EPI-X4 peptides and their derivatives

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

Description

[Technical Field]

[0001] The present invention relates to a peptide that binds to the CXC chemokine receptor type 4 and its derivatives, therapeutic uses of the peptide, and a method for producing the peptide of the present invention. [Background technology]

[0002] CXC chemokine receptor 4 (CXCR4) is expressed in many hematopoietic cells, particularly stem cells and tumor cells. CXCR4 is a G protein-coupled receptor (GPCR) that uses stromal cell-derived factor-1 (SDF-1 or CXCL12) as its sole chemokine ligand. 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, such as tumor growth, cancer cell metastasis, and inflammation. Furthermore, CXCR4 is a major co-receptor for HIV-1 entry into target cells.

[0003] Due to its involvement in numerous processes, CXCR4 is an attractive target for intervention in cancer cell proliferation, differentiation, metastasis, and inflammatory diseases. To date, only one CXCR4 antagonist has received clinical approval (AMD3100, Hendrix et al., 2000), and it is solely for the purpose of mobilizing hematopoietic stem cells in cancer patients with lymphoma and multiple myeloma.

[0004] Peptides derived from the human serum albumin amino acid sequence (EPI-X4 (sequence ID: 1)) have been shown to bind to CXCR4, thereby inhibiting the binding of the native ligand CXCL12 (EP2162462B1). Peptides derived from EPI-X4 (sequence ID: 1) have been shown to bind to CXCR4 more effectively than the original peptide (EP3007717A1). However, effective inhibition of CXCL12 binding requires higher nanomolar values ​​for these peptides, and the peptide half-life is limited due to degradation by protease activity. There is a need for CXCR4 antagonists that bind to CXCR4 more effectively and have improved blood stability and pharmacokinetic properties. The following are prior art documents related to the invention of this application (including documents cited in the international phase after the international filing date and documents cited when the application entered the national phase in other countries): (Prior art document) (Patent Document) (Patent Document 1) International Publication No. 2019 / 048666 (Patent Document 2) International Publication No. 2014 / 198834 (Patent Document 3) International Publication No. 2009 / 004054 (Non-patent literature) (Non-patent document 1) ONOFRIO ZIRAFI ET AL, "Proteolytic processing of human serum albumin generates EPI-X4, an endogenous antagonist of CXCR4", JOURNAL OF LEUKOCYTE BIOLOGY, Vol. 99, No. 6, 01 June 2016 (2016-06-01), page 863-868 [Overview of the Initiative] [Means for solving the problem]

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

[0006] A 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.

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

[0008] 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 together via a cysteine ​​bridge formed between them to form a dimeric peptide.

[0009] A fifth aspect of the present invention relates to a pharmaceutical composition comprising the peptide of the present invention together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticles, cryoprotective agents, excipients and / or diluents.

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

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

[0012] An eighth aspect of the present invention relates to the treatment of hematopoietic disorders, wounds, viral diseases, particularly 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 viruses, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, Roussarcoma virus, Epstein-Barr virus, etc., bacteria and fungi, particularly Pseudomonas, Candida, S. aureus, the treatment of infection processes, the treatment of abnormal infection processes, the treatment of inflammation, particularly periodontal disease, arthritis, inflammatory bowel disease, dermatitis and asthma, the treatment of growth disorders, nervous system disorders, and the blood coagulation cascade. The present invention relates to peptides or pharmaceutical compositions for use in the treatment of hematopoietic disorders, vascular diseases, immune system disorders, improvement of wound and bone healing, neurological disorders, particularly stroke, Parkinson's disease, Alzheimer's disease, and multiple sclerosis, warts, hypogammaglobulinemia, immunodeficiency, myelodysplastic syndrome (WHIM syndrome), and rheumatoid arthritis, cancer, particularly cancers exhibiting the CXCR4 receptor, such as liver cancer, pancreatic cancer, prostate cancer, breast cancer, or other solid tumors, treatment of deficiencies in stem cell recruitment, proliferation, and migration, activation of T cells and support of immunoblasts such as CTL / PD-1, treatment of antifibrosis, treatment or prevention of scars, treatment of heart disease, metabolic disorders, particularly diabetes, and lung diseases, particularly pulmonary fibrosis, bronchitis, and chronic obstructive pulmonary disease (COPD).

[0013] A ninth aspect of the present invention relates to peptides or pharmaceutical compositions of the present invention for use in the prevention and / or treatment of cancer, viral diseases, metabolic disorders, neurological disorders, immune system disorders, or disorders of the blood coagulation cascade and hematopoiesis in mammals, wherein the mammal is preferably 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 in which the peptide according to the present invention is bound to cholesterol.

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

[0017] A further aspect of the present invention relates to a conjugate obtained by linking the peptide according to the present invention to human serum albumin. [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 shows two figures of the X4-HIV-1 assay, where the cell infection rate depends on the concentration of different peptide derivatives. [Figure 2] Figure 2 shows two figures of an antibody competition assay, where the proportion of bound antibodies depends on the concentration of the cleaved palmitoylated variant of peptide JM#21 (sequence ID number: 23) (A) and the terminally modified cleaved palmitoylated variant of peptide JM#21 (sequence ID number: 23) (B). [Figure 3] Figure 3 shows the inhibition of Akt and Erk signaling by CXCL12, where the proportion of phosphorylated Akt and Erk depends on the concentration of different peptide derivatives. [Figure 4] Figure 4 shows the stability of various peptides in whole human plasma. [Figure 5] Figure 5 shows the antibody competition assay, where the proportion of bound antibodies depends on the concentration of the DOTA-binding peptide. [Figure 6] Figure 6 shows two diagrams of the X4-HIV-1 assay, where the cell infection rate depends on the concentration of different peptides bound to polyethylene glycol (A) or poly(vinyl alcohol) and poly(vinylpyrrolidone) (B). [Figure 7] Figure 7 shows two figures of an antibody competition assay, where the proportion of bound antibodies depends on the concentration of cleaved palmitoylated variants of peptides bound to polyethylene glycol (A) or poly(vinyl alcohol) and poly(vinylpyrrolidone) (B). [Figure 8]Figure 8 shows two diagrams of assays testing the activity of DSPE-binding peptides, (A) being the X4-HIV-1 assay and (B) being the antibody competition assay. [Figure 9] Figure 9 shows the inhibition of CXCL12-induced Ca2+- signaling by A) JM#21 (sequence ID number: 23) and its peptide variant, and B) WSC02 (sequence ID number: 2) and its peptide variant. [Figure 10] Figure 10 shows A) the inhibition of CXCL12-induced T cell migration by peptide JM#21 (sequence ID number: 23), and compares JM#21 with conventional peptides EPIX4 (sequence ID number: 1) and WSC02 (sequence ID number: 2), B) short peptide variants of JM#21 (sequence ID number: 23) and WSC02 (sequence ID number: 2), and C) fatty acid-binding peptide variants of JM#21 (sequence ID number: 23) and WSC02 (sequence ID number: 2). [Figure 11] Figure 11 is an explanatory diagram of the computational model developed for the design of novel peptide derivatives. A) Peptide-protein model in water and membrane environments, B) Examination of provisional binding sites, C) Analysis of energy contribution, D) Intermolecular interactions at the binding site. [Figure 12] Figure 12 shows the stability of different peptides in the human S9 liver fraction. [Figure 13] Figure 13 shows the in vivo stability of different peptides. [Figure 14] Figure 14 shows the uptake and distribution of 177Lu-labeled DOTA-coupled peptide and 177Lu-labeled Pentixather into GHOST-CXCR4+ cells. [Figure 15] Figure 15 shows the uptake and distribution of 177Lu / 68Ga-labeled DOTA-coupled peptide and 177Lu / 68Ga-labeled Pentixather into GHOST-CXCR4+ cells. [Figure 16]Figure 16 shows the intracellular uptake of 177Lu-labeled DOTA-coupled peptide and 177Lu-labeled Pentixather in Jurkat cells. [Modes for carrying out the invention]

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

[0020] The peptide derivatives of the present invention exhibit approximately 100 times greater binding efficacy to CXCR4 compared to conventionally known peptides. Furthermore, the present invention provides peptides with significantly higher plasma stability than conventional peptides. Moreover, the present invention provides peptides with significantly higher in vivo circulating half-lives than currently available peptides. As a result, the present invention provides peptides with higher therapeutic efficacy compared to current drugs, as smaller doses are sufficient to provide the desired effect.

[0021] The term "derivative" refers to the full-length fragment of peptide EPI-X4 (sequence ID number: 1) including N-terminal and C-terminal cleavage, the peptide of the present invention including amino acid residue substitutions including D-amino acid residues and modified amino acid residues, and peptides including N- and C-terminal disulfide bonds and extensions. The terms peptide, peptide derivative, and derivative are used synonymously. The term peptide also extends to cyclized peptides if the peptide of the present invention can be provided in a cyclized form.

[0022] Apart from the modifications described above, peptides are preferably coupled with proteins. Examples of proteins to be bound to the peptide include antibodies or human serum albumin (HSA).

[0023] The peptide activity was estimated by different assays. First, activity was verified by an HIV-1 inhibition assay (Figure 1). The inhibitory efficacy 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. For cell entry, the HIV-1 glycoprotein gp120 needs to bind to the receptor, which then leads to cell fusion. When CXCR4 is inhibited by its receptor ligand, HIV-1 entry is inhibited, and infection is suppressed.

[0024] All EPI-X4 derivatives tested dose-dependently and specifically inhibited infection of reporter cells with X4-HIV-1. Peptides EPI-X4 (sequence ID: 1) and WSC02 (sequence ID: 2) (EP3007717B1) were used as reference peptides. Figure 1 shows the results of two assays in figure form, where the percentage of infected cells depends on the logarithmic concentration of the different test peptides (Figures 1A and 1B). Using the estimated mean values ​​across several tests, JM#21 (identification ID: 23) was compared to EPI-X4 (identification ID: 1, IC). 50 =8630nM) and WSC02 (Identification ID number: 2, IC50 Inhibition (IC) is almost 100 times more effective than (310nM). 50 A result of 98nM was derived. It was found that peptide derivatives bound to fatty acids, such as palmitic acid (identification ID number: 75, JM#178; identification ID number: 77, JM#180; identification ID number: 91, JM#194; identification ID number: 92, JM#195; identification ID number: 93, JM#196; identification ID number: 94, JM#197), showed a strong increase in anti-HIV-1 activity. The potency of JM#21 (identification ID number: 23) bound to palmitic acid increased by more than 60 times compared to WSC02 (IC2 of JM#143 (identification ID number: 54)). 50 1) = 5nM (not shown). 2) C-terminal cleavage and amidation of their derivatives further increased anti-HIV-1 activity (JM#192 (Identification ID: 89) = 2nM, not shown, JM#194 (Identification ID: 91) = 2nM). The experiment was performed in triplicate. Error bars indicate standard deviation.

[0025] Next, activity was verified by an antibody competition assay (Figure 2). The values ​​determined by the competition assay represent the potency of the compound competing with the antibody that specifically binds to the CXCR4 binding pocket (ECL2). These values ​​correlate most strongly with the compound's binding affinity to CXCR4. Figure 2 (A and B) shows the results of the two assays, demonstrating that the proportion of bound antibody depends on the concentration of different peptides. The right side of the figure explains the assignment of the curves to the tested peptides. To the right of the legend are 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) is WSC02 (Identification ID number: 2) (IC 50 =350nM) and AMD3100 (IC 50 Antibody competition (low IC) is more effective than (690nM) 50(s) was derived. As a clue for further development of JM#21 (identification ID number: 23), the inventors designed derivatives (e.g., JM#118 (identification ID number: 50)) having an affinity for CXCR4 similar to that of JM#21 (identification ID number: 23) and a molecular weight of 1000 Da or less. Surprisingly, when fatty acids were coupled to these short derivatives, the binding to CXCR4 was enhanced. Compared with EPI-X4 (identification ID number: 1) (IC 50 ~2500 nM), some derivatives bind to the receptor more than 2000-fold more effectively (e.g., IC 50 of: JM#167 (identification ID number: 64) = 2 nM; JM#178 (identification ID number: 75) = 2 nM; JM#191 (identification ID number: 88) = 1 nM), which is about 300-fold more effective than WSC02 (identification ID number: 2). In each assay, three independent experiments were performed for each peptide. Error bars indicate standard deviation.

