Beta-Arrestin Effectors And Compositions And Methods Of Use Thereof

Abstract

This application describes compounds acting as, for example, β-arrestin effectors and uses thereof, in, for example, the treatment of chronic and acute cardiovascular diseases.

1 . A peptide or peptide mimetic comprising the sequence of
 Sar-Zz-Val-Aa-Xx-His-Bb-Yy (SEQ ID NO: 25), wherein:   Zz is Arg or Met;   Aa is Tyr or D-Cys;   Xx is Pro, NMeIle, Ile, cyHex, cyPen, AA01, AA02, or AA03;   Bb is Pro, Cys, Pro-NH-iPr, Pro-NH-neopentyl, Pro-NH-Et, or Pro-NH-Me;   Yy is any amino acid residue, D-Ala, AA01, AA02, AA03, or null;   provided that when Aa is Tyr and Xx is Ile, Bb is not Pro, Pro-NH-iPr, Pro-NH-neopentyl, Pro-NH-Et, or Pro-NH-Me.   
     
     
         2 . The peptide or peptide mimetic of  claim 1 , wherein Yy is alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, or histidine. 
     
     
         3 . The peptide or peptide mimetic of  claim 1 , wherein Yy is AA01, AA02, or AA03. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The peptide or peptide mimetic of  claim 1 , wherein Xx is cyHex or cyPen. 
     
     
         7 . (canceled) 
     
     
         8 . The peptide or peptide mimetic of  claim 1 , wherein Xx is proline, N-Methyl-isoleuceine, or isoleucine. 
     
     
         9 . The peptide or peptide mimetic of  claim 1 , wherein Xx is AA01, AA02, or AA03. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The peptide or peptide mimetic of  claim 1 , wherein Bb is Pro, Cys, Pro-NH-iPr, Pro-NH-neopentyl, Pro-NH-Et, or Pro-NH-Me. 
     
     
         13 . (canceled) 
     
     
         14 . The peptide or peptide mimetic of  claim 1 , wherein Xx is proline and Yy is alanine, D-alanine, isoleucine, leucine, valine, threonine, serine, methionine, or phenylalanine. 
     
     
         15 . The peptide or peptide mimetic of  claim 1 , wherein:
 Xx is cyHex and Yy is AA01, AA02, AA03, alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, or null; or   wherein Xx is cyPen and Yy is AA01, AA02, AA03, alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, or null.   
     
     
         16 - 20 . (canceled) 
     
     
         21 . The peptide or peptide mimetic of  claim 1 , wherein:
 Xx is AA01 and Yy is AA01, AA02, AA03, alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, or null;   Xx is AA02 and Yy is AA01, AA02, AA03, alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, or null; or   Xx is AA03 and Yy is AA01, AA02, AA03, alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, or null.   
     
     
         22 . The peptide or peptide mimetic of  claim 21 , wherein Yy is alanine, isoleucine, leucine, valine, threonine, serine, methionine, or phenylalanine. 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The peptide or peptide mimetic of  claim 1 , wherein Xx is Ile or NMeIle and Yy is AA01, AA02, AA03, alanine, D-alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, or null. 
     
     
         28 . The peptide or peptide mimetic of  claim 27 , wherein Yy is D-alanine or null. 
     
     
         29 . The peptide or peptide mimetic of  claim 27 , wherein Bb is cysteine. 
     
     
         30 . The peptide or peptide mimetic of  claim 1 , wherein Zz is arginine. 
     
     
         31 - 33 . (canceled) 
     
     
         34 . The peptide or peptide mimetic of  claim 1 , wherein the peptide or peptide mimetic comprises a sequence selected from the group consisting of SEQ ID NOs: 1-24 and 29-60. 
     
     
         35 . The peptide or peptide mimetic of  claim 1 , wherein the peptide or peptide mimetic comprises the sequence of
 Sar-Arg-Val-Tyr-Pro-His-Pro-Yy (SEQ ID NO: 26), wherein Yy is alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, or histidine;   Sar-Zz-Val-Tyr-cyHex-His-Bb-Yy (SEQ ID NO: 27), wherein:   ZZ is arginine or methionine,   Bb is Pro, Pro-NH-i-Pr, Pro-NH-neopentyl, Pro-NH-Et, or Pro-NH-Me; and   Yy is alanine, D-alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, histidine, or null;   Sar-Arg-Val-Tyr-cyPen-His-Pro-Yy (SEQ ID NO: 28), wherein Yy is alanine, D-alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, or histidine;   Sar-Arg-Val-Tyr-AA01-His-Pro-Yy (SEQ ID NO: 61), wherein Yy is alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, histidine, or null;   Sar-Arg-Val-Tyr-AA02-His-Pro-Yy (SEQ ID NO: 62), wherein Yy is alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, histidine, or null;   Sar-Arg-Val-D-Cys-Ile-His-Cys-Yy (SEQ ID NO: 63), wherein Yy is alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, histidine, or null; or   Sar-Arg-Val-Tyr-NMeIle-His-Pro-Yy (SEQ ID NO: 64), wherein Yy is alanine, D-alanine, isoleucine, leucine, valine, threonine, serine, methionine, phenylalanine, glycine, aspartic acid, lysine, asparagine, glutamic acid, tryptophan, proline, tyrosine, or histidine.   
     
     
         36 - 52 . (canceled) 
     
     
         53 . A composition comprising:
 a) a peptide or peptide mimetic of  claim 1 ;   b) a peptide or peptide mimetic wherein the members of the sequence of the peptide or peptide mimetic maintain their relative positions as they appear in the sequence described in a), wherein spacers of 1 to 3 amino acids or amino acid analogues are inserted between one or more of the amino acids or amino acid analogues as described in a) and wherein the total length of the peptide or peptide mimetic is from 8 to 25 amino acids and/or amino acid analogues; or   c) a peptide or peptide mimetic that is at least 85% identical to the peptide or peptide mimetics described in a).   
     
     
         54 - 56 . (canceled) 
     
     
         57 . A pharmaceutical composition comprising one or more peptides or peptide mimetics of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         58 . (canceled) 
     
     
         59 . A method of treating a cardiovascular disorder or treating and/or preventing a viral infectious diseases linked to AT1R comprising administering to a subject or subject in need thereof a therapeutically effective amount of one or more peptides or peptide mimetics of  claim 1 . 
     
     
         60 - 64 . (canceled) 
     
     
         65 . The method of  claim 59 , wherein the one or more peptides or peptide mimetics are selected from the group consisting of SEQ ID NOs: 1-24 and 29-60. 
     
     
         66 - 70 . (canceled)