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CN-122029181-A - Peptide complexes with VEGFR-2 agonist activity

CN122029181ACN 122029181 ACN122029181 ACN 122029181ACN-122029181-A

Abstract

Novel compounds having VEGFR-2 agonist activity are provided. A peptide complex or a pharmaceutically acceptable salt thereof, which comprises a first peptide and has VEGFR-2 agonist activity, wherein the first peptide has an amino acid sequence shown in X 1 -W-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -Y-X 9 -X 10 -X 11 -C（ sequence number 1), or consists of an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added or inserted in the amino acid sequence shown in sequence number 1.

Inventors

  • Haruki Yoshinori
  • SHIBATA YOSHIHIRO
  • Shenwa Qiantai

Assignees

  • 肽梦想株式会社

Dates

Publication Date
20260512
Application Date
20240830
Priority Date
20230831

Claims (18)

  1. 1. A peptide complex or a pharmaceutically acceptable salt thereof comprising a first peptide and having VEGFR-2 agonist activity, wherein, The first peptide has an amino acid sequence shown as a X 1 -W-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -Y-X 9 -X 10 -X 11 -C of a sequence number 1 or is composed of an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added or inserted in the amino acid sequence shown as the sequence number 1, X 1 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group or having a substituted or unsubstituted aromatic ring in a side chain, X 2 is an amino acid having a substituted or unsubstituted alkyl group in a side chain, X 3 is an amino acid having a substituted or unsubstituted chain alkyl group in a side chain, X 4 is an amino acid having a substituted or unsubstituted alkyl group in a side chain, X 5 is any amino acid, and the amino acid, X 6 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group in the side chain or having no side chain, X 7 is an amino acid having a substituted or unsubstituted chain alkyl group in a side chain, X 8 is an amino acid having a substituted or unsubstituted chain alkyl group in a side chain, X 9 is an amino acid having a substituted or unsubstituted aromatic ring in the side chain, X 10 is an amino acid having a substituted or unsubstituted alkyl group in a side chain, X 11 is any amino acid.
  2. 2. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, X 2 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group substituted or unsubstituted with an aromatic ring, X 3 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group in a side chain, X 4 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group substituted or unsubstituted with a polar group, X 7 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group or a chain alkyl group having a branch or no branch in the side chain, X 8 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group or a chain alkyl group having a branch or no branch in the side chain, X 10 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group substituted or unsubstituted with an aromatic ring or a heterocycle.
  3. 3. The peptide complex or a pharmaceutically acceptable salt thereof according to claim 2, wherein, X 1 is W, hcit, 4Py2NH2, 3Py6NH2, F4aao or W7N, X 2 is V, tbg, chg or Hty, X 3 is D, Q or MetO2, X 4 is V, tbg, alT or Chg, X 5 is Q, ahp, W, hph, cha, F COO or K, X 6 is D, G or N, X 7 is D or V, and the total number of the components is D or V, X 8 is L, N or Atb, X 9 is F, bph, yph, F G or F4C, X 10 is V, hph, hty, chg or H4Py, X 11 is D, A, S, F, F aao, har or Hyp.
  4. 4. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, X 2 is an amino acid having a chain or cyclic alkyl group in a side chain, X 4 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group or a chain alkyl group having a branch or no branch in the side chain, X 6 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group in a side chain, X 7 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group in a side chain, X 8 is an amino acid having a chain alkyl group substituted or unsubstituted with a polar group or a chain alkyl group having a branch or no branch in the side chain, X 10 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group substituted or unsubstituted with an aromatic ring.
  5. 5. The peptide complex or a pharmaceutically acceptable salt thereof according to claim 4, wherein, X 1 is W or W7N, X 2 is V, tbg or Chg, X 3 is a number D, and the number D, X 4 is V or alT, X 5 is Ahp, cha or K, X 6 is D or N, and the total number of the components is D or N, X 7 is a number D, and the number D, X 8 is L, N or Atb, X 9 is F or F4G, X 10 is V, hty or Chg, X 11 is D or S.
  6. 6. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, The first peptide has an amino acid sequence represented by W-W-V-D-V-Q-D-D-L-Y-F-V-D-C as sequence number 2, or is composed of an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added or inserted in the amino acid sequence represented by sequence number 2.
  7. 7. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, The first peptide has an amino acid sequence to which glycine has been added at the C-terminus.
  8. 8. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, The first peptide is a peptide composed of an amino acid sequence represented by any one of SEQ ID NOS 3 to 51.
  9. 9. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, The first peptide is a cyclic peptide.
  10. 10. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, The first peptide is a cyclic peptide having an N-terminal amino acid residue which is a chloroacetylated amino acid residue, a cysteine residue within the peptide, and the N-terminal amino acid residue and the cysteine residue being bound.
  11. 11. The peptide complex or pharmaceutically acceptable salt thereof according to claim 1, wherein, The peptide complex is composed of the first peptide, the second peptide and a linker connecting the first peptide and the second peptide, The second peptide may be the same as or different from the first peptide, has an amino acid sequence shown in SEQ ID No. 1, or is composed of an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added or inserted in the amino acid sequence shown in SEQ ID No. 1.
  12. 12. The peptide complex or pharmaceutically acceptable salt thereof according to claim 11, wherein, The homology of the first peptide and the second peptide is more than 90% and less than 100%.
  13. 13. The peptide complex or pharmaceutically acceptable salt thereof according to claim 11, wherein, The first peptide and the second peptide are peptides having the same sequence.
  14. 14. The peptide complex or pharmaceutically acceptable salt thereof according to claim 11, wherein, The 6 th amino acid of the first peptide is bound to the 6 th amino acid of the second peptide or the C-terminus of the first peptide is bound to the C-terminus of the second peptide via the linker.
  15. 15. The peptide complex or pharmaceutically acceptable salt thereof according to claim 11, wherein, The linker is a PEG linker or a linker added with 1-6 amino acids to the PEG linker.
  16. 16. A composition comprising the peptide complex of claim 1 or a pharmaceutically acceptable salt thereof and a carrier.
  17. 17. A composition for cell culture comprising the peptide complex or a pharmaceutically acceptable salt thereof according to claim 1 and a carrier, and is used for cell culture.
  18. 18. A composition comprising the peptide complex of claim 1 or a pharmaceutically acceptable salt thereof and a carrier, and for use in medical, diagnostic or research applications.

