Peptidomimetic macrocycles

Abstract

The present invention provides novel peptidomimetic macrocycles and methods of using such macrocycles for the treatment of viral disease.

1 .- 23 . (canceled) 
     
     
         24 . A composition comprising:
 a) a peptidomimetic macrocycle comprising an amino acid sequence wherein two amino acids in the amino acid sequence are cross-linked by a crosslinker, wherein the crosslinker comprises a 1, 4-disubstituted triazole and does not comprise a 1, 5-substituted triazole;   b) a Cu(I) species; and   c) a Ru(II) species.   
     
     
         25 . The composition of claim  1 , wherein the peptidomimetic macrocycle comprises a helix. 
     
     
         26 . The composition of claim  1 , wherein the helix is an alpha helix. 
     
     
         27 . The composition of claim  1 , wherein the peptidomimetic macrocycle comprises a beta turn. 
     
     
         28 . The composition of claim  1 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         29 . The composition of claim  1 , wherein the peptidomimetic macrocycle comprises more than one stabilized secondary structure. 
     
     
         30 . The composition of claim  1 , wherein the crosslinker spans one turn of a secondary structure of the peptidomimetic macrocycle. 
     
     
         31 . The composition of claim  1 , wherein the 1, 5-disubstituted triazole has a formula 
       
         
           
           
               
               
           
         
       
       and the 1, 4-disubstituted triazole has a formula 
       
         
           
           
               
               
           
         
         wherein L 1  and L 2  are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —]n, each being optionally substituted with R 5 ; 
         each R 4  is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
         each K is O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; 
         each R 5  is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; 
         each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; and 
         n is an integer from 1 to 5. 
       
     
     
         32 . The composition of claim  8 , wherein each L 1  and L 2  is independently an alkylene. 
     
     
         33 . A composition comprising:
 a) a peptidomimetic macrocycle comprising:
 i) an amino acid sequence wherein two amino acids are cross-linked by a hydrocarbon crosslinker; 
 ii) an azido moiety; and 
 iii) an alkyne moiety; and 
   b) a Ru(II) species.   
     
     
         34 . The composition of  claim 33 , wherein the peptidomimetic macrocycle comprises a helix. 
     
     
         35 . The composition of  claim 34 , wherein the helix is an alpha helix. 
     
     
         36 . The composition of  claim 33 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         37 . The composition of  claim 33 , wherein the peptidomimetic macrocycle comprises more than one stabilized secondary structure. 
     
     
         38 . The composition of  claim 33 , wherein the cross-linked amino acids are at position i and i+3 of the peptidomimetic macrocycle. 
     
     
         39 . The composition of  claim 33 , wherein the crosslinker spans one or two turns of a secondary structure of the peptidomimetic macrocycle. 
     
     
         40 . A composition comprising:
 a) a peptidomimetic macrocycle comprising:
 i) an amino acid sequence wherein two amino acids are cross-linked by a triazole-containing crosslinker; and 
 ii) two terminal olefin moieties; and 
   b) a Cu(I) species.   
     
     
         41 . The composition of  claim 40 , wherein the peptidomimetic macrocycle comprises a beta turn. 
     
     
         42 . The composition of  claim 40 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         43 . The composition of  claim 40 , wherein the peptidomimetic macrocycle comprises a stabilized secondary structure.