[0026] Thirdly, the activity of EPI-X4 derivatives was validated by their effects on ERK (extracellular signal-regulated kinase) and AKT (serine / threonine protein kinase) signaling via CXCL12 / CXCR4 (Figure 3). In this assay, cells expressing CXCR4 were stimulated with CXCL12, a CXCR4 chemokine ligand, to induce phosphorylation of ERK and AKT. Pre-incubation 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 concentrations of the different peptides. All EPI-X4 derivatives tested blocked CXCL12-induced signaling in a dose-dependent manner. JM#21 (Identification ID: 23) blocked signaling more effectively than WSC02. 10 μM WSC02 (Identification ID: 2) reduced AKT signaling by approximately 50%, while JM#21 (Identification ID: 23) caused approximately 85% inhibition at the same concentration. JM#21 blocked CXCL12-induced AKT signaling by approximately 50% at a concentration of 1 μM, which was approximately 10 times more effective than WSC02 (Identification ID: 2). Furthermore, ERK signaling was effectively blocked by JM#21 (Identification ID: 23) (60% reduction at a concentration of 1 μM), whereas WSC02 (Identification ID: 2) reduced Erk phosphorylation by only 20% at the same concentration. It was also confirmed that JM#21 (Identification ID: 23) was more effective than AMD3100 (approximately 60% reduction in AKT phosphorylation at 10 μM) and EPI-X4 (Identification ID: 1) (approximately 40% reduction at 10 μM). Furthermore, JM#18 (Identification ID: 20) exhibited very strong antagonistic activity in this assay. JM#18 (Identification ID: 20) blocked approximately 40% of CXCL12-induced AKT and ERK signaling at a concentration of 0.1 μM and nearly 70% at a concentration of 1 μM (not shown). Interestingly, palmitic acid coupling increased the antagonistic activity. At a concentration of 10 μM, all palmitic acid coupling derivatives tested blocked 100% of CXCL12-mediated AKT and ERK signaling.JM#143 (identification ID: 54), a fatty acid-bound derivative of JM#21 (identification ID: 23), was found to block AKT and ERK phosphorylation by nearly 70% at a concentration of 1 μM, and to reduce the signal by 20-25% even at a concentration of 0.1 μM. Surprisingly, palmitate-bound WSC02 (JM#169, identification ID: 66) exhibited very strong antagonistic activity, already suppressing AKT signaling by 85% and ERK signaling by more than 70% at a concentration of 0.1 μM, and completely blocking AKT signaling and almost completely blocking ERK signaling at a concentration of 1 μM. In each assay, 2-3 independent experiments were performed on triplates for each peptide. Error bars represent the 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 in complete human plasma or blood (>99%), and its functional activity was measured after either 2 hours or 8 hours and compared to samples that were not incubated in plasma or blood.

[0028] In Figure 4, peptide stability is indicated by the percentage of binding antibody, which depends on the molar concentration of the peptide. The functional stability of both WSC02 (Identification ID: 2) and JM#21 (Identification ID: 23) was significantly lower than that of EPI-X4 (Identification ID: 1) (t1 / 2 = 17 mins) (Figure 4A). After 2 hours, both optimized peptides were completely inactive. The rapid degradation of their variants was also confirmed using mass spectrometry. Furthermore, cleaved variants of both (JM#114 (Identification ID: 49), Figure 4B, and JM#118 (Identification ID: 50), Figure 4C) were rapidly inactivated in plasma. Using mass spectrometry, the inventors showed that enzymatic degradation of EPI-X4 (Identification ID: 1) derivatives was exclusively detected at the N-terminus. The EPI-X4 (identification ID number: 1) variant modified at the N-terminus (JM#25 (identification ID number: 27)-JM#44 (identification ID number: 46)) showed a significantly increased functional plasma stability compared to WSC02 (identification ID number: 2). On the other hand, anti-CXCR4 activity remained unaffected or only slightly affected (IC50 in the following HIV-1 inhibition assays: JM#28 (identification ID number: 30) = 246 nM; JM#36 (identification ID number: 38) = 206 nM; JM#43 (identification ID number: 45) = 810 nM). This activity persisted at 2 hours and 8 hours after plasma culture (remaining activity as follows: JM#28 (identification ID number: 30) = 96% at 2 hours, 77% at 8 hours; JM#36 (identification ID number: 38) = 85% at 2 hours, 81% at 8 hours; JM#43 (identification ID number: 45) = 100% at 2 hours and 8 hours). Further testing revealed that peptides JM#173 (identification ID number: 70) and JM#174 (identification ID number: 71) retained 100% of their initial activity even after 8 hours of plasma incubation, demonstrating their complete stability in human plasma (not shown). This was a surprising finding, considering that their corresponding peptides JM#114 (identification ID number: 49) and JM#118 (identification ID number: 50), which were not N-terminally modified with d-amino acids, were rapidly inactivated in plasma (Figures 4B, 4C).Due to their significantly 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 inventors aimed to further enhance plasma stability (and bioavailability) and therefore designed EPI-X4 (Identification ID: 1) derivatives bound to fatty acids (e.g., palmitic acid). Many of the derivatives bound to fatty acids, such as JM#21 (JM#143 (Identification ID: 54)-JM#145 (Identification ID: 56)) bound to fatty acids, were found to exhibit significantly improved plasma stability and retain no activity even after 8 hours of culture. Surprisingly, the same is true for most cleaved and fatty acid-bound forms of JM#21 (Identification ID: 23), WSC02 (Identification ID: 2), or similar (e.g., EgJM#170 (Identification ID: 67), Figure 4D - JM#172 (Identification ID: 69), Figure 4E, and JM#191 (Identification ID: 88) - JM#193 (Identification ID: 90) (JM#192 is in 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 (Identification ID: 91) - JM#197 (Identification ID: 94)).

[0030] An alternative stabilization approach was PEGylation of JM#21 (Identification ID number: 23). PEGylation had little to no effect on the variant's anti-CXCR4 activity (IC50 in HIV-1 inhibition assays below: SC024 (20kDa) = 118nM, SC029 (telechelic peptide conjugate, 20kDa) = 98nM, SC033 (5kDa) = 716nM), however, it strongly increased functional plasma stability (residual activity after 8-hour plasma incubation, same below: SC024 = 30%, SC029 = 38%, SC033 = 72%). Figures 4A-C show three individual 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. Stimulation of CXCL12 in B cells expressing CXCR4 results in strong calcium release. In the presence of a CXCR4 antagonist, this response is reduced. We observed a reduction in cytokine-induced calcium signaling with 1 μM JM#21 (identification ID number: 23), which was far greater than the reduction observed with the same concentration of WSC02 (identification ID number: 2). The fatty acid-bound JM#21 (identification ID number: 23) variant (JM#143 (identification ID number: 54), JM#144 (identification ID number: 55), JM#170 (identification ID number: 67), JM#192 (identification ID number: 89), JM#194 (identification ID number: 91)) (Figure 9A), and the fatty acid-bound WSC02 (identification ID number: 2) variant (Figure 9B) nearly completely blocked the calcium signal 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 (Identification ID: 23) was more effective than WSC02 (Identification ID: 2) and EPI-X4 (Identification ID: 1) (Figure 10A). The cleaved forms of JM#21 (Identification ID: 23) (JM#114 (Identification ID: 49), JM#118 (Identification ID: 50)) were even more effective than the full-length peptide (Figure 10B). This effect can also be seen for the cleaved forms of WSC02 (Identification ID: 2) (JM#106 (Identification ID: 47), JM#110 (Identification ID: 48)). The tested fatty acid-binding variants of JM#21 (Identification ID: 23) (particularly JM#143 (Identification ID: 54)) exhibited strongly increased antagonistic activity in CXCL12-induced cell migration (Figure 10C). Three independent experiments were performed for each peptide. Error bars indicate the standard deviation. Further testing revealed high activity of JM#192 (Identification ID: 89) and JM#194 (Identification ID: 91) in inhibiting T cell CXCL12-induced migration (not shown). Furthermore, it was found that longer fatty acid binding of peptides appears to be beneficial in inhibiting cancer cell migration. In particular, all stearic acid variants tested showed unexpectedly high activity. For example, the presence of 30 nM peptide JM#255 (Identification ID: 150) already resulted in almost complete inhibition of cell migration (not shown).

[0033] Furthermore, the stability of the peptides in human S9 liver fraction (in the presence of coenzymes) was tested (Fig.). While most peptide therapeutics are primarily excreted via blood degradation, hepatic clearance may play a crucial role, especially for lipophilic fatty acid conjugates. Therefore, peptides were added to human S9 liver fraction to simulate and predict hepatic metabolic clearance. The residual peptide activity after 2 and 8 hours was measured by antibody competition assays, and IC50 was obtained. 50The values ​​were normalized to the unincubated sample (t=0). The peptides tested included N-terminal modified variants (JM#28 (Identification ID: 30), JM#29 (Identification ID: 31), JM#36 (Identification ID: 38), JM#43 (Identification ID: 45), JM#173 (Identification ID: 70)), and fatty acid-bound JM#21 (Identification ID: 23). :23) The variants were JM#143 (Identification ID: 54) (C16) and JM#198 (Identification ID: 95) (C18), as well as cleaved fatty acid conjugates (JM#192 (Identification ID: 89), JM#194 (Identification ID: 91), JM#235 (Identification ID: 130), JM#255 (SEQIDNO: 150), JM#257 (SEQIDNO: 152)). All derivatives tested were characterized by relatively high antagonistic activity and excellent stability in human plasma. Both WSC02 (Identification ID: 2) and JM#21 (Identification ID: 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, with the exception of derivative JM#192 (Identification ID: 89), which showed faster inactivation (Figure 12A). After 8 hours of incubation, all non-fatty acid variants were almost completely inactivated, with the exception of JM#173 (Identification ID: 70), which retained approximately 14% activity (Figure 12B). Notably, JM#173 (Identification ID: 70) was completely resistant to plasma enzymes. Regarding fatty acid conjugates, the stearic acid conjugate JM#198 (Identification ID: 95) was more stable than its palmitoylated counterpart JM#143 (Identification ID: 54) (Figure 12B). Furthermore, N-terminal modifications appear to have a positive effect on enzyme stability. Variants JM#192 (Identification ID: 89) and JM#255 (Identification ID: 150) had unmodified N-terminuses and were degraded more rapidly compared to their N-terminally modified variants (JM#194 (Identification ID: 91), JM#235 (Identification ID: 130), and JM#257 (Identification ID: 152) (Figure 12B). Three independent experiments were performed for each peptide. Error bars indicate the 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 by an antibody competition assay. As a control, the peptide was added to native plasma (ex vivo). IC 50 The values ​​were determined by nonlinear regression assuming an in vivo blood volume of 1.8 ml. Residual activity was calculated as IC 50 (exvivo) / IC 50The results were obtained using (in vivo) x100. The peptides tested were JM#143 (identification ID number: 54), JM#144 (identification ID number: 55), JM#192 (identification ID number: 89), JM#180 (identification ID number: 77), JM#194 (identification ID number: 91), JM#235 (identification ID number: 130), JM#198 (identification ID number: 95), JM#255 (identification ID number: 150), JM#257 (identification ID number: 152), and JM#204 (identification ID number: 99). Surprisingly, the activity of palmitoylated 7-mer JM#192 (identification ID number: 89) was completely lost after 4 hours. In contrast, N-terminal modifications (JM#180 (Identification ID: 77), JM#194 (Identification ID: 91), JM#235 (Identification ID: 130)) appear to protect the peptide from scavenging or enzymatic inactivation. With JM#180 (Identification ID: 77) and JM#194 (Identification ID: 91), approximately 9% of the conjugates maintained activity in plasma even 8 hours after injection (not shown). The highest bioavailability at 4 hours was determined to be the glutamate linker-deficient variants JM#144 (Identification ID: 55) and JM#180 (Identification ID: 77) (with 27% and 29% activity remaining, respectively). The length of the conjugated fatty acid affects in vivo stability and bioavailability. The stearic acid (C18)-conjugated JM#198 (Identification ID: 95) maintained its full activity and was available in plasma even 4 hours after injection. In contrast, the activity of the myristoylated (C14) derivative JM#204 (Identification ID: 99) was lost after this time. Derivative JM#198 (Identification ID: 95) retained 33% activity 8 hours after injection and finally disappeared completely after 24 hours (not shown). Even though the stearic acid stabilization properties did not completely transfer to the shorter-stabilizing JM#255 (Identification ID: 150) and JM#257 (Identification ID: 152), the C18 conjugate is an excellent peptide derivative. JM#198 (Identification ID: 95) is characterized by high enzyme resistance, a relatively long circulating half-life, and excellent antagonistic activity. Data from two mice, measured redundantly, are shown. Error bars indicate standard deviation.

