Endothelial-cell binding peptides for diagnosis and therapy
OwnerJeno Gyuris, Lou Lamphere +2inventors
InventorsJeno Gyuris, Lou Lamphere, Aaron J. Morris, Katherine Tsaioun
Life of this patent
Estimating the term…
Abstract
The present invention relates to peptides and their derivatives which bind to endothelial cells and inhibit their proliferation in in vitro assays, e.g., also referred to herein as endothelial cell binding peptide (ECBP) or ECBP sequence. These compositions may be combined with a pharmaceutically acceptable excipient or carrier and used to inhibit angiogenesis and angiogenesis-related diseases such as cancer, arthritis, macular degeneration, and diabetic retinopathy.
Claims66
An isolated, synthetic or recombinant peptide or polypeptide which includes one or more ECBP sequences, each having an amino acid sequence independently represented in any of the following sequences:
- 5 T-h-s-X-X-X-X-u-s-G-s-G-K or (SEQ ID NO:
- 531) h-p-X-X-Y-t-h-X-s-s or (SEQ ID NO:
- 532) S-X-X-u-M-s-V or (SEQ ID NO:
- 533) t-h-h-s-L-R-h-X-a-u or (SEQ ID NO:
- 534) s-s-G-h-X-s-X-a-a-h-p-s or (SEQ ID NO:
- 535) p-s-a-h-X-X-T-s-V-P-h or (SEQ ID NO:
- 536) L-X-N-p-s-p-p-t-G-t-t-t or (SEQ ID NO:
- 537) h-h-P-+-h-h-L-p-p-h-h-t or (SEQ ID NO:
- 538) s-s-l-h-s-h-s-s-X-p-p-A or (SEQ ID NO:
- 539) S-s-c-N-H-X-t-X-X-c-s or (SEQ ID NO:
- 540) s-t-h-H-X-X-X-t-X-h-s-L or (SEQ ID NO:
- 541) h-h-h-T-S-h-p-X-X-t-X-t-s-h or (SEQ ID NO:
- 542) h-X-h-X-S-h-s-h-p-L-p or (SEQ ID NO:
- 543) s-X-T-hX-p-X-H-s-oh-s or (SEQ ID NO:
- 544) t-o-s-T-S-h-h-s-s or (SEQ ID NO:
- 545) L-P-s-X-K-p-h-T-p-u-h-s or (SEQ ID NO:
- 546) h-S-P-t-Q-Q-p-hp-s-x-T-u or (SEQ ID NO:
- 547) t-W-K-s-P-S or (SEQ ID NO:
- 548) h-T-S-P-h-h or (SEQ ID NO:
- 549) u-h-p-S-t-h-T-h or (SEQ ID NO:
- 550) h-h-h-h-P-H-X-h-t-s or (SEQ ID NO:
- 551) A-X-X-p-X-X-o-p-P-h-h or (SEQ ID NO:
- 552) s-h-h-G-o-L-h-X-p-s-T-t-s-s or (SEQ ID NO:
- 553) h-p-X-H-h-X-X-p-S-o-X-t or (SEQ ID NO:
- 554) u-X-u-X-h-s-X-X-P-R-X-h or (SEQ ID NO:
- 555) h-h-X-R-P-X-X-M-P or (SEQ ID NO:
- 556) h-s-Q-T-s-T-X-h-X-h-h or (SEQ ID NO:
- 557) p-A-s-s-s-X-X-p-s-p-h-u or (SEQ ID NO:
- 558) s-S-h-t-M-K-P-S-P-p-P-L-s-A or (SEQ ID NO:
- 559) s-A-h-P-A-t-p-h-X-t-h-s-s or (SEQ ID NO:
