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 peptidomimetic macrocycle comprising a crosslinker linking the α-positions of at least two amino acids and an amino acid sequence that is at least 60% identical to the amino acid sequence MDVNPTLLFLKVPAQ (SEQ ID NO: 1). 
     
     
         25 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least about 80% identical to the amino acid sequence MDVNPTLLFLKVPAQ (SEQ ID NO: 1). 
     
     
         26 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least about 90% identical to the amino acid sequence MDVNPTLLFLKVPAQ (SEQ ID NO: 1). 
     
     
         27 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least about 60% identical to the amino acid sequence NleDVNAibTLLFLKVAAQ (SEQ ID NO: 64). 
     
     
         28 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least about 80% identical to the amino acid sequence NleDVNAibTLLFLKVAAQ (SEQ ID NO: 64). 
     
     
         29 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least about 60% identical to the amino acid sequence NleDVNAibTLLFLKVAibAQ (SEQ ID NO: 2). 
     
     
         30 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an amino acid sequence that is at least about 80% identical to the amino acid sequence NleDVNAibTLLFLKVAibAQ (SEQ ID NO: 2). 
     
     
         31 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises a helix. 
     
     
         32 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises a 3 10  helix. 
     
     
         33 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         34 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle comprises an alpha helix. 
     
     
         35 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle has a structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         each A, C, D, and E is independently a natural or non-natural amino acid; 
         each B is independently a natural or non-natural amino acid, amino acid analog, or 
       
       
         
           
           
               
               
           
         
         each R 1  and R 2  are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; 
         each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
         each L is independently a macrocycle-forming linker of the formula -L 1 -L 2 -; 
         each L 1  and L 2  is 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 independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
         each K is independently 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; 
         each R 7  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; 
         each R 8  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
         each v and w are independently integers from 1-1000; 
         u is an integer from 1-10; 
         each x, y and z are independently integers from 0-10; and 
         each n is independently an integer from 1-5. 
       
     
     
         36 . The peptidomimetic macrocycle of  claim 35 , wherein x+y+z is 3. 
     
     
         37 . The peptidomimetic macrocycle of  claim 35 , wherein x+y+z=6. 
     
     
         38 . The peptidomimetic macrocycle of  claim 35 , wherein R 1  is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. 
     
     
         39 . The peptidomimetic macrocycle of  claim 35 , wherein R 1  and R 2  are independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. 
     
     
         40 . The peptidomimetic macrocycle of  claim 35 , wherein R 1  and R 2  are methylene. 
     
     
         41 . The peptidomimetic macrocycle of  claim 24 , wherein the peptidomimetic macrocycle binds to a viral polymerase or an influenza virus. 
     
     
         42 . A method of treating influenza infection in a subject, the method comprising administering to the subject a peptidomimetic macrocycle of  claim 24 .