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KR-20260062945-A - Peptide complex having VEGFR-2 agonist activity

KR20260062945AKR 20260062945 AKR20260062945 AKR 20260062945AKR-20260062945-A

Abstract

The present invention provides a new compound having VEGFR-2 agonist activity. A peptide complex or a pharmaceutically acceptable salt thereof comprising a first peptide and having VEGFR-2 agonist activity, wherein the first peptide comprises an amino acid sequence represented by X1 -W- X2 - X3 - X4 - X5 - X6 - X7 - X8 - YX9 - X10 - X11 -C (SEQ No. 1) or an amino acid sequence represented by SEQ No. 1 in which 1 to 3 amino acids are substituted, deleted, added, or inserted.

Inventors

  • 스즈키 요시노리
  • 시바타 요시히로
  • 카미쿠보 켄타

Assignees

  • 페프티드림 아이엔씨.

Dates

Publication Date
20260507
Application Date
20240830
Priority Date
20230831

Claims (18)

  1. A peptide complex comprising a first peptide and having VEGFR-2 agonist activity, or a pharmaceutically acceptable salt thereof, The above-mentioned first peptide is, Having an amino acid sequence represented by X 1 -WX 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -YX 9 -X 10 -X 11 -C (Sequence No. 1), or The amino acid sequence represented by SEQ ID NO. 1 is composed of an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added, or inserted, and X1 is an amino acid having a chain-type alkyl group that may be substituted with a polar group on the side chain, or having an aromatic ring that may be substituted, and X 2 is an amino acid having an alkyl group that may be substituted as a side chain, and X 3 is an amino acid having a chain-type alkyl group that may be substituted with a side chain, and X 4 is an amino acid having an alkyl group that may be substituted as a side chain, and X 5 is any amino acid, and X6 is an amino acid having a chain-type alkyl group that may be substituted with a polar group in the side chain, or having no side chain, and X 7 is an amino acid having a chain-type alkyl group that may be substituted with a side chain, and X 8 is an amino acid having a chain-type alkyl group that may be substituted with a side chain, and X 9 is an amino acid having an aromatic ring that may be substituted with a side chain, and X 10 is an amino acid having an alkyl group that may be substituted as a side chain, and X 11 is any amino acid, Peptide complex or pharmaceutically acceptable salt thereof.
  2. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, X 2 is an amino acid having a chain-type or cyclic alkyl group in its side chain, or having a chain-type alkyl group that may be substituted with an aromatic ring, and X3 is an amino acid having a chain-type alkyl group that may be substituted with a polar group on the side chain, and X 4 is an amino acid having a chain-type or cyclic alkyl group in its side chain, or having a chain-type alkyl group that may be substituted with a polar group, and X 7 is an amino acid having a chain-type alkyl group that may be substituted with a polar group on the side chain, or a chain-type alkyl group that may be branched, and X 8 is an amino acid having a chain-type alkyl group that may be substituted with a polar group in the side chain, or a chain-type alkyl group that may be branched, and X 10 is an amino acid having a chain-like or cyclic alkyl group in a side chain, or having a chain-like alkyl group substituted with an aromatic ring or a heterocyclic ring, Peptide complex or pharmaceutically acceptable salt thereof.
  3. In the peptide complex or its pharmaceutically acceptable salt described in claim 2, X 1 is W, Hcit, 4Py2NH2, 3Py6NH2, F4aao, or W7N, and X 2 is V, Tbg, Chg, or Hty, and X 3 is D, Q, or MetO2, and X 4 is V, Tbg, alT, or Chg, and X 5 is Q, Ahp, W, Hph, Cha, F4COO, or K, and X 6 is D, G, or N, and X 7 is D or V, and X 8 is L, N, or Atb, and X 9 is F, Bph, Yph, F4G, or F4C, and X 10 is V, Hph, Hty, Chg, or H4Py, and X 11 is D, A, S, F, F4aao, Har, or Hyp, Peptide complex or pharmaceutically acceptable salt thereof.