- 560) T-p-s-Y-P-s-R-h-G-s-p-P-H-P-c or (SEQ ID NO:
- 561) s-X-P-s-h-G-P-h-A-a or (SEQ ID NO:
- 562) s-h-W-X-s-X-X-h-s or (SEQ ID NO:
- 563) s-T-G-s-s-s-P-X-S-t or (SEQ ID NO:
- 564) s-s-s or (SEQ ID NO:
- 565) s-T-X-H-s-s-p or (SEQ ID NO:
- 566) A-t-s-s-P-+-V-h-s-L-s or (SEQ ID NO:
- 567) s-.-h-P-P-t-t-L or (SEQ ID NO:
- 568) t-X-X-X-L-X-s-s-h-s-p-s or (SEQ ID NO:
- 569) L-P-X-X-X-h-L or (SEQ ID NO:
- 570) T-t-h-h-s-h-P-R-h-X-t or (SEQ ID NO:
- 571) L-X-X-s-X-X-X-O-p-q or (SEQ ID NO:
- 572) s-X-h-L-p-T-P-t-X-c-a-p-N or (SEQ ID NO:
- 573) h-t-h-X-s-P-P-X-h-X-X-s or (SEQ ID NO:
- 574) h-h-h-P-X-h-T-s-X-X-S-p or (SEQ ID NO:
- 575) t-s-s-X-Q-P-S-X-h-s-A-p or (SEQ ID NO:
- 576) E-t-X-s-L-X-R-h-L or (SEQ ID NO:
- 577) H-t-X-p-X-P-P-s-L-h-p-X-L or (SEQ ID NO:
- 578) p-h-s-X-s-l-l-P-X-p-h-X-F or (SEQ ID NO:
- 579) p-p-X-X-s-A-h-X-s-l-u-P-X-s or (SEQ ID NO:
- 580) H-h-s-X-S-P-p-h-s-W-s-X-L or (SEQ ID NO:
- 581) W-P-h-t-D-h-P or (SEQ ID NO:
- 582) s-p-T-t-A-P-l-s-X-s-s-h or (SEQ ID NO:
- 583) h-X-s-s-h-T-o-h-R-S or (SEQ ID NO:
- 584) t-h-X-h-s-o-t-X-A-P-A-t-P-h or (SEQ ID NO:
- 585) M-+-X-s-h-p-A-P-s-s-t-A-h-H or (SEQ ID NO:
- 586) u-p-t-p-p-X-X-h-T-h-s-s-h-X-s or (SEQ ID NO:
- 587) Y-Y-P-A-X-S-t-h-p-o-R-s or (SEQ ID NO:
- 588) t-T-t-T-h-L-a-u-X-t-p-t or (SEQ ID NO:
- 589) p-X-X-h-H-s-T-h-p-s-H-t-h or (SEQ ID NO:
- 590) s-N-X-X-X-X-T-X-s-t-p-s-X-h-p or (SEQ ID NO:
- 591) A-t-o-h-s-P-X-A-s-h-h or (SEQ ID NO:
- 592) h-H-s-X-p-h-N-X-X-s-T-X-s-+-s or (SEQ ID NO:
- 593) Y-q-h-X-s-X-p-s-X-p or (SEQ ID NO:
- 594) p-s-h-s-+-F-N-X-s-X-p-P or (SEQ ID NO:
- 595) s-p-h-s-X-h-s-P-u-X-h or (SEQ ID NO:
- 596) T-X-t-N-u-X-X-s-X-M-+-t or (SEQ ID NO:
- 597) S-M-V-Y-G-X-p-X-s-X-A or (SEQ ID NO:
- 5981) o-s-X-X-h-p-X-X-+-S-h-P-P-R-h or (SEQ ID NO:
- 599) t-h-t-P-h-S-X-S-h-X-h-P or (SEQ ID NO:
- 600) u-s-X-l-X-h-X-s-p-s or (SEQ ID NO:
- 601) h-t-Q-S-h-l-+-s-h-h-h-h or (SEQ ID NO:
- 602) s-p-p-X-h-s-L-t-S-s-p-X-h-h-h-D or (SEQ ID NO:
- 603) S-l-n-x-h-X-X-X-X-X-d-s or (SEQ ID NO:
- 604) S-L-H-X-L-X-t-D-h-h-h or (SEQ ID NO:
- 605) h-X-h-h-D-+-R-t-A-X-h-h or (SEQ ID NO:
- 606) p-X-u-X-X-X-X-R-X-s or (SEQ ID NO:
- 607) E-t-M-a-h-S-X-L or (SEQ ID NO:
- 608) N-X-X-X-X-p-p-h-h-t or (SEQ ID NO:
- 609) s-X-X-a-p-S-T-h-p-A-p-A or (SEQ ID NO:
- 610) S-p-X-h-X-t-Q-R-X-h-p-h or (SEQ ID NO:
- 611) p-X-h-X-Q-X-X-X-A-X-h-P or (SEQ ID NO:
- 612) u-s-X-p-h-t-X-S-S-h-t-h or (SEQ ID NO:
- 613) s-h-+-s-p-S-X-X-X-s-l-s-Y-p or (SEQ ID NO:
- 614) s-M-s-s-h-h-p-S-s-X-s-s-R or (SEQ ID NO:
- 615) h-h-s-h-Q-S-X-X-X-X-h or (SEQ ID NO:
- 616) o-X-h-s-S-M-h-h-h-s or (SEQ ID NO:
- 617) h-s-V-h-u-S-s-X-X-T or (SEQ ID NO:
- 618) h-S-t-L-P-H-h-X-L-s or (SEQ ID NO:
- 619) H-u-L-P-h-T-h-p-s-A-h or (SEQ ID NO:
- 620) h-h-X-p-p-T-H-X-h-P-h-p-s or (SEQ ID NO:
- 621) t-s-h-p-T-s-t-h-h-s-A or (SEQ ID NO:
- 622) t-s-T-s-Q-h-h-h-X-p-t-h or (SEQ ID NO:
- 623) h-X-h-s-p-D-V-p-h-X-h-h or (SEQ ID NO:
- 624) h-h-h-D-s-p-p-s-X-s-t-s-X-t or (SEQ ID NO:
- 625) p-X-X-X-X-X-R-h-T-X-h or (SEQ ID NO:
- 626) s-N-t-h-o-D-s-u-R-h or (SEQ ID NO:
- 627) I-X-X-X-c-L-T-X-P-s-P-t or (SEQ ID NO:
- 628) u-s-p-s-t-h-Q-s-R-t-h or (SEQ ID NO:
- 629) T-p-p-c-X-h-s-X-s-Y-h-A or (SEQ ID NO:
- 630) P-p-H-h-R-X-h-S-s-t-X-h or (SEQ ID NO:
- 631) s-p-+-c-h-p-X-u-R-t-h-p or (SEQ ID NO:
- 632) H-X-a-p-+-s-X-a-Y-p-s-A (SEQ ID NO:
- 633)
- wherein
- X represents any amino acid residue;
- o represents an amino acid with an alcoholic side chain, e.g., Ser or Thr;
- l represents an amino acid with an aliphatic side chain, e.g., lie or Leu or Val;
- a represents an amino acid with an aromatic side chain, e.g., Phe or His or Trp or Tyr;
- c represents an amino acid with a charged side chain, e.g., Glu or Asp or His or Lys or Arg;
- h represents an amino acid with a hydrophobic side chain, e.g., Ala or Cys or Phe or Gly or His or Ile or Lys or Leu or Met or Arg or Thr or Val Try or Tyr;
- − represents an amino acid with a negatively charged side chain, e.g., Glu or Asp;
- p represents an amino acid with a polar side chain, e.g., Cys or Asp or Glu or His or Lys or Asn or Gin or Arg or Ser or Thr;
- + represents an amino acid with a positive side chain, e.g., His or Lys or Arg;
- s represents an amino acid with a small side chain, e.g., Ala or Cys or Asp or Gly or Asn or Pro or Ser or Thr or Val;
- u represents an amino acid with a tiny side chain, e.g., Ala or Gly or Ser;
- and
- t represents an amino acid most likely situated at a turn, e.g., Ala or Cys or Asp or Glu or Gly or His or Lys or Asn or Gln or Arg or Ser or Thr.
