Improved peptide pharmaceuticals for insulin resistance

Abstract

Described herein are methods of syntheses and therapeutic uses of covalently modified peptides and/or proteins. The covalently modified peptides and/or proteins allow for improved pharmaceutical properties of peptide and protein-based therapeutics.

1 . A peptide product comprising a surfactant X, covalently attached to a peptide, the peptide comprising a linker amino acid U and at least amino acid residues aa 1 -aa 20  of SEQ. ID. NO. 1: 
       
         
           
           
               
               
           
         
         wherein the surfactant X is a group of Formula I: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 1a  is independently, at each occurrence, a bond, H, a substituted or unsubstituted C 1 -C 30  alkyl group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group, or a steroid nucleus containing moiety; 
 R 1b , R 1c , and R 1d  are each, independently at each occurrence, a bond, H, a substituted or unsubstituted C 1 -C 30  alkyl group, a substituted or unsubstituted alkoxyaryl group, or a substituted or unsubstituted aralkyl group; 
 W 1  is independently, at each occurrence, —CH 2 —, —CH 2 —O—, —(C═O), —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C—S)—NH—, or —CH 2 —S—; 
 W 2  is —O—, —CH 2 — or —S—; 
 R 2  is a bond to U, 
 n is 1, 2 or 3; and 
 
       
       
         
           
                 
               
                   Formula II 
                 
                   (SEQ. ID. NO. 1) 
                 
                   aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -aa 8 -aa 9 -aa 10 -aa 11 -aa 12 - 
                 
                     
                 
                   aa 13 -aa 14 -aa 15 -aa 16 -aa 17 -aa 18 -aa 19 -aa 20 -aa 21 -aa 22 -aa 23 - 
                 
                     
                 
                   aa 24 -aa 25 -aa 26 -aa 27 -aa 28 -aa 29 -aa 30 -aa 31 -aa 32 -aa 33 -aa 34 - 
                 
                     
                 
                   aa 35 -aa 36 -aa 37 -Z 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein:
 Z is OH, or —NH—R 3 , wherein R 3  is H, or C1-C 12  substituted or unsubstituted alkyl, or a PEG chain of less than 10 Da; 
 aa 1  is His, N—Ac-His, pGlu-His, or N—R 3 -His; 
 aa 2  is Ser, Ala, Gly, Aib, Ac4c, or Ac5c; 
 aa 3  is Gln, or Cit; 
 aa 4  is Gly, or D-Ala; 
 aa 5  is Thr, or Ser; 
 aa 6  is Phe, Trp, F2Phe, Me2Phe, or Nal2; 
 aa 7  is Thr, or Ser; 
 aa 8  is Ser, or Asp; 
 aa 9  is Asp, or Glu; 
 aa 10  is Tyr, Leu, Met, Nal2, Bip, or Bip2EtMeO; 
 aa 11  is Ser, Asn, or U; 
 aa 12  is Lys, Glu, Ser, Arg, or U; 
 aa 13  is Tyr, Gln, Cit, or U; 
 aa 14  is Leu, Met, Nle, or U; 
 aa 15  is Asp, Glu, or U; 
 aa 16  is Ser, Gly, Glu, Aib, Ac5c, Lys, Arg, or U; 
 aa 17  is Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, or U; 
 aa 18  is Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U; 
 aa 19  is Ala, Val, Aib, Ac4c, Ac5c, or U; 
 aa 20  is Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U; 
 aa 21  is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U; 
 aa 22  is absent or Phe, Trp, Nal2, Aib, Ac4c, Ac5c, or U 
 aa 23  is absent or Val, Ile, Aib, Ac4c, Ac5c, or U; 
 aa 24  is absent or Gln, Ala, Glu, Cit, or U; 
 aa 25  is absent or Trp, Nal2, or U; 
 aa 26  is absent or Leu, or U; 
 aa 27  is absent or Met, Val, Nle, Lys, or U; 
 aa 28  is absent or Asn, Lys, or U; 
 aa 29  is absent or Thr, Gly, Aib, Ac4c, Ac5c, or U; 
 aa 30  is absent or Lys, Aib, Ac4c, Ac5c, or U; 
 aa 31  is absent or Arg, Aib, Ac4c, Ac5c, or U; 
 aa 32  is absent or Asn, Aib, Ac4c, Ac5c, or U; 
 aa 33  is absent or Arg, Aib, Ac4c, Ac5c, or U; 
 aa 34  is absent or Asn, Aib, Ac4c, Ac5c, or U; 
 aa 35  is absent or Asn, Aib, Ac4c, Ac5c, or U; 
 aa 36  is absent or Ile, Aib, Ac4c, Ac5C, or U; 
 aa 36  is absent or Ala, Aib, Ac4c, Ac5C, or U; 
 aa 37  is absent or U; 
 U is a natural or unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X; 
 
         wherein any two of aa 11 -aa 37  are optionally cyclized through their side chains to form a lactam linkage; and 
         provided that one, or at least one of aa 11 -aa 37  is the linker amino acid U covalently attached to X. 
       