  4. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, X 2 is an amino acid having a chain-like or cyclic alkyl group in a side chain, and X 4 is an amino acid having a chain-type alkyl group that may be substituted with a polar group on the side chain, or a chain-type alkyl group that may be branched, and X6 is an amino acid having a chain-type alkyl group that may be substituted with a polar group in the side chain, and X 7 is an amino acid having a chain-type alkyl group that may be substituted with a polar group in the side chain, and X 8 is an amino acid having a chain-type alkyl group that may be substituted with a polar group in the side chain, or a chain-type alkyl group that may be branched, and X 10 is an amino acid having a chain-type or cyclic alkyl group in its side chain, or having a chain-type alkyl group that may be substituted with an aromatic ring, Peptide complex or pharmaceutically acceptable salt thereof.
  5. In the peptide complex or its pharmaceutically acceptable salt described in paragraph 4, X 1 is W or W7N, and X 2 is V, Tbg, or Ch g , and X 3 is D, and X 4 is V or alT, and X 5 is Ahp, Cha, or K, and X 6 is D or N, and X 7 is D, X 8 is L, N, or Atb, and X 9 is F or F4G, and X 10 is V, Hty, or Chg, and X 11 is D or S, Peptide complex or pharmaceutically acceptable salt thereof.
  6. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, The above-mentioned first peptide is, Having the amino acid sequence represented by WWVDVQDDLYFVDC (SEQN 2), or The amino acid sequence represented by SEQ ID NO. 2, comprising an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added, or inserted. Peptide complex or pharmaceutically acceptable salt thereof.
  7. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, The first peptide is a peptide complex or a pharmaceutically acceptable salt thereof having an amino acid sequence with glycine added to the C-terminus.
  8. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, The above-mentioned first peptide is a peptide complex or a pharmaceutically acceptable salt thereof that is a peptide having an amino acid sequence represented by any one of SEQ ID NOs 3 to 51.
  9. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, The first peptide is a peptide complex that is a cyclic peptide or a pharmaceutically acceptable salt thereof.
  10. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, The above-mentioned first peptide is a chloroacetylated amino acid residue having an N-terminal amino acid residue and a cysteine residue within the peptide, and is a cyclic peptide in which the N-terminal amino acid residue and the cysteine residue are bonded, a peptide complex or a pharmaceutically acceptable salt thereof.
  11. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 1, The above peptide complex comprises the first peptide and the second peptide, and a linker connecting the first peptide and the second peptide, and The second peptide may be identical to or different from the first peptide, and may have an amino acid sequence represented by SEQ ID NO. 1 or The amino acid sequence represented by SEQ ID NO. 1, comprising an amino acid sequence in which 1 to 3 amino acids are substituted, deleted, added, or inserted. Peptide complex or pharmaceutically acceptable salt thereof.
  12. A peptide complex or a pharmaceutically acceptable salt thereof described in claim 11, wherein the homology between the first peptide and the second peptide is 90% or more and 100% or less.
  13. A peptide complex or a pharmaceutically acceptable salt thereof described in claim 11, wherein the first peptide and the second peptide are peptides having the same arrangement.
  14. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 11, A peptide complex or a pharmaceutically acceptable salt thereof in which the 6th amino acid of the first peptide and the 6th amino acid of the second peptide, or the C-terminus of the first peptide and the C-terminus of the second peptide are joined through the linker.
  15. In the peptide complex or pharmaceutically acceptable salt thereof described in claim 11, A peptide complex or its pharmaceutically acceptable salt, wherein the above linker is a PEG linker or a linker to which 1 to 6 amino acids are added to a PEG linker.
  16. A composition comprising the peptide complex described in claim 1 or a pharmaceutically acceptable salt thereof and a carrier.
  17. A cell culture composition comprising the peptide complex described in claim 1 or a pharmaceutically acceptable salt thereof and a carrier, used for cell culture.
  18. A composition comprising the peptide complex described in claim 1 or a pharmaceutically acceptable salt thereof and a carrier, used for medical, diagnostic, or research purposes.