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

[0036] The peptides in Group 1 were measured at the maximum inhibitory concentration (IC) at half limit as determined by the X4-HIV-1 inhibition assay. 50 The peptide has inhibitory activity characterized by having a concentration of 5 nM or less (to estimate its ability to inhibit X4-HIV-1 infection). The X4-HIV inhibitory assay is designed to measure the activity of the peptide of the present invention by its efficiency in preventing infection of tissue culture cells by CXCR4-tropic HIV-1 variants.

[0037] Group 2 peptides are measured by IC in HIV inhibition assays. 50 It has inhibitory activity characterized by a concentration of 5-10 nM.

[0038] Group 3 peptides are measured by IC in HIV inhibition assays. 50 It has inhibitory activity characterized by having a concentration of 10-50 nM.

[0039] The peptides in Group 4 were measured by IC in an HIV inhibition assay. 50 It has inhibitory activity characterized by having a concentration of 50-150 nM.

[0040] Group 5 peptides are measured by IC in HIV inhibition assays. 50 It has inhibitory activity characterized by having a concentration of 150 nM or higher.

[0041] The peptides in group 6 were measured by an antibody competition assay. 50 A key characteristic is that the IC50 is less than 25 nM. These peptides, when measured in an HIV inhibition assay, show an IC50 greater than 150 nM. 50 It holds.

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

[0043] A characteristic of the peptides in Group 8 is that their relative activity is 100% after 2 hours of plasma culture, but is lower (75-99%) after 8 hours of plasma culture.

[0044] The peptides in Group 9 are characterized by a relative activity of 70-99% after 2 hours of plasma culture.

[0045] The peptides in group 10 were IC 50 These peptides are characterized by having a molecular weight of 50 nM or less and a relative activity of 100% after 8 hours of plasma culture. In other words, these peptides were shown to maintain high activity over a relatively long period of time.

[0046] The peptides in Group 11 are cyclized peptides. These peptides are particularly well-suited for oral delivery (oral administration) to patient-like subjects. Cyclization results in increased peptide stability against protease-mediated degradation and shields positively charged amino acid residues.

[0047] As used herein, the term cyclic peptide (or cyclic peptide) means a peptide having a cyclic sequence of bonds. This can be via a linkage between the amino terminus and carboxyl terminus of a peptide, a linkage between the amino terminus and a side chain of a peptide, a linkage between the carboxyl terminus and a side chain of a peptide, or a linkage between two side chains of a peptide.

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

[0049] The inventors further synthesized the following linear equivalents of the cyclized peptides of group 11. 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 (Identification ID number: 154, JM#258 straight line) IPRW(dC)RKCP-NH2((Identification ID number: 156, JM#259 straight line)

[0050] Linear equivalents are used as control peptides in assays to characterize cyclic 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 peptides have been shown to inhibit protease activity. Such modifications have the advantage of increasing the plasma stability of the peptide, as evidenced by its half-life of 29 hours.

[0052] The coupling of fatty acids, namely palmitic acid, decanoic acid, myristic acid, oleic acid, and stearic acid, has been shown to impart high activity to peptides. Furthermore, fatty acid coupling can extend the circulation of peptides at a certain concentration in vivo. The same is true when other fatty acids, such as lauric acid, saturated C16 fatty acids, saturated C18 fatty acids, and saturated C20 fatty acids, are coupled.

[0053] In peptide Identification ID number: 121 (JM#230), an OEG-OEG-γGlu linker (2xOEG-γGlu linker) is used to bind the fatty acid to the peptide. OEG represents the residue of 8-amino-3,6-dioxaoctanoic acid (i.e., the group of formula -NH-(CH2)2-0-(CH2)2-0-CH2-CO-). The two OEG entities of the linker are successively bound to the lysine side chain of the peptide. The fatty acid is bound to the two OEG entities via the γ-glutamic acid entity of the linker.

[0054] Cholesterol has been shown to enhance the relative stability and biological utility of peptides in human plasma.

[0055] A second embodiment of the present invention relates to a peptide comprising the following amino acid sequence, selected from any of groups 1 to 11: -Group 7 consists of the following: 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 (Identification 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 (Identification ID number: 147, JM#252) ILRWSRK(Glu-Ara)LPCVS(Identification ID number: 148, JM#253) ILRWSRK(Ste)-NH2 (Identification ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (Identification ID number: 150, JM#255) d-LLRWSRK(Ste)-NH2 (Identification ID number: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (Identification 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 the following: ILRWSRKMPCLS (Identification 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 (Identification ID number: 150, JM#255) -Group 2 consists of the following: 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 (Identification ID number: 152, JM#257) -Group 3 consists of the following: 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 (Identification ID Number: 100, JM#205) ILRWSRK(Myr)LPCVS(Identification ID number: 107, JM#216) ILRWSRK(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 the following: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (Identification 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 (Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (Identification ID number: 97, JM#200) ILRWSRK(Lau)LPCVS(Identification ID number: 105, JM#214) d-LLRWSRK(Ste)-NH2 (Identification ID number: 151, JM#256) ILRWSRK(Myr)-NH2 (Identification ID number: 159, JM#262) -Group 5 consists of the following: 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(Identification ID Number: 164) -Group 6 consists of the following: 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 (Identification ID number: 95, JM#198) ILRWSRK(Glu-Ste)LPSVS(Identification ID Number: 164) -Group 8 consists of the following: 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 the following: 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 (Identification 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 the following: 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 (Identification ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (Identification ID number: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (Identification ID number: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) -Group 11 consists of the following: In ILRWCRKPC-NH2, the cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (sequence ID number: 109, JM#218). In ILRW(dC)RKPC-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (sequence ID number: 111, JM#219). In IPRW(dC)RKC-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 8 via a disulfide bond, forming a cyclic peptide (sequence ID number: 113, JM#220). In ILRWSRKLPCVS, the lysine at position 7 is bound to the carboxyl terminus via a peptide bond, forming a cyclic peptide (sequence ID number: 115, JM#221). In ILRWSKKLPCVS, the lysine at position 6 is bound to the carboxyl terminus via a peptide bond, forming a cyclic peptide (sequence ID number: 116, JM#222). In IPRW(dC)RKP, the d-cysteine ​​at position 5 is bound to the proline at position 8 via a thioester bond, forming a cyclic peptide (sequence ID number: 122, JM#231). In ILRW(dC)RKP, the d-cysteine ​​at position 5 is bound to the proline at position 8 via a thioester bond, forming a cyclic peptide (sequence ID number: 124, JM#232). In IPRW(dS)RKP, the d-serine at position 5 is linked to the proline at position 8 via an ester bond, forming a cyclic peptide (sequence ID number: 126, JM#233). In ILRW(dS)RKP, the d-serine at position 5 is linked to the proline at position 8 via an ester bond, forming a cyclic peptide (sequence ID number: 128, JM#234). In IMRWCRKPC-NH2, the cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (sequence ID number: 153, JM#258). In IPRW(dC)RKCP-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 8 via a disulfide bond, forming a cyclic peptide (sequence ID number: 155, JM#259). The '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 having a glutamate linker, 'Dec' indicates decanoic acid on the preceding amino acid, 'Glu-Dec' indicates decanoic acid on the preceding amino acid having a glutamate linker, 'Myr' indicates myristic acid on the preceding amino acid, 'Glu-Myr' indicates myristic acid on the preceding amino acid having a glutamate 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 having a glutamate 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, and 'Glu-Lau' indicates having a glutamate linker OEG-OEG-γGlu-C18 diacid indicates lauric acid on the preceding amino acid, Glu-Ole indicates oleic acid on the preceding amino acid having a glutamic acid linker, C16 diacid indicates saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates saturated C16 fatty diacid on the preceding amino acid having a glutamic acid linker, C18 diacid indicates saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates saturated C18 fatty diacid on the preceding amino acid having a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates saturated C18 fatty diacid on the preceding amino acid having a 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 having a glutamic acid linker, and The peptide is conjugated with a compounding agent.

[0056] In other words, the second aspect of the present invention relates to a conjugate in which the peptide and the complexing agent according to the present invention are bound together.

[0057] In preferred embodiments, the peptide is C-terminally conjugated to a conjugating agent. It has been shown that the C-terminal conjugation of the conjugating agent does not affect the activity of the peptide.

[0058] In preferred embodiments, the complexing agent is, for example, a chelating agent such as dodecanetetraacetic acid (DOTA) or deferoxamine. Other examples include 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 preferred embodiments, the complexing agent is dodecanetetraacetic acid (DOTA) or deferoxamine. The conjugated peptide is preferably labeled with a radionuclide.

[0060] DOTA is preferably bound to the peptide via a lysine residue. If there is no lysine available in the peptide, DOTA is bound to the peptide via an additional lysine residue attached to the C-terminal amino acid of the peptide.

[0061] If a peptide is C-terminally bound to DOTA, and the peptide has an amino acid other than lysine as its C-terminal amino acid, DOTA is bound to the peptide via additional lysine bound to the peptide's C-terminal amino acid. If the peptide has lysine as its C-terminal amino acid, DOTA is bound to the peptide's C-terminal lysine, or DOTA is bound to the peptide via additional lysine bound to the peptide's C-terminal lysine.

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

[0063] Deferoxamine is preferably bound to the peptide via a cysteine ​​residue. If the peptide does not contain cysteine, deferoxamine is bound to the peptide via an additional cysteine ​​attached to the C-terminal amino acid of the peptide.

[0064] If a peptide is C-terminally linked to deferoxamine, and the peptide has an amino acid other than cysteine ​​as its C-terminal amino acid, deferoxamine is linked to the peptide via an additional cysteine ​​bonded to the peptide's C-terminal amino acid. If the peptide has cysteine ​​as its C-terminal amino acid, deferoxamine is linked to the peptide's C-terminal cysteine, or deferoxamine is linked to the peptide via an additional cysteine ​​bonded to the peptide's C-terminal cysteine.

[0065] Alternatively, deferoxamine may be conjugated to the peptide via a lysine residue. The above description regarding the conjugation of deferoxamine via a cysteine ​​residue also applies to the conjugation of deferoxamine via a lysine residue.