Description

Peptide complexes with VEGFR-2 agonist activity Technical Field The present invention relates to a novel peptide complex having VEGFR-2 agonist activity, and a composition for cell culture comprising the same. The present invention also relates to a novel peptide complex having a cell proliferation activity derived from a VEGFR-2 agonist activity, and a composition for cell culture comprising the same. Background Angiogenesis is important in normal physiological processes including embryonic development, follicular development, and wound therapy, and as a main mediator of angiogenesis, vascular endothelial growth factor (vascular endothelial growth factor, VEGF) is exemplified. The receptor for VEGF, VEGFR, is a receptor type tyrosine kinase, and three proteins VEGFR-1 through VEGFR-3 exist. In particular, the binding of VEGF to VEGFR-2 induces dimerization of the receptor and autophosphorylation of tyrosine residues, which induces activation of some of the signaling cascades, inducing differentiation, proliferation and migration of endothelial cells, vascular permeability and angiogenesis. Studies have been reported on wound therapy using VEGFR-2 agonists, treatment of liver dysfunction and liver diseases, and treatment of prevention of liver injury and kidney diseases (patent documents 1, 2, 3, and 4), but no VEGFR-2 agonist peptide has been reported that can be chemically synthesized using the natural VEGF or a variant thereof as the VEGFR-2 agonist. Prior art literature Patent literature Patent document 1 Japanese patent publication No. 2008-546707 Patent document 2 Japanese patent laid-open No. 2010-159466 Patent document 3 Japanese patent application 5111729 Patent document 4 Japanese patent application laid-open No. 2009-541207 Non-patent literature Non-patent documents 1:Rom J Morphol Embryol 2018, 59, 455. Non-patent documents 2:Biomolecules 2020, 10, 1673. Non-patent documents 3:Biology Methods and Protocols, 2023, 8, bpac, 034. Non-patent documents 4:Scientific Reports 2020, 10, 17937. Non-patent document 5:Scientific Reports 4:6716 doi: 10.1038/srep06716. Non-patent documents 6:Developmental Cell 2020, 54, 516. Non-patent literature 7:Cell Reports 2018, 23, 1620. Disclosure of Invention Problems to be solved by the invention One embodiment of the present invention provides novel compounds having VEGFR-2 agonist activity. In addition, one embodiment of the present invention also provides novel compounds having cell proliferation potency derived from VEGFR-2 agonist activity. Means for solving the problems Although not limited thereto, the present invention includes the following aspects. [1] A peptide complex or a pharmaceutically acceptable salt thereof comprising a first peptide and having VEGFR-2 agonist activity, The first peptide has an amino acid sequence shown in X1-W-X2-X3-X4-X5-X6-X7-X8-Y-X9-X10-X11-C（ sequence number 1), or is composed of an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added or inserted in the amino acid sequence shown in sequence number 1, X 1 is an amino acid having a chain alkyl group which may be substituted with a polar group or having an aromatic ring which may be substituted in a side chain, X 2 is an amino acid having an alkyl group which may be substituted in a side chain, X 3 is an amino acid having a chain alkyl group which may be substituted in a side chain, X 4 is an amino acid having an alkyl group which may be substituted in a side chain, X 5 is any amino acid, and the amino acid, X 6 is an amino acid having a chain alkyl group which may be substituted with a polar group in a side chain or having no side chain, X 7 is an amino acid having a chain alkyl group which may be substituted in a side chain, X 8 is an amino acid having a chain alkyl group which may be substituted in a side chain, X 9 is an amino acid having an aromatic ring which may be substituted in a side chain, X 10 is an amino acid having an alkyl group which may be substituted in a side chain, X 11 is any amino acid. [2] The peptide complex or a pharmaceutically acceptable salt thereof according to [1], wherein, X 2 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group which may be substituted with an aromatic ring, X 3 is an amino acid having a chain alkyl group which may be substituted with a polar group in a side chain, X 4 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group which may be substituted with a polar group, X 7 is an amino acid having a chain alkyl group which may be substituted with a polar group or a chain alkyl group which may be branched in a side chain, X 8 is an amino acid having a chain alkyl group which may be substituted with a polar group or a chain alkyl group which may be branched in a side chain, X 10 is an amino acid having a chain or cyclic alkyl group in a side chain or a chain alkyl group which may be substituted with an aromatic ring or a heterocycle.