at position 5 is linked to the cysteine ​​at position 9 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 153, JM#258) IPRW(d-C)RKCP-NH2, where the d-cysteine ​​at position 5 is linked to the cysteine ​​at position 8 via a disulfide bond to form a cyclic peptide (SEQ ID NO: 155, JM#259) d- before the amino acid indicates a D-amino acid, Pal indicates palmitic acid on the preceding amino acid, Glu-Pal indicates palmitic acid on the preceding amino acid with a glutamic acid linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid with a glutamic acid linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid with a glutamic acid linker, Ole indicates oleic acid on the preceding amino acid, Ste indicates stearic acid on the preceding amino acid, Glu-Ste indicates stearic acid on the preceding amino acid with a glutamic acid linker, Chl indicates cholesterol on the preceding amino acid, Ac indicates substitution of an amino group with an acetyl group, Lau indicates lauric acid on the preceding amino acid, Glu-Lau indicates substitution of a glutamic acid linker wherein Glu-Ole indicates lauric acid on the preceding amino acid with a glutamic acid linker, Glu-Ole indicates oleic acid on the preceding amino acid with a glutamic acid linker, C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates a saturated C16 fatty diacid on the preceding amino acid with a glutamic acid linker, C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates a saturated C18 fatty diacid on the preceding amino acid with an OEG-OEG-γ glutamic acid linker, OEG indicates a residue of 8-amino-3,6-dioxaoctanoic acid, Ara indicates a saturated C20 fatty acid on the preceding amino acid, and Glu-Ara indicates a saturated C20 fatty acid on the preceding amino acid with a glutamic acid linker.

2. 2. The peptide of claim 1, wherein the peptide is conjugated to a complexing agent, the complexing agent being dodecanetetraacetic acid (DOTA) or deferoxamine.

3. The peptide of claim 1 , wherein the peptide is conjugated to a polymer.

4. The peptide of claim 3 , wherein the peptide is linked to PEG.

5. The peptide of claim 4, wherein the peptide is conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

6. The peptide of claim 3 , wherein the peptide is conjugated to poly(vinyl alcohol).

7. The peptide of claim 3 , wherein the peptide is conjugated to poly(vinylpyrrolidone).

8. The peptide according to any one of claims 3 to 7, wherein the polymer is linked to a further peptide, said further peptide being preferably a copy of the peptide according to claim 1.

9. The peptide of claim 2 , wherein the peptide is labeled with a radionuclide.

10. A peptide consisting of two identical monomer peptides according to any one of claims 1 to 9, wherein the monomer peptides are linked to each other via a cysteine ​​bridge formed between the monomer peptides to form a dimeric peptide.

11. A pharmaceutical composition comprising a peptide according to any of claims 1 to 10 together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticle, cryoprotectant, excipient and / or diluent.

12. A peptide according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in medicine.

13. Use of a peptide according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for the preparation of a formulation for oral administration, inhalation administration, intravenous administration, topical administration, intranasal administration, intraperitoneal administration, subcutaneous administration and / or other injectable forms.

14. 14. The use according to claim 13, wherein the peptide or pharmaceutical composition is used for the preparation of a lyophilized formulation of a buffer formulation.

15. A method for producing the peptide of claim 1 by solid phase synthesis.

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