[0066] The above description regarding the conjugation of DOTA and deferoxamine also applies 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 with the chelating agent DOTA, and the peptide is preferably conjugated at its C-terminus with DOTA. DOTA (also known as tetraxetan) is an organic compound represented by the formula (CH2CH2NCH2CO2H)4. This molecule consists of a 12-membered tetraaza (i.e., containing four nitrogen atoms) ring at its center. DOTA (dodecane tetraacetic acid) is an abbreviation for this tetracarboxylic acid and its conjugate base. DOTA-bound peptides can be conjugated with radionuclides (e.g., 68 Ga and 177Suitable for labeling with Lu. As a result, these peptides are useful for applications in diagnostic and therapeutic approaches. The EPI-X4 (identification ID number: 1) derivative of the present invention, which is specific to CXCR4, can be used to blend diagnostic and therapeutic applications in the same molecule (radioanostics). Radioanostics using these peptides provides new imaging and therapeutic options for patients suffering from malignancies that express CXCR4.

[0068] Figure 5 shows the antibody competition assay (based on one representative experiment per peptide), where the percentage of bound antibodies depends on the molar concentration of the indicated peptide. It is demonstrated that the DOTA-conjugated peptides JM#206 (Identification ID: 101) (JM#21 with DOTA (Identification ID: 23)) and JM#207 (Identification ID: 102) (JM#122 with DOTA (Identification ID: 51)) substituted antibodies as efficiently as the unconjugated JM#21 (Identification ID: 23). Similarly, both DOTA-conjugated peptides suppressed HIV-1 infection with similar potency to the unconjugated peptides.

[0069] The inventors further synthesized the following DOTA-binding peptides: Peptide with identification ID number: 165 (JM#29 (Identification ID number: 31)) to which DOTA is bound via an additional lysine bonded to the C-terminal amino acid of the peptide; Peptide with identification ID number: 166 (JM#118 (Identification ID number: 50) to which DOTA is bound via the C-terminal lysine bonded to the peptide); Peptide with identification ID number: 167 (JM#118 (Identification ID number: 50) to which DOTA is bound via an additional lysine bonded to the C-terminal amino acid of the peptide); Peptide with identification ID number: 168 (JM#17 3 (Identification ID number: 70) DOTA binds to the peptide via the C-terminal lysine of the peptide), Identification ID number: 169 (JM#173 (Identification ID number: 70) DOTA binds to the peptide via additional lysine bound to the C-terminal amino acid of the peptide), Identification ID number: 170 (JM#235 (Identification ID number: 130) with DOTA bound to the peptide via the C-terminal lysine of the peptide), Identification ID number: 171 (JM#235 (Identification ID number: 130) with DOTA bound to the peptide via additional lysine bound to the C-terminal amino acid of the peptide).

[0070] DOTA-bound peptide 177 Lu or 68 The material was radioactively labeled with Ga (see further examples below, Figure 14-16).

[0071] In another particularly preferred embodiment, the complexing agent is the chelating agent deferoxamine. In other words, the peptide is conjugated with the chelating agent deferoxamine, and the peptide is preferably conjugated at its C-terminus with deferoxamine. Deferoxamine is also called desferrioxamine. The deferoxamine-bound peptide can be conjugated with radionuclides, for example, 68 Ga, 177 Lu and 89Suitable for labeling with Zr. As a result, these peptides are useful for applications in diagnostic and therapeutic approaches. The inventors confirmed the suitability of radiolabeled deferoxamine-conjugated peptides as tumor imaging probes and as probes for peptide distribution analysis in, for example, mouse models. For this purpose, the inventors synthesized the following deferoxamine-conjugated peptides: C-deferoxamine-conjugated JM#122 (identification ID number: 51), C-deferoxamine-conjugated JM#194 (identification ID number: 91), C-deferoxamine-conjugated peptide with identification ID number: 163, and C-deferoxamine-conjugated peptide with identification ID number: 164, where C represents an additional cysteine ​​bound to the C-terminal amino acid of the peptide, and deferoxamine was conjugated to the peptide as (succinimodopropionyldesferoxamine) acetate via this additional cysteine. 89 It was radioactively labeled with Zr.

[0072] For example, 89 The in vivo distribution of Zr-labeled C-deferoxamine conjugate JM#122 (identification ID number: 51) in mice was analyzed. To this end, the labeled conjugate was intravenously injected into the tail vein of immunodeficient mice, and then radioactivity in the body was localized and quantified using positron emission tomography (PET). The results revealed that the peptide was absorbed into the kidneys 5 minutes after injection and subsequently released into the bladder.

[0073] Peptide JM#122 (Identification ID: 51) was derived from JM#21 (Identification ID: 23) by replacing the cysteine ​​at position 10 with serine. Peptide Identification ID: 163 is derived from JM#143 (Identification ID: 54) by replacing the cysteine ​​at position 10 with serine. Peptide Identification ID: 164 is derived from JM#198 (Identification ID: 95) by replacing the cysteine ​​at position 10 with serine. The serine substitution of cysteine ​​facilitated the binding of deferoxamine to the additional cysteine ​​bonded to the C-terminal amino acid of the peptide. Peptide JM#194 (Identification ID: 91) does not contain cysteine, so no amino acid substitution was performed before the binding of deferoxamine to this peptide.

[0074] A third embodiment of the present invention relates to a peptide consisting of the following amino acid sequence, selected from any of groups 1 to 11: -Group 7 consists of the following: 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 (Identification 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 (Identification ID number: 147, JM#252) ILRWSRK(Glu-Ara)LPCVS(Identification ID number: 148, JM#253) ILRWSRK(Ste)-NH2 (Identification ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (Identification ID number: 150, JM#255) d-LLRWSRK(Ste)-NH2 (Identification ID number: 151, JM#256) d-LLRWSRK(Glu-Ste)-NH2 (Identification 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 the following: ILRWSRKMPCLS (Identification 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 (Identification ID number: 150, JM#255) -Group 2 consists of the following: 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 (Identification ID number: 152, JM#257) -Group 3 consists of the following: 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 (Identification ID Number: 100, JM#205) ILRWSRK(Myr)LPCVS(Identification ID number: 107, JM#216) ILRWSRK(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 the following: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (Identification 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 (Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (Identification ID number: 97, JM#200) ILRWSRK(Lau)LPCVS(Identification ID number: 105, JM#214) d-LLRWSRK(Ste)-NH2 (Identification ID number: 151, JM#256) ILRWSRK(Myr)-NH2 (Identification ID number: 159, JM#262) -Group 5 consists of the following: 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(Identification ID Number: 164) -Group 6 consists of the following: 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 (Identification ID number: 95, JM#198) ILRWSRK(Glu-Ste)LPSVS(Identification ID Number: 164) -Group 8 consists of the following: 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 the following: 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 (Identification 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 the following: 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 (Identification ID number: 149, JM#254) ILRWSRK(Glu-Ste)-NH2 (Identification ID number: 150, JM#255) d-LLRWSRK(Glu-Ste)-NH2 (Identification ID number: 152, JM#257) d-LLRWSRK(Glu-Myr)-NH2 (Identification ID number: 157, JM#260) -Group 11 consists of the following: In ILRWCRKPC-NH2, the cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (sequence ID number: 109, JM#218). In ILRW(dC)RKPC-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (sequence ID number: 111, JM#219). In IPRW(dC)RKC-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 8 via a disulfide bond, forming a cyclic peptide (sequence ID number: 113, JM#220). In ILRWSRKLPCVS, the lysine at position 7 is bound to the carboxyl terminus via a peptide bond, forming a cyclic peptide (sequence ID number: 115, JM#221). In ILRWSKKLPCVS, the lysine at position 6 is bound to the carboxyl terminus via a peptide bond, forming a cyclic peptide (sequence ID number: 116, JM#222). In IPRW(dC)RKP, the d-cysteine ​​at position 5 is bound to the proline at position 8 via a thioester bond, forming a cyclic peptide (sequence ID number: 122, JM#231). In ILRW(dC)RKP, the d-cysteine ​​at position 5 is bound to the proline at position 8 via a thioester bond, forming a cyclic peptide (sequence ID number: 124, JM#232). In IPRW(dS)RKP, the d-serine at position 5 is linked to the proline at position 8 via an ester bond, forming a cyclic peptide (sequence ID number: 126, JM#233). In ILRW(dS)RKP, the d-serine at position 5 is linked to the proline at position 8 via an ester bond, forming a cyclic peptide (sequence ID number: 128, JM#234). In IMRWCRKPC-NH2, the cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (sequence ID number: 153, JM#258). In IPRW(dC)RKCP-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 8 via a disulfide bond, forming a cyclic peptide (sequence ID number: 155, JM#259). The '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 having a glutamate linker, 'Dec' indicates decanoic acid on the preceding amino acid, 'Glu-Dec' indicates decanoic acid on the preceding amino acid having a glutamate linker, 'Myr' indicates myristic acid on the preceding amino acid, 'Glu-Myr' indicates myristic acid on the preceding amino acid having a glutamate 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 having a glutamate 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, and 'Glu-Lau' indicates having a glutamate linker OEG-OEG-γGlu-C18 diacid indicates lauric acid on the preceding amino acid, Glu-Ole indicates oleic acid on the preceding amino acid having a glutamic acid linker, C16 diacid indicates saturated C16 fatty diacid on the preceding amino acid, Glu-C16 diacid indicates saturated C16 fatty diacid on the preceding amino acid having a glutamic acid linker, C18 diacid indicates saturated C18 fatty diacid on the preceding amino acid, Glu-C18 diacid indicates saturated C18 fatty diacid on the preceding amino acid having a glutamic acid linker, OEG-OEG-γGlu-C18 diacid indicates saturated C18 fatty diacid on the preceding amino acid having a 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 having a glutamic acid linker, and The peptide is bound to the polymer.

[0075] In other words, a third aspect of the present invention relates to a conjugate in which a peptide and a polymer are bound together according to the present invention.

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

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

[0078] The polymer may alternatively be bound to the peptide via a lysine residue. The above description regarding polymer binding via cysteine ​​residues also applies to polymer binding via lysine residues.

[0079] Polymer-bound peptides have been shown to exhibit high relative stability in human plasma and a long biological availability time. The polymer alters the physical and chemical properties of the bound peptide, such as its hydrophilicity and size, thereby inhibiting its renal excretion. Furthermore, the binding polymer encapsulates the peptide, advantageously protecting it from degradation by proteases and antibody activity. Peptide activity is enhanced by the coupling polymer.

[0080] In a preferred embodiment, the polymer-bound peptide binds to a further 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 bound to PEG.

[0082] A more preferred polymer is poly(vinyl alcohol) (PVA). In other words, the peptide is preferably bound to poly(vinyl alcohol). PVA is an alternative to PEG when a patient has developed anti-PEG antibodies.

[0083] Furthermore, a preferred polymer is poly(vinylpyrrolidone) (PVP). In other words, the peptide is preferably bound to poly(vinylpyrrolidone). PVA provides a further alternative to PEG when a patient develops anti-PEG antibodies.

[0084] The coupling polymer has an appropriate molecular weight, such as 5-20 kDa. Other molecular weights are possible if necessary, depending on the application. In HIV-1 infection inhibition, the 20 kDa variant was found to be more active than the 5 kDa variant, while in antibody competition, both showed similar activity.

[0085] In a preferred embodiment, the conjugated polymer may be bound to two copies of the same monomer peptide. Coupling of different monomer peptides is also possible. Preferably, the peptide copies are bound to one end of the polymer. Alternatively, the peptide copies can be bound to different ends of the polymer (telechelic peptide conjugate). A polymer with a peptide copy at one end (SC066) has been shown to have higher activity than a polymer with peptide copies bound to different ends (SC029).

[0086] In other words, it is preferable that the polymer of the polymer-bound peptide is bound to a further peptide, which is preferably a copy of the peptide of the present invention. The peptide is preferably bound at one end of the polymer.

[0087] The effects of the polymer-bound variants are shown in Figures 6 and 7. The polymers were coupled to peptide JM#21 (Identification ID: 23). PEG-bound 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) showed activity estimated by blocking HIV-1 infection, which is comparable to the state-of-the-art CXCR4 antagonist AMD3100 and JM#21 (Identification ID: 23) (Figure 6A). The same was true for antibody competition assays, where the PEG-bound derivatives bound to CXCR4 with similar affinity to JM#21 (Identification ID: 23) and AMD3100 (Figure 7A). The polymer with two peptide copies at one end (SC066) was shown to have higher activity than the polymer with peptide copies bound at different ends (SC029). In antibody competition assays, the derivative SC066 (two peptide copies at one end of PEG) showed even higher activity than JM#21 (identification ID number: 23) and AMD3100. Three independent experiments (Figure 6) or two independent experiments (Figure 7) were performed for each peptide and assay. Error bars represent the standard deviation.