An isolated or recombinant peptide or polypeptide which includes one or more ECBP sequence, each having an amino acid sequence independently represented in any of the following sequences:
- 6 A-D-Y-R-S-SV-G-G-G-K or (SEQ ID NO:
- 634) L-S-N-N-s-K-H or (SEQ ID NO:
- 635) G-P-H-L-M-L-Q-N-K-L-R or (SEQ ID NO:
- 636) S-S-S-D-N-H-X-u-Q-L-H-T or (SEQ ID NO:
- 637) s-u-R-H-Q-S-W-H-P-H-D or (SEQ ID NO:
- 638) h-S-P-t-Q-Q-R-h-H-N-S-T or (SEQ ID NO:
- 639) A-P-I-H-L-H-S-c-P-L-L-H or (SEQ ID NO:
- 640) H-o-X-T-K-P-L or (SEQ ID NO:
- 641) H-s-I-Y-P-R-p or (SEQ ID NO:
- 642) Q-P-h-P-T-S-I or (SEQ ID NO:
- 643) h-A-s-u-S-M-P-T-s-R-L-A or (SEQ ID NO:
- 644) Y-H-h-P-P-S-s-T-P-L-s-A or (SEQ ID NO:
- 645) s-s-s-s-M-K-P-S-P-X-P or (SEQ ID NO:
- 646) T-T-s-Y-P-A-R-W-G-A-H-P or (SEQ ID NO:
- 647) L-P-I-s-K-A-L or (SEQ ID NO:
- 648) A-h-L-T-G-P-R or (SEQ ID NO:
- 649) p-S-L-H-Q-R-L or (SEQ ID NO:
- 650) H-Q-I-T-Q-P-p-S-L-L-S-P or (SEQ ID NO:
- 651) A-I-P-X-V-P or (SEQ ID NO:
- 652) H-K-A-P-S-P-K-h-D-W-s-P or (SEQ ID NO:
- 653) E-T-p-A-P-L or (SEQ ID NO:
- 654) G-E-T-X-A-P-h or (SEQ ID NO:
- 655) M-K-S-s-I-P-A-P-s-G-G or (SEQ ID NO:
- 656) S-P-F-R-A-P-s or (SEQ ID NO:
- 657) Y-P-h-R-A-P-T-s-Q-A-h-H or (SEQ ID NO:
- 658) S-T-A-o-Y-T-R or (SEQ ID NO:
- 659) Y-Y-P-A-u-S-T-I-Q-S-R-P or (SEQ ID NO:
- 660) H-D-T-Y-s-s-H or (SEQ ID NO:
- 661) H-A-A-T-M-P or (SEQ ID NO:
- 662) S-R-F-N-X-D or (SEQ ID NO:
- 663) T-X-p-N-G-P-S or (SEQ ID NO:
- 664) G-X-T-P-S-h-A or (SEQ ID NO:
- 665) S-M-V-Y-G-N-p-L-P-S-A-L or (SEQ ID NO:
- 666) h-A-h-S-M-P-P or (SEQ ID NO:
- 667) T-E-Q-p-W-I-K-N-I-Y-A-R or (SEQ ID NO:
- 668) A-L-H-S-A-R or (SEQ ID NO:
- 669) h-L-H-S-D-R-A-L-M-I-D or (SEQ m NO:
- 670) S-A-P-L-t-S or (SEQ ID NO:
- 671) H-S-S-T-h-R-A or (SEQ ID NO:
- 672) S-p-P-W-s-A-Q-R-E-L-S-V or (SEQ ID NO:
- 673) u-T-W-S-H-H-h-S-S-u-u-L or (SEQ ID NO:
- 674) G-W-S-S-Y-R or (SEQ ID NO:
- 675) A-M-s-P-R-p-H-S-s-P-S-V or (SEQ ID NO:
- 676) M-P-A-V-M-S-S-s-Q-V-P-R or (SEQ ID NO:
- 677) L-L-A-D-T-T-H-H-h-P-W-T or (SEQ ID NO:
- 678) K-N-L-N-T-T-u-M-Y-A-A-S or (SEQ ID NO:
- 679) I-L-A-X-D-L-T-X-X-G-P or (SEQ ID NO:
- 680) O-G-K-W-Q-P-R or (SEQ ID NO:
- 681) G-L-Q-u-R-H-I or (SEQ ID NO:
- 682) K-h-I-P-t-T-Y or (SEQ ID NO:
- 683) Q-S-H-Y-R-X-I-S-P-A-Q-V (SEQ ID NO:
- 684)
- wherein
- X represents any amino acid residue;
- o represents an amino acid with an alcoholic side chain, e.g., Ser or Thr;
- l represents an amino acid with an aliphatic side chain, e.g., Ile or Leu or Val;
- a represents an amino acid with an aromatic side chain, e.g., Phe or His or Trp or Tyr;
- c represents an amino acid with a charged side chain, e.g., Glu or Asp or His or Lys or Arg;
- h represents an amino acid with a hydrophobic side chain, e.g., Ala or Cys or Phe or Gly or His or Ile or Lys or Leu or Met or Arg or Thr or Val Try or Tyr;
- − represents an amino acid with a negatively charged side chain, e.g., Glu or Asp;
- p represents an amino acid with a polar side chain, e.g., Cys or Asp or Glu or His or Lys or Asn or Gln or Arg or Ser or Thr;
- + represents an amino acid with a positive side chain, e.g., His or Lys or Arg;
- s represents an amino acid with a small side chain, e.g., Ala or Cys or Asp or Gly or Asn or Pro or Ser or Thr or Val;
- u represents an amino acid with a tiny side chain, e.g., Ala or Gly or Ser;
- and
- t represents an amino acid most likely situated at a turn, e.g., Ala or Cys or Asp or Glu or Gly or His or Lys or Asn or Gln or Arg or Ser or Thr.
