Mimetic peptides derived from collagen type iv and their use for treating angiogenesis- and lymphangiogenesis- dependent diseases

Abstract

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 .