[0088] The activities 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) are shown in Figures 8B and 9B. All derivatives exhibited activity equivalent to JM#21 (identification ID number: 23) and AMD3100, with derivatives SC060 and SC061, which possess two peptide copies at one end of PVP and PVA respectively, showing even higher activity. Three independent experiments were performed for each peptide. Error bars represent the standard deviation.

[0089] In a further preferred embodiment, the PEG-bound peptide is bound 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. Since DSPE is bound to the peptide via PEG, it has the formula 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]. It is also preferable that DSPE is bound (via PEG) to a further peptide. The further peptide is preferably a copy of the peptide of the present invention. The peptide is preferably bound at one end of PEG.

[0090] In Figure 8, the DSPE-bound derivatives SC001 (1 peptide copy) and SC069 (2 peptide copies at one end) were found to have higher activity than cholesterol-bound SC043, JM#21 (identification ID number: 23), EPI-X4 (identification ID number: 1), WSC02 (identification ID number: 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 modified peptides in human plasma, the inventors found that cholesterol-binding SC043 exhibited the highest stability (relative activity measured 8 hours after plasma incubation was 100%). This was followed by PEG-binding peptide SC033 (average molecular weight 5 kDa) (relative activity measured 2 hours after plasma incubation was 87%), PEG-binding peptide SC029 (average molecular weight 20 kDa), and SC024 (average molecular weight 20 kDa).

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

[0093] Furthermore, the polymer was coupled to peptides JM#29 (identification ID number: 31), JM#118 (identification ID number: 50), and JM#173 (identification ID number: 70). In the case of JM#29 (identification ID number: 31), the polymer was bound to the cysteine ​​at position 10 of the peptide. In the cases of JM#118 (identification ID number: 50) and JM#173 (identification ID number: 70), an additional cysteine ​​was bound to the C-terminal amino acid of the peptide, and the polymer was bound to the peptide via this additional cysteine. The synthesis of the polymer-bound peptides was carried out in the same manner as the synthesis of the polymer-bound derivative of peptide JM#21 (identification ID number: 23). The inventors predict that polymer-bound derivatives of peptides JM#29 (identification ID number: 31), JM#118 (identification ID number: 50), and JM#173 (identification ID number: 70) will exhibit activity similar to that of the polymer-bound derivative of peptide JM#21 (identification ID number: 23) (Figures 6-8). The polymer-bound derivatives of peptides JM#29 (identification ID number: 31), JM#118 (identification ID number: 50), and JM#173 (identification ID number: 70) were confirmed to be very stable in human plasma.

[0094] DSPE-PEG-bound peptides can be used in the formulation of 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 appears on the inside of the nanocarrier (micelle formation). The drug may be an anticancer agent, such as a chemotherapeutic agent like doxorubicin. Nanocarriers are suitable for improving the targeting of the drug to the target site. The penetration enhancer is preferably an intestinal osmotic enhancer that promotes oral delivery of macromolecules such as the DSPE-PEG-bound peptide 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-bound peptide is bound to a chelating agent. The chelating agent is preferably bound to the peptide via a lysine residue. The above description regarding the binding of the polymer to the peptide via a lysine residue also applies to the binding of the chelator to the peptide. The resulting conjugate is preferably labeled with a radionuclide via the chelating agent. This also applies to polymer-bound peptides in which the polymer of the polymer-bound peptide is bound to a further peptide, as described above. That is, the polymer-bound peptide may be bound to a further peptide via the polymer and further bound to a chelator, in which case the further peptide is preferably a copy of the peptide of the present invention. The polymer is preferably PEG.

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

[0097] Suitable chelating agents include, for example, dodecanetetraacetic acid (DOTA) and deferoxamine. Other examples include 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 cysteine ​​bridges formed between them to form a dimeric peptide. Dimeric peptides comprising two different monomeric peptides are also possible, but dimeric peptides comprising two identical monomeric peptides are more effective. The dimeric peptide exhibits higher activity compared to twice the amount of each monomeric peptide (both versions have already been disclosed in EP3007717).

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

[0100] In preferred embodiments, the dimer peptide is bound to a polymer. The above description of polymer-bound peptides also applies to polymer-bound dimer peptides.

[0101] A fifth aspect of the present invention relates to a pharmaceutical composition comprising the peptide of the present invention together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticles, cryoprotectants, excipients and / or diluents. The pharmaceutical composition may further contain binders, disintegrants, lubricants, colorants, sweeteners, flavorings, preservatives and / or the like. The components are selected for use in a particular application. For example, mesoporous nanoparticles are advantageous for the sustained release of the peptide. 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 are ideally suited to lipid delivery systems because they are very small, positively charged, or already lipophilic, which facilitates packaging.

[0103] The peptide of the present invention may be formulated together with an osmotic enhancer. The osmotic enhancer is preferably an intestinal osmotic enhancer that promotes oral delivery of the peptide of the present invention. The osmotic enhancer may be, for example, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC).

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

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

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

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

[0108] In a preferred embodiment, the pharmaceutical composition is prepared as an oral formulation. In this case, the peptide may be formulated together with the above-mentioned penetration enhancer.

[0109] An eighth aspect of the present invention relates to peptides or pharmaceutical compositions of the present invention for use in the treatment of hematopoietic disorders, particularly in supporting the recruitment, proliferation, and migration of stem cells; to peptides or pharmaceutical compositions of the present invention for use in the treatment of wounds, particularly wounds caused by burns; infections caused by viral diseases, particularly HIV-1, HIV-2, SARS-CoV-2, cytomegalovirus, herpes simplex virus (types 1 and 2), varicella-zoster virus, hepatitis A and B viruses, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, Rous sarcoma virus, and Epstein-Barr virus; infections caused by bacteria and fungi, particularly Pseudomonas, Candida, and S. aerus, including aureus, infection processes, and abnormal infection processes; treatment of inflammation (particularly periodontal disease); treatment of growth disorders, nervous system disorders, blood coagulation cascade and hematopoietic disorders, vascular diseases, immune system disorders, wounds, and bone healing. It is used in the treatment of conditions such as: improvement of malformations; neurological disorders, particularly stroke, Parkinson's disease, Alzheimer's disease, and multiple sclerosis; treatment of warts, hypogammaglobulinemia, immunodeficiency, myelodysplastic syndromes (WHIM syndrome) and rheumatoid arthritis; cancer, particularly cancers exhibiting the CXCR4 receptor, preferably liver, pancreatic, prostate, breast cancer or other solid tumors; treatment of lack of stem cell recruitment, proliferation and migration, T cell activation, and support of immunoblasts, preferably cytotoxic T lymphocytes having programmed cell death receptor 1 (CTL / PD-1); treatment of antifibrosis, treatment or prevention of scars; treatment of heart disease, particularly heart failure; treatment of metabolic disorders, particularly diabetes; and treatment of lung diseases, particularly pulmonary fibrosis, bronchitis, and chronic obstructive pulmonary disease (COPD).

[0110] The experimental data support the efficacy of the claimed peptide derivatives for the diseases described above. In the case of JM#21 (Identification ID: 23), this peptide may be shown to counteract the in vitro and in vivo growth and migration of acute myeloid leukemia (AML) cells, primary patient material, and Waldenström macroglobulinopathy (WM) cells carrying 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 (Identification ID: 23) was shown to dose-dependently and efficiently block the CXCR4 12G5 epitope in AML cells, inhibit the migration of AML cells along the CXCL12 gradient, reduce CXCL12-induced ERK phosphorylation in AML cells, and reduce the engraftment ability of CXCR4 AML patient primary samples in NSG mice, but with no inhibitory effect on the engraftment ability of CD34+ normal cells. In relation to WM cells, JM#21 (identification ID number: 23) was shown to dose-dependently block the CXCR4 12G5 epitope in WM cells, regardless of the presence or absence of different CXCR4 mutations, impair the migration along the 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 peptides or pharmaceutical compositions 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 mammals, wherein the mammal is preferably human. The terms “prevention” and “treatment” include the step of administering to a mammal a pharmaceutically effective amount of the peptides or pharmaceutical compositions of the present invention, or a salt or hydrate thereof, that is effective in treating the above conditions.

[0112] The peptides or pharmaceutical compositions of the present invention are preferably for use in the prevention and / or treatment of CXCR4-expressing cancers. 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 hematopoietic CXCR4-expressing cancers such as AML, WM, and B-cell lymphoma.

[0113] The peptides or pharmaceutical compositions of the present invention are preferably intended for use in the treatment of inflammation. This includes the treatment of inflammatory diseases such as atopic dermatitis, allergic asthma, colitis, and arthritis.

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

[0115] The peptide or pharmaceutical composition of the present invention is preferably intended for use in the treatment of infection caused by SARS-CoV-2. In SARS-CoV-2 infection, 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 producing the peptides of the present invention by solid-phase synthesis. If this is not possible, for example, in the case of peptides coupled to polymers, other methods are selected for the production of their derivatives. In a preferred embodiment, monomer peptides are provided and coupled under oxidative reaction conditions in which the SH bond can be oxidized to obtain an -SS- bond.

[0117] The peptide according to the present invention may be coupled with cholesterol. Therefore, a further aspect of the present invention relates to a conjugate in which the peptide according to the present invention is bound to cholesterol. Cholesterol has been shown to increase the relative stability of the peptide in human plasma, as well as its bioavailability. Cholesterol is preferably bound to the peptide via a lysine residue or a cysteine ​​residue. The above description regarding the binding of polymers to peptides via cysteine ​​or lysine residues also applies to the binding of cholesterol to peptides.

[0118] When cholesterol is bound to a peptide via a cysteine ​​residue, the cholesterol 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 inventors coupled cholesterol via PEG to the cysteine ​​residues of peptides JM#21 (identification ID number: 23) and JM#29 (identification ID number: 31). The inventors also coupled cholesterol via PEG to an additional cysteine ​​attached to the C-terminal amino acid of peptides JM#118 (identification ID number: 50) and JM#173 (identification ID number: 70).

[0119] When cholesterol is attached to a peptide via a lysine residue, the cholesterol can be attached directly to the peptide or via a linker. The linker is selected to have an appropriate length. The linker is preferably a glutamate linker. As an example, the inventors synthesize and analyze peptide JM#184 (identification ID number: 81) (JM#21 (identification ID number: 23) in which cholesterol is directly attached to the lysine at position 7 of the peptide).

[0120] The peptides of the present invention may be bound to saturated and / or unsaturated fatty acids. The saturated and / or unsaturated fatty acids are preferably bound to the peptide via lysine residues. The above description regarding the binding of polymers and peptides via lysine residues also applies to the binding of saturated and / or unsaturated fatty acids to peptides. The saturated and / or unsaturated fatty acids are bound to the peptide directly or via a linker. The linker is selected to have an appropriate length. The linker is preferably a glutamate linker.

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

[0122] As described above, the peptide of the present invention is preferably coupled with a protein. The protein to be bound 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 according to the present invention is bound to a protein.

[0123] In a preferred embodiment, the peptide of the present invention is conjugated to human serum albumin. The peptide is preferably conjugated to albumin via disulfide ribling. For this purpose, the peptide, for example, JM#21 (identification ID number: 23), is preferably conjugated to albumin via an allyl linker. The allyl linker can be linked to the disulfide bridge in albumin without disrupting the integrity of the protein. The cysteine ​​at position 34 (Cys34), the only cysteine ​​in albumin, is preferably protected before the reaction to maintain access to Cys34-binding drugs such as aldoxorubicin. Albumin has a long circulating half-life and accumulates in solid tumor tissue and inflammatory sites, which are also target sites for the peptide of the present invention. Therefore, the albumin-binding peptide is highly stable in human plasma and provides a platform for targeting tumor or inflammatory sites. The therapeutic effect of the albumin-binding peptide will be achieved via CXCR4. Additional therapeutic effects may be achieved through drugs that are further bound to albumin (e.g., via Cys34).

