MIMETIC PEPTIDES DERIVED FROM COLLAGEN TYPE IV AND THEIR USE FOR TREATING ANGIOGENESIS- AND LYMPHANGIOGENESIS- DEPENDENT DISEASES
Mimetic peptides having anti-angiogenic and anti-tumorigenic properties and methods of their use for treating cancer, ocular diseases, such as age-related macular degeneration, and other angiogenesis-dependent diseases are disclosed. More particularly, active non-cysteine analogs (mimetics), which exhibit anti-angiogenic activity in endothelial cell proliferation, migration, adhesion, and tube formation assays, anti-migratory activity in human breast cancer cells in vitro, anti-angiogenic and anti-tumorigenic activity in vivo in breast cancer sonogram models and age-related macular degeneration models are disclosed. The presently disclosed mimetic peptides also exhibit anti-lymphangiogenic and directly anti-tumorigenic properties.
1 .- 52 . (canceled)
53 . A non-naturally occurring peptide comprising the amino acid sequence LRRFSTXPINNVXNF (SEQ ID No:1), wherein X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 10 is M, A, G, dA, or Nle; X at position 11 is F, A, Y, G, or 4-ClPhe; X at position 12 and position 18 are Abu, S and A, wherein the peptide exhibits anti-angiogenic, anti-vascular permeability, anti-tumorigenesis and/or anti-lymphangiogenic properties, and wherein the peptide does not comprise the amino acid sequence LRRFSTMPFMFCNINNVCNF (SEQ ID No:19).
54 . The non-naturally occurring peptide of claim 53 , wherein the peptide does not comprise amino acids FMF at positions 9, 10 and 11, respectively.
55 . The non-naturally occurring peptide of claim 53 , wherein the peptide does not comprise the amino acid sequence LRRFSTMPFMFCNINNVCNF (SEQ ID No:19) with C substituted by Abu, S or A.
56 . The non-naturally occurring peptide of claim 53 , wherein X at position 7 is not M.
57 . The non-naturally occurring peptide of claim 54 , wherein the non-naturally occurring peptide comprises at least one of the following amino acid sequences:
(SEQ ID No: 4)
LRRFSTMPAMFAbuNINNVAbuNF;
(SEQ ID No: 5)
LRRFSTMPFAFAbuNINNVAbuNF;
(SEQ ID No: 6)
LRRFSTMPFMAAbuNINNVAbuNF;
(SEQ ID No: 7)
LRRFSTMPFNleFAbuNINNVAbuNF;
and
(SEQ ID No: 8)
LRRFSTMPFM4-ClPheAbuNINNVAbuNF.
58 . The non-naturally occurring peptide of claim 53 , wherein at least one C-terminal amino acid and/or at least one N-terminal amino acid of SEQ ID NO:1 is deleted, wherein the peptide inhibits the proliferation, adhesion, migration, and/or tube formation of endothelial cells, and wherein the isolated peptide comprises at least one of the following amino acid sequences:
(SEQ ID NO: 18)
LRRFSTMPFMFAbuNINV;
(SEQ ID NO: 20)
LRRFSTMPFMFAbuNINN;
(SEQ ID NO: 21)
LRRFSTMPFMFTNINV;
(SEQ ID NO: 29)
FMFAbuNINNVAbuNF;
(SEQ ID NO: 30)
STMPFAbuNINNVAbuNF;
(SEQ ID NO: 31)
NINNVAbuNF;
and
(SEQ ID NO: 35)
FAbuNINNVAbuN.
59 . A composition comprising a pharmaceutically acceptable substance and an effective amount of at least one non-naturally occurring peptide of claim 53 .
60 . A kit comprising a non-naturally occurring peptide of claim 53 .
61 . A non-naturally occurring peptide having an amino acid sequence at least 90% identical to the amino acid sequence of at least one non-naturally occurring peptide of claim 53 .
62 . The non-naturally occurring peptide of claim 61 , wherein the peptide does not comprise amino acids FMF at positions 9, 10 and 11, respectively.
63 . The non-naturally occurring peptide of claim 61 , wherein the peptide does not comprise the amino acid sequence LRRFSTMPFMFCNINNVCNF (SEQ ID No:19) with C substituted by Abu, S or A.
64 . The non-naturally occurring peptide of claim 61 , wherein X at position 7 is not M.
65 . The non-naturally occurring peptide of claim 61 , wherein the amino acid sequence is at least 95% identical to the amino acid sequence of the at least one non-naturally occurring peptide.
66 . The non-naturally occurring peptide of claim 61 , wherein the amino acid sequence is at least 96% identical to the amino acid sequence of the at least one non-naturally occurring peptide.
67 . The non-naturally occurring peptide of claim 61 , wherein the amino acid sequence is at least 97% identical to the amino acid sequence of the at least one non-naturally occurring peptide.
68 . The non-naturally occurring peptide of claim 61 , wherein the amino acid sequence is at least 98% identical to the amino acid sequence of at least one non-naturally occurring peptide of claim 1 .
69 . The non-naturally occurring peptide of claim 61 , wherein the amino acid sequence is at least 99% identical to the amino acid sequence of the at least one non-naturally occurring peptide.
70 . A composition comprising a pharmaceutically acceptable substance and an effective amount of at least one non-naturally occurring peptide of claim 61 .
71 . A kit comprising a non-naturally occurring peptide of claim 61 .