An isolated, synthetic or recombinant peptide or polypeptide which includes one or more ECBP sequences, each having an amino acid sequence independently represented in any of SEQ ID Nos:
- 1-530.
A method for promoting the proliferation and/or migration of endothelial cells comprising treating the cells with an ECBP agonist in an amount sufficient to promote proliferation and/or migration of the treated cells.
A method for reducing the proliferation and/or migration of endothelial cells comprising treating the cells with an ECBP antagonist in an amount sufficient to reduce proliferation and/or migration of the treated cells.
A method for reducing angiogenesis comprising treating an mammal with an ECBP antagonist in an amount sufficient to reduce angiogenesis at one or more sites in the treated mammal.
A method for promoting angiogenesis comprising treating an mammal with an ECBP agonist in an amount sufficient to promote angiogenesis at one or more sites in the treated mammal.
A medicament for promoting angiogenesis comprising an ECBP agonist in an amount sufficient to promote angiogenesis at one or more sites in the treated mammal.
A method for manufacturing a medicament for promoting angiogenesis comprising admixing an ECBP agonist, in an amount sufficient to promote angiogenesis at one or more sites in a treated mammal, with a pharmaceutically acceptable excipient.
A medicament for reducing angiogenesis comprising an ECBP antagonist in an amount sufficient to reduce angiogenesis at one or more sites in the treated mammal.
A method for manufacturing a medicament for inhibiting angiogenesis comprising admixing an ECBP antagonist, in an amount sufficient to reduce angiogenesis at one or more sites in a treated mammal, with a pharmaceutically acceptable excipient.
A method of conducting a drug discovery business comprising:
- (i) identifying, from a variegated library of peptides, members of the library bind to endothelial cells;
- (ii) from the members of the library identified in step (i), identifying peptides which inhibit or promote growth and/or migration of endothelial cells;
- (iii) conducting therapeutic profiling of an agent including the peptide identified in step (ii), or peptidomimetic thereof or a protein containing the peptide for efficacy and toxicity in mammals;
- and
- (iv) formulating a pharmaceutical preparation including one or more agents identified in step (iii) as having an acceptable therapeutic profile.
A method of conducting a drug discovery business comprising:
- (i) identifying, from a variegated library of peptides, members of the library bind to endothelial cells;
- (ii) from the members of the library identified in step (i), identifying peptides which inhibit or promote growth and/or migration of endothelial cells;
- (iii) conducting therapeutic profiling of an agent including the peptide identified in step (ii), or peptidomimetic thereof or a protein containing the peptide for efficacy and toxicity in mammals;
- and
- (iv) licensing, to a third party, the rights for further drug development of one or more agents identified in step (iii) as having an acceptable therapeutic profile.
A method of conducting a drug discovery business comprising:
- (i) identifying, from a variegated library of peptides, members of the library bind to endothelial cells;
- (ii) from the members of the library identified in step (i), identifying peptides which inhibit or promote growth and/or migration of endothelial cells;
- (iii) licensing, to a third party, the rights for further drug development based on one or more peptides identified in step (ii).
Dependencies are inferred from the claim text.