[0124] Furthermore, the peptide of the present invention may be conjugated to a scaffold protein other than human serum albumin. The scaffold protein may be, for example, avidin.

[0125] In a preferred embodiment, the peptide of the present invention is conjugated to an antibody. The antibody is preferably a monoclonal antibody having a plasma circulating half-life comparable to that of albumin. By using a branched linker, heterodimers with peptides targeting other therapeutically important receptors (e.g., soma mastin 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 peptide of the present invention is conjugated to a broadly neutralizing HIV-1 antibody (bNAb), thereby creating a bispecific EPI-X4-bNAb construct suitable for the treatment and prophylaxis of HIV-1. The broadly neutralizing HIV-1 antibody neutralizes multiple HIV-1 virus strains.

[0127] In a preferred embodiment, the peptide of the present invention is conjugated to a maleimide linker. The maleimide linker is preferably conjugated to the peptide via a cysteine ​​residue. The above description regarding the conjugation of the polymer to the peptide via a cysteine ​​residue also applies to the conjugation of the maleimide linker to the 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. The peptide conjugated to the maleimide linker, e.g., JM#173 (Identification ID number: 70), is assumed to react with albumin in vivo (conjugating the peptide to Cys34 on albumin via the maleimide linker), and is therefore very stable in human plasma but non-lipophilic (similar to the fatty acid-binding peptide version). As an example, the inventors used peptides JM#21 (identification ID number: 23) and JM#29 (identification ID number: 31) to add bis-1,13-(3-maleimidopropionyl)amide)-4,7,10-trioxatridecane (mal-DPEG(3)-mal) or α,ω-bismaleimide polyethylene glycol (PEG-MW2.000Da) (mal-PEG-mal) via peptide cysteine. The inventors further designed a conjugate JM#173-C-mal-PEG-mal using peptide JM#173 (identification ID number: 70), in which the maleimide linker mal-PEG-mal is bound to an additional cysteine ​​that binds to the C-terminal amino acid of JM#173 (identification ID number: 70).

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

[0129] All of the above further descriptions relating to the peptides of the present invention, particularly preferred embodiments, uses, medical uses and methods, also apply to peptides bound to cholesterol, unsaturated fatty acids, drugs, proteins or maleimide linkers.

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

[0131] Peptides with identification ID numbers s. 15, 19, 22, 23, and 24 showed IC50 (IQ50) of less than 5 nM when measured by an X4-HIV-1 inhibition assay. 50 It was found to possess inhibitory activity characterized by the following:

[0132] Peptide with identification ID number 21 showed positive results in an HIV inhibition assay. 50 It was found to possess inhibitory activity characterized by a concentration of 5-10 nM.

[0133] All of the information described in relation to the peptides of the present invention, particularly preferred embodiments, uses, medical uses and methods, also apply 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 constitute part of this disclosure. d-ILRWSRKEYEK(Pal)EYE (Identification ID number: 134, JM#239) d-ILRWSRK(Pal)EK(Pal)(Identification ID number: 135, JM#240) In ILRW(dC)RK(Pal)PC-NH2, the d-cysteine ​​at position 5 is bound to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (Identification ID number: 136, JM#241). In d-ILRW(dC)RKPC-NH2, the d-cysteine ​​at position 5 is bonded to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (Identification ID number: 137, JM#242). In d-ILRW(dC)RK(Pal)PC-NH2, the d-cysteine ​​at position 5 is bonded to the cysteine ​​at position 9 via a disulfide bond, forming a cyclic peptide (Identification ID number: 138, JM#243).

[0135] The activity of the peptide with identification ID number s. was insufficient. Peptides 134-138 were found to be insufficient.

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

[0137] Further disclosed are methods for 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 mammals, comprising administering the peptide or pharmaceutical composition of the present invention to a mammal, where the mammal is preferably human; the method of the present invention is administered to the mammal. Cancer is preferably CXCR4-expressing cancer. 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 hematopoietic CXCR4-expressing cancers such as AML, WM, and B-cell lymphoma. Immune system disorders 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. Viral stocks of CXCR4-tropic NL4-3 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 collected and cell debris was removed by centrifugation. Aliquots were stored at -80°C. For infection of TZM-bl cells in the presence of the inhibitor, 1 x 10⁶ cells were used in 70 μl DMEM containing 2.5% FCS. 5 Cells were seeded at a density of cells / ml. The compound was diluted in PBS and 10 μl was added. After 15 minutes, cells were inoculated with 20 μl of diluted virus. Infection rates were measured 3 days later using a Gal-Screen system (Applied Biosystems).

[0139] Antibody competition assay. Competition between compound and antibody binding was performed in SupT1 cells. For this purpose, cells were washed with PBS containing 1% FCS, and then seeded at 50,000 cells per well in a 96V-well plate. The buffer was removed, and the plate was pre-cooled to 4°C. The compound was diluted in PBS, and the antibody (clone 12G5, APC labeled) was diluted in PBS containing 1% FCS. The antibody was used at a concentration close to its determined Kd. Subsequently, 15 μl of the compound was added to the cells, followed immediately by 15 μl of the antibody. The plate was incubated at 4°C in the dark for 2 hours. The 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 used directly, or subsequently centrifuged at 2,500 x g for 15 minutes to obtain plasma. Plasma from six donors was pooled and stored aliquot at -80°C. The compound was diluted 200-fold with human plasma or whole blood to a final concentration of 20 μM. Samples at t=0 were collected immediately and stored at -80°C. Plasma / compound or blood / compound mixtures were 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. Competition of 12G5-APC antibody was performed as described above. For functional stability of blood / peptide, samples were thawed and centrifuged at 14,000 rpm to remove cells and debris. The supernatant was diluted with PBS and the 12G5-antibody competition assay was performed. After a 2-hour incubation, the cells were washed and 50 μl of 1-step-Fix / Lyse solution (Thermo Fisher #00-5333-54) was added at room temperature for 15 minutes. The cells were then washed again and the bound antibodies were analyzed.

[0141] Stability assay in human S9 liver fraction. Pooled human liver S9 fraction was obtained from Thermo Fisher Scientific at a total protein concentration of 20 mg / ml. The fraction was stored at -80°C in 25 μl aliquots. For stability experiments, they were diluted to a final concentration of 0.5 mg / ml with Tris buffer. Cofactors (or buffers) 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 the peptide or compound at a concentration of 20 μM and gently stirring at 37°C. Enzyme stability was measured 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. Four hours after injection, the mice were killed by cervical dislocation. Mouse plasma was obtained by cardiac puncture. The blood was diluted 19:1 with 0.16M NaEDTA and centrifuged at 2000×g at 4°C for 20 minutes to obtain plasma. The plasma was stored at -80°C until residual peptide activity in the plasma was measured using a 12G5 antibody competition test. Peptide activity in the plasma was compared to the activity of plasma samples to which the peptide had been added.

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

[0144] Migration assays were performed using a 96-well transwell assay plate (Corning Incorporated, Kennebunk, ME, USA) equipped with a 5 μm polycarbonate filter. First, the lower chamber was filled with 235 μl of assay buffer (RPMI supplemented with 0.1% BSA), with or without serial dilutions of 100 ng / ml CXCL12 and CXCR4 inhibitor compounds (in assay buffer). Next, 75 μL (0.5 x 10⁵ cells) of Jurkat cells (in assay buffer), with or without the compounds, were added to the upper chamber. After 4 hours at 37°C (5% CO₂), 100 μL of the lower chamber was transferred to a new 96V-well plate and analyzed using Cell-Titer-Glo® assay (Promega, Madison, WI, USA). The percentage of migrated cells was calculated according to Balabanian et al. (2005). To obtain relative migration rates, the percentage of migrating cells was normalized to a control group consisting only of CXCL12.

[0145] Ca++ signaling For calcium measurement, 1 × 10⁶ BCR-ABL-modified mouse bone marrow cells were incubated at 37°C for 45 minutes in Iscove medium supplemented with 1% FCS (Pan Biotech) with 5 μg / mL Indo-1 (Molecular Probes) and 0.5 μg / mL Pluronic F-127 (Molecular Probes). The cells were then washed by centrifugation, and the cell pellet was resuspended in Iscove medium containing 1% FCS and treated with EPI-X4 derivative (1 μM or 0.5 μM) at room temperature for 10 minutes. The cells were pre-warmed at 37°C for 5 minutes. Calcium flux was assessed by FACS measurement using BD LSR Fortessa. After a 30-second 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 designing the enhanced EPI-X4 (Identification ID: 1) derivative was to determine how the peptide binds to CXCR4. Using this knowledge, the inventors were able to improve ligand efficiency by designing a shorter peptide that is potentially more active than EPI-X4 (Identification ID: 1). Thus, the computational approach consisted of the following steps.

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

[0148] b. Docking calculations and homology modeling for initial search of EPI-X4 binding sites in CXCR4.

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

[0150] d. The inventors performed atomic molecular dynamics (MD) simulations of each model to analyze factors such as ligand flexibility, interaction interface area, solvent reach, and hydrogen bonding interactions in different binding modes. After analyzing all these parameters, it was found that D is 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 e.MD simulations, the inventors 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] f. The inventors also conducted extensive coarse-grained (CG) MD simulations using non-equilibrium dynamics to investigate the self-assembly of the CXCR4-EPI-X4 complex from the unbound state. These CG simulations further demonstrated that D is the most preferred mode, as predicted by atomic MD (Figure 11D).

[0153] Using information on how EPI-X4 (identification ID number: 1) binds to CXCR4 and the individual contributions of each peptide residue to binding, the inventors designed a shortened peptide derivative with a neutral C-terminus that they predicted would be more efficient than EPI-X4 (identification ID number: 1). In this way, a set of peptides was identified and its experimental activity was evaluated.

[0154] Toxicity in zebrafish. To test the toxic effects in zebrafish, non-villi-containing fish embryos (24 hours post-fertilization) were exposed to the compound for 24 hours and then assayed using a stereomicroscope. Each assay was performed in double succession on 3 x 10 embryos (in 100 μl) for each concentration (total n=60). The highest concentration of peptide solvent was used as the negative control. As a positive control for acute toxicity, 6 μM pleurocidine antimicrobial peptide NRC-03 (GRRKRKWLRRIGKGVKIIGGAALDHL-NH2) (identification ID number: 103) was used.

[0155] Polymer-bonded peptide synthesis. Materials 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol) 2000Da](ammonium salt) (Cat number PG2-DSML-2k) and cholesterol-poly(ethylene glycol)maleimide 5000Da (PG2-CSML-5k) were purchased from Nanocs Inc. (New York, USA). Methoxypoly(ethylene glycol) 20kDa maleimide (Cat number PJK-231) and dimaleimide poly(ethylene glycol) 20kDa (Cat number 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 Ulysotop. Dichloromethane (CH2Cl2), acetonitrile (MeCN), tetrahydrofuran (THF), and toluene (PhMe) were obtained using an MBraun SPS-800 solvent purification system. Ultrapure water was dispensed from a MilliQ Direct 8 (Millipore) [18.2 MΩ·cm].

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

[0157] SDS-PAGE analysis was performed using NuPAGE® bis-tris4-12% precast gel (Invitrogen) in an electrophoresis tank. Samples were prepared with NuPAGE® LDS sample buffer (4×). The sample volume was typically 10 μL. NuPAGE® MOPS SDS running buffer (20×) was used as the running buffer. The electrophoresis voltage 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 reverse-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 solvent A being 5% acetonitrile containing 0.01% TFA and solvent B being 100% acetonitrile containing 0.01% TFA. The solvents used were HPLC grade. The gradient used was 30-60% solvent B over 25 minutes. UV detection at a flow rate of 2 mL / min and wavelength of 280 nm was used for the analysis.