Description

Peptide complex having VEGFR-2 agonist activity [0001] The present invention relates to a novel peptide complex having VEGFR-2 agonist activity and a composition for cell culture comprising the peptide complex. In addition, the present invention relates to a novel peptide complex having cell proliferation ability derived from VEGFR-2 agonist activity and a composition for cell culture comprising the peptide complex. [0002] Angiogenesis is important in normal physiological processes, including embryonic development, follicular development, and wound healing, and vascular endothelial growth factor (VEGF) can be cited as a major mediator of angiogenesis. VEGFR, the receptor for VEGF, is a type of receptor tyrosine kinase, and there are three types of proteins: VEGFR-1 to VEGFR-3. In particular, the binding of VEGF to VEGFR-2 induces receptor dimerization and autophosphorylation of tyrosine residues; this autophosphorylation induces the activation of various signaling cascades and leads to the differentiation, proliferation, and migration of endothelial cells, as well as vascular permeability and angiogenesis. Studies on wound healing, treatment of liver dysfunction or liver disease, protection from liver damage, and treatment of kidney disease using VEGFR-2 agonists have been reported (Patent Documents 1, 2, 3, 4), but the VEGFR-2 agonists used in these studies are natural VEGF or variants thereof, and no chemically synthesizable VEGFR-2 agonist peptides have been reported. [0008] Figure 1A shows the results of a Human Phospho-RTK Array analysis evaluation using the peptide complex and VEGF165a of the present invention. Figure 1A illustrates an array map of target factors. Figure 1B shows the evaluation results. [0009] The present invention includes the following embodiments without limitation. Unless otherwise stated herein, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. The materials, materials, and examples disclosed herein are merely illustrative and are not intended to be limiting. Where the phrase “in one embodiment” is used herein, it means that the invention is not limited to that embodiment, i.e., is non-limiting. [0010] The first invention of this specification relates to a peptide complex or a pharmaceutically acceptable salt thereof. This peptide complex or the pharmaceutically acceptable salt thereof comprises a first peptide and has VEGFR-2 agonist activity. Furthermore, this peptide complex or the pharmaceutically acceptable salt thereof has cell proliferation ability derived from VEGFR-2 agonist activity. The pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt of the peptide complex. The pharmaceutically acceptable salt is as described below. Hereinafter, for simplicity, the peptide complex or the pharmaceutically acceptable salt thereof may be simply referred to as the peptide complex. [0011] peptide complex In one embodiment, the peptide complex of the present invention comprises a first peptide and has VEGFR-2 agonist activity. In addition, in one embodiment, the peptide complex of the present invention has cell proliferation ability derived from VEGFR-2 agonist activity. The above-mentioned peptide complex is a peptide, a peptide-containing compound, or a pharmaceutically acceptable salt thereof comprising a first peptide and other peptides and compounds. The above-mentioned peptide complex may comprise one or two or more (three or more or four or more) the first peptide. The above-mentioned peptide complex may also comprise one or two or more subpeptides different from the first peptide. It is preferable that the first peptide or subpeptides are bound to the above-mentioned peptide complex through a linker. The above-mentioned peptide complex may be a homomultimer comprising only peptides having the same amino acid sequence. The above-mentioned peptide complex may be a heteromultimer comprising peptides having different amino acid sequences. The above-mentioned peptide complex has two first peptides having the same amino acid sequence, and is preferably a homodimer in which the two first peptides are linked through a linker. In the homodimer, the two peptide portions may have completely identical amino acid sequences or substantially identical amino acid sequences. The above-mentioned peptide complex has VEGFR-2 agonist activity, but the first peptide or the portion peptide constituting the peptide complex may also have VEGFR-2 agonist activity. As shown in the example, the first peptide exhibits VEGFR-2 agonist activity by assuming a peptide complex structure through a linker. [0012] In one embodiment, the peptide complex of the present invention may comprise a first peptide, a second peptide, and a linker connecting the first peptide and the second peptide. In this case, the second peptide may be identical to or different from the first peptide, and it is preferable that the second peptide has