     
     
         2 . The peptide product of  claim 1 , wherein n is 1. 
     
     
         3 . A peptide product of  claim 1 , wherein X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1a  is H, a protecting group, a substituted or unsubstituted C 1 -C 30  alkyl group, or a steroid nucleus containing moiety; 
 
         R 1b , R 1c , and R 1d  are each, independently at each occurrence, H, a protecting group, or a substituted or unsubstituted C 1 -C 30  alkyl group; 
         W 1  is independently, at each occurrence, —CH 2 —, —CH 2 —O—, —(C═O), —(C═O)—O—, —(C═O)—NH—, —(C═S)—, —(C—S)—NH—, or —CH 2 —S—; 
         W 2  is —O—, —S—; and, 
         R 2  is a bond to U. 
       
     
     
         4 . The peptide product of  claim 3 , wherein X has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 . (canceled) 
     
     
         6 . The peptide product of  claim 3 , wherein X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1a  is H, a protecting group, a substituted or unsubstituted C 1 -C 30  alkyl group, or a steroid nucleus containing moiety; 
 
         R 1b , R 1c , and R 1d  are each, independently at each occurrence, H, a protecting group, or a substituted or unsubstituted C 1 -C 30  alkyl group; 
         W 1  is —(C═O); 
         W 2  is —O—; 
         R 2  is a bond to U. 
       
     
     
         7 . The peptide product of  claim 3 , wherein X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1a  is a substituted or unsubstituted C 1 -C 30  alkyl group; 
 R 1b , R 1c , and R 1d  are H; 
 W 1  is —(C═O); 
 W 2  is —O—; and 
 R 2  is a bond to U. 
 
       
     
     
         8 . The peptide product of  claim 1 , wherein R 1a  is a substituted or unsubstituted C 1 -C 30  alkyl group, a substituted or unsubstituted C 6 -C 20  alkyl group, or a substituted or unsubstituted C 12 -C 2  alkyl group. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The peptide product of  claim 1 , wherein the surfactant X is a 1-alkyl glycoside class surfactant. 
     
     
         12 . The peptide product of  claim 1 , wherein X is comprised of 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecylbeta D-glucuronic acid, 1-dodecyl beta D-glucuronic acid, 1-decyl beta-D-glucuronic acid, 1-octyl beta-D-glucuronic acid, 1-eicosyl beta-D-diglucuronic acid, 1-octadecyl beta-D-diglucuronic acid, 1-hexadecyl beta-D-diglucuronic acid, 1-tetradecyl beta-D-diglucuronic acid, 1-dodecyl beta-D-diglucuronic acid, 1-decyl beta-D-diglucuronic acid, 1-octyl beta-D-diglucuronic acid, or functionalized 1-ecosyl beta-D-glucose, 1-octadecyl beta-D-glucose, 1-hexadecyl beta-D-glucose, 1-tetradecyl beta-D-glucose, 1-dodecyl beta-D-glucose, 1-decyl beta-D-glucose, 1-octyl beta-D-glucose, 1-eicosyl beta-D-maltoside, 1-octadecyl beta-D-maltoside, 1-hexadecyl beta-D-maltoside, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, or 1-octyl beta-D-maltoside. 
     
     
         13 . The peptide product of  claim 1 , wherein U is selected from Lys, Cys, Orn, or an unnatural amino acid comprising a functional group used for covalent attachment to the surfactant X. 
     
     
         14 - 18 . (canceled) 
     
     
         19 . The peptide product of  claim 1 , wherein aa 2  is an Aib or Ac4c residue. 
     
     
         20 . The peptide product of  claim 1 , wherein the peptide comprises one or more Aib residues. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . The peptide product of  claim 1 , wherein aa 16  and aa 20  are cyclized to form a lactam linkage. 
     
     
         26 - 31 . (canceled) 
     
     
         32 . A pharmaceutical composition comprising a therapeutically effective amount of a peptide product of  claim 1 , or acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         33 . A method of treating a condition associated with insulin resistance comprising administration of a compound of  claim 1  to an individual in need thereof. 
     
     
         34 . The method of  claim 33 , wherein the insulin resistance is diabetes or cardiovascular disease. 
     
     
         35 - 38 . (canceled) 
     
     
         39 . The method of  claim 33 , wherein the administration of said peptide product causes weight loss. 
     
     
         40 - 57 . (canceled) 
     
     
         58 . The peptide product of  claim 1 , wherein the peptide comprises at least aa 1 -aa 26  of SEQ ID NO. 1. 
     
     
         59 . The peptide product of  claim 58 , wherein aa 17  is U(X) and aa 16  and aa 20  are cyclized to form a lactam linkage. 
     
     
         60 . The peptide product of  claim 59 , wherein X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1a  is a substituted or unsubstituted C 1 -C 30  alkyl group; 
 R 1b , R 1c , and R 1d  are H; 
 W 1  is —(C═O); 
 W 2  is —O—; and 
 
         R 2  is a bond to U.