[0159] Poly(ethylene glycol)(PEG) (0.05-0.1 g) was added to a 50 mL Schlenk flask fitted with an azeotropic distillation rubber septum and a magnetic star bar for PEG compounds, and the flask was 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 eye strap. When the stopper on the side arm was slowly opened to create a vacuum, the toluene was observed to slowly foam. The flask was gently rotated to avoid splashing of the mixture. Any moisture formed on the outer wall of the flask was wiped away until all solvent had been removed from the flask. The flask was left to stand at room temperature in a vacuum for a further 30 minutes.

[0160] Reagent synthesis [ka]

[0161] Synthesis of 4-(3-(p-trillthio)-2-(p-trillthio)methyl)propanoyl)benzoic acid. 4-(3-(p-trillthio)-2-((p-trillthio)methyl)propanoyl)benzoic acid 1, Prepared as described in previous literature 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 bissulfide PEG 20kDa. Toluene-dried methoxypoly(ethylene glycol)amine (mPEG-NH2, 20000 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-tollulthio)-2-((p-tollulthio)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 funnel evaporation, and the viscous crude product residue was redissolved in acetone while gently warming. Next, the flask is placed in a dry ice bath to precipitate the product, which is then isolated by centrifugation drying to obtain PEG bissulfide. 2 It was 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 PEG20kDa. Bis-sulfide PEG20kDa 2(50 mg, 1 equiv., 2.5 μmol) and potassium peroxymonosulfate Oxone® (3.08 mg, 4 equiv., 10 μmol) were dissolved in 3 mL of 50% methanol aqueous solution. The reaction mixture was stirred overnight at room temperature. After this, volatile components were removed by rotary evaporation, and the mixture was purified by acetone / dry ice precipitation as described above. The resulting solid was dried in a desiccator to obtain a white, fluffy solid: bis-sulfone PEG. I got 3 (24 mg, 48%) 1 The 1H-NMR (CDCl3) results were 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), and 8.07 (d, 2H). [ka]

[0164] Synthesis of NHS-activated bis-sulfide 4. Under an argon atmosphere, 4-(2,2-bis[(p-tolylsulfonyl)methyl]acetyl)benzoic acid 1 A mixture of (0.5 g, 1 equiv., 1.15 mmol), N-Hydroxysucinimide (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 hours, 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 on magnesium sulfate. After gravity filtration, volatile substances were removed under vacuum, yielding the desired active NHS ester. 4 The product was obtained as a solid (0.39 g, 78% yield). 1 The following results were obtained for 1H-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), and 8.05 (d, 2H). [ka]

[0165] Synthesis of DSPE-PEG-bis-sulfide 2kDa. 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol) 2kDa](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 hours. After this, dichloromethane was removed from the filtrate by rotary evaporation, and the viscous crude product residue was redissolved in acetone while gently warming. Next, the flask was placed in a dry ice bath to precipitate the product, which was then centrifuged and dried in a vacuum to obtain DSPE-PEG bis-sulfide. 6 It was 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-PEG2kDa by sulfide oxidation. Bis-sulfide DSPE-PEG2kDa 5 (26.5 mg, 1 equiv., 8.28 μmol) and potassium peroxymonosulfate Oxone® (10.2 mg, 4 equiv., 33.1 μmol) were dissolved in a 50% methanol (3 mL) aqueous solution. The reaction mixture was stirred overnight at room temperature. After this, volatile components were removed by rotary evaporation, and the mixture was purified by acetone / dry ice precipitation as described above. The resulting solid was dried in a desiccator to obtain bis-sulfone DSPEPEG as a white solid. I got 6 (16.3 mg, 56.2%). 1The 1H-NMR (CDCl3) results were 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), and 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. The reaction mixture was stirred at room temperature for 48 hours, after which the product was precipitated in ethyl ether and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and freeze-dried to obtain 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] Production of bis-sulfone PVP20kDa by sulfide oxidation. Bis-sulfide PVP20kDa9 (66.5 mg, 1 equiv., 2.74 μmol) and potassium peroxymonosulfate Oxone® (5.07 mg, 4 equiv., 11 μmol) were dissolved in 3 mL of 50% methanol aqueous solution. The reaction mixture was stirred overnight at room temperature. After this, volatile components were removed by rotary evaporation, and purification was achieved by DMF / ethyl ether precipitation as described above. The obtained solid was dried in a desiccator to obtain 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 bissulfide 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 bissulfide (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 hours. After this, the product was precipitated in heptane and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and freeze-dried to obtain PVA bissulfide 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 20kDa by sulfide oxidation. Bis-sulfide PVA 20kDa (78.2 mg, 1 equiv., 3.85 μmol) and potassium peroxymonosulfate Oxone® (4.74 mg, 4 equiv., 15.4 μmol) were dissolved in 3 mL of 50% methanol aqueous solution. The reaction mixture was stirred overnight at room temperature. After this, volatile components were removed by rotary evaporation, and the mixture was purified by DMSO / heptane precipitation as described above. The obtained solid was dried in a desiccator to obtain 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 methylformamide (DMF, 2 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 48 hours. The product was then precipitated in ethyl ether and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and lyophilized to obtain 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, 0.20.2 μmol) was added, and the mixture was stirred at room temperature for 48 hours. After this time, the product was precipitated in heptane and isolated by centrifugation. The resulting white precipitate was diluted with MQ water and freeze-dried to obtain 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. The collected fractions were analyzed by 280 nm UV-Vis spectroscopy to determine the presence and binding of the peptides. After lyophilization, the peptide conjugate was typically obtained as a solid. [Table 1]

[0174] General procedure for maleimide diconjugation. 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. This mixture was incubated at room temperature for 4 hours. After this, the bioconjugate was separated from the native peptide by LH20 gel filtration using ACN / MQ water as the eluent. The collected fractions were analyzed by 280 nm UV-Vis spectroscopy to determine the presence of the peptide and the complex. After lyophilization, the peptide conjugate was obtained as a solid.

[0175] The general procedure for bis-sulfone conjugation involved adding 1 equivalent of each bis-alkylation reagent to 1 mL of 50 mM sodium phosphate buffer containing 20 mM MEDTA, pH 7.8, with 10 equivalents of excess native peptide per 1 mL. For PVA conjugation, the reagent was first dissolved in 100 μL of DMSO and heated to 60°C to dissolve. This mixture was incubated at room temperature for 48 hours. After this, the bioconjugate was separated from the native peptide by gel filtration. The collected fractions were analyzed by 280 nm UV-Vis spectroscopy 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] [Examples]

[0176] Radiolabeling of DOTA-bound peptides and evaluation of radiolabeled conjugates DOTA-conjugated peptide In this example, the following DOTA-labeled peptides were used. DOTA-K-JM#21 (Identification ID number: 101, JM#206) (JM#21 (Identification ID number: 23) in which DOTA is bound to the peptide via an additional lysine bonded to the C-terminal amino acid of the peptide), DOTA-K-JM#122 (Identification ID number: 102, JM#207) (JM#122 (Identification ID number: 51) in which DOTA is bound via an additional lysine bonded to the C-terminal amino acid of the peptide), DOTA-K-JM#29 (Identification ID number: 165) (JM#29 (Identification ID number: 31) in which DOTA is bound to the peptide via an additional lysine bonded to the C-terminal amino acid of the peptide), DOTA-JM#118 (Identification ID number: 166) (JM#118 (Identification ID number: 50) with DOTA bound via the C-terminal lysine of the peptide), DOTA-K-JM#173 (Identification ID number: 169) (JM#173 (Identification ID number: 70) has DOTA bound to the peptide via an additional lysine bonded to the C-terminal amino acid of the peptide), and DOTA-K-JM#235 (Identification ID number: 171) (JM#235 (Identification ID number: 130) to which DOTA is bound via an additional lysine bonded to the C-terminal amino acid of the peptide).

[0177] Radio labeling 177 Lu-labeled versions of DOTA-conjugated peptides contain 3 nmol of peptides with different activities. 177After incubation with Lu]LuCl3 (150-450 MBq), the mixture was prepared in ammonium acetate buffer (0.4 M, pH 5.2). For cysteine-containing peptides, 10% ethanol (excluding Pentixather) was added to the reaction mixture to prevent radiolysis. DTT (10 mM) was also added to prevent dimerization of the 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 3 nmol of peptide with different activity [ 68 After incubation with Ga]GaCl3 (10-200 MBq) at 95°C for 15 minutes, a Ga-labeled version of the DOTA-conjugated peptide was prepared in sodium acetate buffer (0.2 M, pH 4-4.5). 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) differed at different time points. 177 In Lu-complex, the time intervals are 0, 1, 2, 4, and 24 hours. 68 In the Ga-complex, the radiochemical purity of each radiolabel conjugate was determined at 0, 1, and 2 hours and evaluated by measurement at room temperature. For this reason, aliquots of the labeling solution were stored at room temperature. RP-HPLC injection was performed continuously at the desired time points.

[0180] By measuring radiochemical purity, [ 177The radioactive instability of Lu]Lu-labeled DOTA-conjugated peptides was tracked over time (Table 3). The 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 78±1% of the radiolabeled aggregate remained after 24 hours with Lu]Lu-DOTA-K-JM#207. [Table 3]

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

[0182] Lipophilicity is an important physicochemical property of potential radiotracers and is involved in their distribution in the body, excretion, pharmacokinetics, and plasma protein binding. Reference molecules [ 177 Lu]Lu-Pentixather(log DO / PBSpH7.4 Compared to -1.53±0.08), [ 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 The remaining value is 0.29 ± 0.10. 177 Lu-labeled conjugates were found to be moderately lipophilic (Table 4). 68 In the case of 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 It exhibited superior lipophilicity compared to -2.67±0.36 (Table 4). [Table 4]

[0183] Uptake into cells and distribution GHOST-CXCR4+ cells (1x10) seeded in a 24-well plate 5 In cells / wells, 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 at different time points (15, 30, and 60 minutes). 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 recovery 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). Results are expressed as a percentage of the applied radioactivity and are shown in Figures 14 and 15, both showing the results of cell uptake at 60 minutes.

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

[0185] 177 Based on the above results obtained for the Lu-labeled complexes, the most performant molecule (JM#173-K-DOTA (identification ID number: 169)) was selected and evaluated in vitro using Ga-68. Even in this case, 68 Ga]Ga-DOTA-K-JM#​​​​​​​​​​​​​​​​​Both Lu]Lu-DOTA-K-JM#173 were found to show very similar cellular uptake in Jurkat cells (Fig. 16).

[0187] Small animal SPECT / CT and PET / CT imaging SPECT / CT: 177 The whole body distribution of Lu]Lu-Pentixather 177 Lu]Lu-DOTA-K-JM#173 and 177 Lu]Lu-DOTA-K-JM#235 were compared. Healthy Balb / c mice were injected with 15 - 20 MBq (100 pmol) of 177 the Lu-labeled complex via the tail vein, and SPECT / CT images were acquired 4 hours post-injection (p.i.). For image acquisition, the mice were euthanized by CO2 inhalation 4 hours later, measured with an appropriate dose calibrator, and head-position imaging was performed in the supine position using a SPECT / CT system dedicated for small animal imaging (NanoSPECT / CTTM Bioscan Inc.). The images were reconstructed using an exclusive HiSPECT iterative reconstruction method and fused with CT images using exclusive InVivoScope (manufactured by Bioscan) software.

