Improved peptide pharmaceuticals

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 GLP-1 receptor (GLP1R) and/or glucagon receptor (GCGR) binding peptide, the peptide product comprising: 
       
         
           
           
               
               
           
         
         wherein X is 
       
       
         
           
           
               
               
           
         
         
           wherein 
           A is a hydrophobic group comprising a C 1 -C 30  alkyl chain or an aralkyl chain; and 
           B is a hydrophilic saccharide group covalently attached to the peptide via a linker amino acid U, wherein U is a natural or unnatural amino acid. 
         
       
     
     
         2 . The peptide product of  claim 1 , wherein the peptide binds GLP1R and GCGR. 
     
     
         3 . The peptide product of  claim 1 , wherein A is a substituted or unsubstituted C 3 -C 20  alkyl chain. 
     
     
         4 . The peptide product of  claim 1 , wherein the surfactant X is an N-linked alkyl glycoside comprising one or more hydroxyl functions modified to be a carboxylic acid. 
     
     
         5 . The peptide product of  claim 1 , wherein the the surfactant X comprises a carboxylic acid group. 
     
     
         6 . The peptide product of  claim 1 , wherein the saccharide is selected from glucose, mannose, maltose, a glucuronic acid, galacturonic acid, diglucuronic acid and maltouronic acid. 
     
     
         7 . The peptide product of  claim 1 , wherein the surfactant is a 1-alkyl glycoside class surfactant. 
     
     
         8 . The peptide product of  claim 1 , wherein the saccharide group is attached to the peptide via an amide bond. 
     
     
         9 . The peptide product of  claim 1 , wherein the surfactant 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. 
     
     
         10 . The peptide product of  claim 1 , wherein the peptide product comprises a covalently linked N-omega-1-alkyl β-D-glucuronyl. 
     
     
         11 . The peptide product of  claim 1 , wherein the peptide comprises aa 1  to aa 26  of SEQ ID NO: 304;
 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 -Z (SEQ. ID. NO. 304)   wherein:   Z is OH, or —NH—R 3 , wherein R 3  is H, or C 1 -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(X);   aa 13  is absent or Tyr, Gln, Cit, or U(X);   aa 14  is absent or Leu, Met, Nle, or U(X);   aa 15  is absent or Asp, Glu, or U(X);   aa 16  is absent or Ser, Gly, Glu, Aib, Ac5c, Lys, Arg, or U(X);   aa 17  is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, or U(X);   aa 18  is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U(X);   aa 19  is absent or Ala, Val, Aib, Ac4c, Ac5c, or U(X);   aa 20  is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U(X);   aa 21  is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U(X);   aa 22  is absent or Phe, Trp, Nal2, Aib, Ac4c, Ac5c, or U(X);   aa 23  is absent or Val, Ile, Aib, Ac4c, Ac5c, or U(X);   aa 24  is absent or Gln, Ala, Glu, Cit, or U(X);   aa 25  is absent or Trp, Nal2, or U(X);   aa 26  is absent or Leu, or U(X);   aa 27  is absent;   aa 28  is absent;   aa 29  is absent;   wherein any two of aa 1 -aa 26  are optionally cyclized through their side chains to form a lactam linkage; and
 provided that one, or at least one of aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22 , aa 23 , aa 24 , or aa 25  is the linker amino acid U covalently attached to the surfactant X. 
   
     
     
         12 . The peptide product of  claim 1 , wherein the peptide comprises SEQ ID NO: 305 
       
         
           
                 
               
                   (SEQ ID. NO. 305) 
                 
                   His 1 -aa 2 -aa 3 -Gly 4 -Thr 5 -aa 6 -Thr 7 -Ser 8 -Asp 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 -Z 
                 
             
                
                
                
                
               
            
           
         
         wherein:
 Z is OH, or —NH—R 3 , wherein R 3  is H or substituted or unsubstituted C 1 -C 12  alkyl; or a PEG chain of less than 10 Da;
 aa 2  is Ser, Ala, Gly, Aib, Ac4c, or Ac5c; 
 aa 3  is Gln, or Cit; 
 aa 6  is Phe, Trp, F2Phe, Me2Phe, MePhe, or Nal2; 
 aa 10  is Tyr, Leu, Met, Nal2, Bip, or Bip2EtMeO; 
 aa 11  is Ser, Asn, or U(X); 
 aa 12  is Lys, Glu, Ser, or U(X); 
 aa 13  is absent or Tyr, Gln, Cit, or U(X); 
 aa 14  is absent or Leu, Met, Nle, or U(X); 
 aa 15  is absent or Asp, Glu, or U(X); 
 aa 16  is absent or Ser, Gly, Glu, Aib, Ac4c, Ac5c, Lys, R, or U(X); 
 aa 17  is absent or Arg, hArg, Gln, Glu, Cit, Aib, Ac4c, Ac5c, or U(X); 
 aa 18  is absent or Arg, hArg, Ala, Aib, Ac4c, Ac5c, or U(X); 
 aa 19  is absent or Ala, Val, Aib, Ac4c, Ac5c, or U(X); 
 aa 20  is absent or Gln, Lys, Arg, Cit, Glu, Aib, Ac4c, Ac5c, or U(X); 
 aa 21  is absent or Asp, Glu, Leu, Aib, Ac4c, Ac5c, or U(X); 
 aa 22  is absent or Phe, Aib, Ac4c, Ac5c, or U(X) 
 aa 23  is absent or Val, Ile, Aib, Ac4c, Ac5c, or U(X); 
 
 wherein any two of aa 1 -aa 23  are optionally cyclized through their side chains to form a lactam linkage; and
 provided that one, or at least one of aa 16 , aa 17 , aa 18 , aa 19 , aa 20 , aa 21 , aa 22  is the linker amino acid U covalently attached to the surfactant X. 
 
 
       
     
     
         13 . (canceled) 
     
     
         14 . The peptide product of  claim 1 , wherein the surfactant X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is a substituted or unsubstituted C 1 -C 30  alkyl chain, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted aralkyl group; 
 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— or —S—; 
 R 2  is a bond to U. 
 
       
     
     
         15 . The peptide product of  claim 14 , wherein the surfactant X has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The peptide product of  claim 14 , wherein the surfactant X has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The peptide product of  claim 14 , wherein the surfactant X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is a substituted C 3 -C 20  alkyl group; 
 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)—NH—; 
 W 2  is —O—; 
 R 2  is a bond to U. 
 
       
     
     
         18 . The peptide product of  claim 14 , wherein the surfactant X has the structure: 
       
         
           
           
               
               
           
         
         wherein:
 A is a substituted C 3 -C 20  alkyl group; 
 R 1b , R 1c , and R 1d  are H; 
 W 1  is —(C═O)—NH—; 
 W 2  is —O—; and 
 R 2  is a bond to U. 
 
       
     
     
         19 . The peptide product of  claim 1 , wherein the hydrophobic group A is a substituted or unsubstituted C 6 -C 18  alkyl group and the hydrophilic group is selected from glucose, maltose, glucuronic acid, diglucuronic acid or maltouronic acid. 
     
     
         20 - 37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising a therapeutically effective amount of the peptide product of  claim 1 , or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         39 . A method for improving the pharmaceutical and medicinal behavior of a peptide, thereby improving its duration of action, bioavailability or its stability in formulation, comprising covalent attachment of a surfactant X to the peptide, wherein X is as defined in  claim 1 . 
     
     
         40 . (canceled)