[0188] PET / CT: 68 Ga]Ga-Pentixather and 68 Ga]Ga-DOTA-K-JM#173 were measured and compared for their whole body distribution by performing PET / CT imaging. Healthy Balb / c mice were injected with 5 - 6 MBq (200 pmol) of 68 the Ga-labeled complex via the tail vein injection, and PET / CT images were acquired. For image acquisition, the mice were euthanized by CO2 inhalation 1 hour later, measured with an appropriate dose calibrator, and imaging from the head was performed in the supine position using a PET / CT system dedicated for small animal imaging (Molecubes). The 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 Pentixather as a reference. Highly lipophilic compounds [ 177 Lu]Lu-DOTA-K-JM#235 was also evaluated by SPECT / CT imaging, and its distribution pattern was determined. It has low lipophilicity. 177 Lu]Lu-DOTA-K-JM#173(logD pH7.4 (=-2.72±0.22) mainly accumulates in the kidneys and is highly lipophilic. 177 Lu]Lu-DOTA-K-JM#235(logD pH7.4 Pentixather (logD = 0.29 ± 0.102) was observed to accumulate predominantly in the liver, including some background activity, resulting in a distinguishable pharmacokinetic behavior. pH7.4 =-1.53±0.08) is, along with higher background activity, [ 177 It showed similar uptake into the liver as Lu]Lu-DOTA-K-JM#235.

[0190] conclusion Radiolabeled DOTA-conjugated peptides are evaluated in terms of lipophilicity, stability, and cellular uptake in GHOST-CXCR4+ cells. Of the conjugates tested, [ 177 Lu]Lu-DOTA-K-JM#173 and its diagnostic counterparts[ 68 Ga]Ga-DOTA-K-JM#173 is a conjugate and reference to [ 177 Compared to Lu]Lu-Pentixather, it showed the highest cellular uptake into GHOST-CXCR4+ cells, making it the most promising radiolabeled DOTA conjugate peptide.

[0191] moreover,[ 177 Lu]Lu-DOTA-K-JM#173 and [ 68Ga]Ga-DOTA-K-JM#173 was not specifically taken up by any organ in vitro. However, this lack of uptake by other organs may be due to the specificity of these compounds to human CXCR4. On the other hand, the accumulation in the kidneys is due to excretion in the urine. 177 Renal accumulation is considered preferable to hepatic accumulation, as seen with Lu]Lu-Pentixather. While renal uptake of radioactivity can be reduced with renal protective agents, thereby lowering off-target radiotoxicity, hepatic absorption cannot be reduced, which is a major drawback in imaging and treatment. From this perspective, [ 177 Lu]Lu-DOTA-K-JM#173 appears to be a suitable radiopharmaceutical.

[0192] Furthermore, the following clauses are disclosed. 1. A peptide consisting of the following amino acid sequence, selected from any of groups 1 to 11: -Group 7 consists of the following: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (Identification ID number: 19, JM#17) ILRWSRKMPCLS (Identification ID number: 20, JM#18) ILRWSRKMPCMS (Identification ID number: 22, JM#20) ILRWSRKLPCVS (Identification 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 the following: ILRWSRKMPCFS (Identification 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 the following: 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 (Identification ID Number: 100, JM#205) -Group 4 consists of the following: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (Identification 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 (Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (Identification ID number: 97, JM#200) -Group 5 consists of the following: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (Identification 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 (Identification 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 (Identification ID number: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (Identification ID number: 99, JM#204) -Group 6 consists of the following: 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 (Identification ID number: 95, JM#198) -Group 7 consists of the following: 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 the following: 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 the following: 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 (Identification 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 the following: 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) The 'd-' preceding 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 having a glutamate linker, 'Dec' indicates decanoic acid on the preceding amino acid, 'Glu-Dec' indicates decanoic acid on the preceding amino acid having a glutamate linker, 'Myr' indicates myristic acid on the preceding amino acid, 'Glu-Myr' indicates myristic acid on the preceding amino acid having a glutamate 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 having a glutamate linker, 'Chl' indicates cholesterol, and 'Ac' indicates that the amino group has been substituted with an acetyl group. 2. A peptide consisting of the following amino acid sequence, selected from any of groups 1 to 11: -Group 7 consists of the following: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (Identification ID number: 19, JM#17) ILRWSRKMPCLS (Identification ID number: 20, JM#18) ILRWSRKMPCMS (Identification ID number: 22, JM#20) ILRWSRKLPCVS (Identification 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 the following: ILRWSRKMPCFS (Identification 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 the following: 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 (Identification ID Number: 100, JM#205) -Group 4 consists of the following: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (Identification 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 (Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (Identification ID number: 97, JM#200) -Group 5 consists of the following: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (Identification 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 (Identification 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 (Identification ID number: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (Identification ID number: 99, JM#204) -Group 6 consists of the following: 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 (Identification ID number: 95, JM#198) -Group 7 consists of the following: 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 the following: 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 the following: 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 (Identification 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 the following: 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) The 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 having a glutamate linker, Dec indicates decanoic acid on the preceding amino acid, Glu-Dec indicates decanoic acid on the preceding amino acid having a glutamate linker, Myr indicates myristic acid on the preceding amino acid, Glu-Myr indicates myristic acid on the preceding amino acid having a glutamate 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 having a glutamate linker, Chl indicates cholesterol, and Ac indicates that the amino group has been substituted with an acetyl group, and The peptide is bound to the conjugating agent at its C-terminus. 3. A peptide consisting of the following amino acid sequence, selected from any of groups 1 to 11: -Group 7 consists of the following: ILRWSRKMPCVS (Identification ID number: 15, JM#13) IMRWSRKMPCVS (Identification ID number: 19, JM#17) ILRWSRKMPCLS (Identification ID number: 20, JM#18) ILRWSRKMPCMS (Identification ID number: 22, JM#20) ILRWSRKLPCVS (Identification 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 the following: ILRWSRKMPCFS (Identification 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 the following: 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 (Identification ID Number: 100, JM#205) -Group 4 consists of the following: ILRWSRKVPCVS (Identification ID number: 10, JM#8) IFRWSRKVPCVS (Identification ID number: 12, JM#10) MLRWSRKMPCVS (Identification ID number: 29, JM#27) MMRWSRKMPCVS (Identification 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 (Identification ID number: 59, JM#149) d-LMRWSRKK(Glu-Pal)-NH2 (Identification ID number: 92, JM#195) ILRWSRK-AcLPCVS (Identification ID number: 97, JM#200) -Group 5 consists of the following: ILRWSKKVPCVS (Identification ID number: 3, JM#1) IFRWSKKVPCVS (Identification ID number: 4, JM#2) IVRWSRKVPCVS (Identification ID number: 5, JM#3) IVRWSHKVPCVS (Identification 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 (Identification 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 (Identification ID number: 95, JM#198) ILRWSRK(Glu-Myr)LPCVS (Identification ID number: 99, JM#204) -Group 6 consists of the following: 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 (Identification ID number: 95, JM#198) -Group 7 consists of the following: 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 the following: 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 the following: 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 (Identification 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 the following: 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) The '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 having a glutamate linker, 'Dec' indicates decanoic acid on the preceding amino acid, 'Glu-Dec' indicates decanoic acid on the preceding amino acid having a glutamate linker, 'Myr' indicates myristic acid on the preceding amino acid, 'Glu-Myr' indicates myristic acid on the preceding amino acid having a glutamate 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 having a glutamate linker, 'Chl' indicates cholesterol, and 'Ac' indicates that the amino group has been substituted with an acetyl group. The peptide is conjugated to a polymer. 4. The peptide according to 3, wherein the peptide is bound to PEG. 5. The peptide according to 4, wherein the peptide is bound to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine. 6. The peptide according to 3, wherein the peptide is bonded to poly(vinyl alcohol). 7. The peptide according to 3, wherein the peptide is poly(vinylpyrrolidone). 8. A peptide comprising two identical monomeric peptides as described in any of the preceding paragraphs, wherein the monomeric peptides are linked together via a cysteine ​​bridge formed between them to form a dimeric peptide. 9. A peptide or pharmaceutical composition as described in any of the preceding paragraphs, for use in medical treatment. 10. A pharmaceutical composition comprising the peptide described in any of the preceding paragraphs, together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticles, cryoprotectant, cryoprotectant, excipient and / or diluent. 11. Use of the peptide or pharmaceutical composition described in any of the preceding paragraphs for the preparation of formulations in oral, inhalation, intravenous, topical, intranasal, intraperitoneal, subcutaneous, and / or other injectable forms. 12. The use according to 11, wherein the peptide or the pharmaceutical composition is used in the preparation of a lyophilized formulation of a buffer formulation. 13. Treatment of hematopoietic disorders, especially support for stem cell recruitment, proliferation and migration; treatment of wounds, especially burn wounds; treatment of viral diseases, especially HIV-1, HIV-2, cytomegalovirus, herpes simplex virus (types 1 and 2), varicella-zoster virus, hepatitis A and B viruses, influenza virus, poliovirus, rhinovirus, rubella virus, measles virus, rabies virus, rassarcoma virus, and Epstein-Barr virus infections; treatment of bacterial and fungal infections, especially Pseudomonas, Candida, and S. aerus infections; treatment of infection processes and abnormal infection processes; treatment of inflammation, especially periodontal disease; treatment of growth disorders; neurological disorders; blood coagulation cascade and hematopoietic disorders. Peptides or pharmaceutical compositions according to any of the preceding paragraphs for use in the treatment of vascular diseases, immune system disorders, improvement of wound and bone healing, use in the treatment of neurological disorders, particularly stroke, Parkinson's disease, Alzheimer's disease, and multiple sclerosis, treatment in the treatment of warts, hypogammaglobulinemia, immunodeficiency, myelocatexi syndrome, and rheumatoid arthritis, in the treatment of cancer, particularly cancers exhibiting the CXCR receptor, preferably liver, pancreatic, prostate, breast cancer, or other solid tumors, in the treatment of lack of stem cell recruitment, proliferation, and migration, activation of T cells, and support of immunoblasts, preferably cytotoxic T lymphocytes having programmed cell death receptor 1, in the treatment of antifibrosis, treatment or prevention of scars, in the treatment of heart disease, particularly heart failure, and in the treatment of metabolic diseases, particularly diabetes. 14. Methods for preventing and / or treating cancer, viral diseases, metabolic disorders, neurological disorders, immune system disorders, and blood coagulation cascades and hematopoietic disorders in mammals, including humans. 15. A method for producing any of the peptides described in the preceding paragraph 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 that binds to CXC chemokine receptor type 4 (CXCR4), The peptide has stability that allows it to maintain its activity in human plasma for at least 8 hours. The peptide is selected from the group consisting of the following: Sequence ID number: 45 (JM#43), Sequence ID number: 70 (JM#173), Sequence ID number: 71 (JM#174), Sequence ID number: 54 (JM#143), Sequence ID number: 55 (JM#144), Sequence ID number: 56 (JM#145), Sequence ID number: 67 (JM#170), Sequence ID number: 69 (JM#172), Sequence ID number: 88 (JM#191), Sequence ID number: 90 (JM#193), Sequence ID number: 89 (JM#192), Sequence ID number: 91 (JM#194), Sequence ID number: 92 (JM#195), Sequence ID number: 93 (JM#196), and Sequence ID number: 94 (JM#197)

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

3. The peptide according to claim 1, wherein the peptide is bound to a polymer.

4. The peptide according to claim 3, wherein the peptide is bound to PEG.

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

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

7. The peptide according to claim 3, wherein the peptide is bound to poly(vinylpyrrolidone).

8. The peptide according to any one of claims 3 to 7, wherein the polymer is bound to a further peptide, and the further peptide is a peptide having the same amino acid sequence as the peptide described in claim 1.

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

10. A peptide comprising two identical monomeric peptides as described in any one of claims 1 to 9, wherein the monomeric peptides are linked together via a cysteine ​​bridge formed between them to form a dimeric peptide.

11. A pharmaceutical composition comprising the peptide according to any one of claims 1 to 10, together with at least one pharmaceutically acceptable carrier, mesoporous nanoparticles, cryoprotectant, 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 pharmaceuticals.

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

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 described in claim 1 by solid-phase synthesis.

Images