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 - 47 . (canceled) 
     
     
         48 . A peptide product comprising a surfactant X covalently attached to a peptide, the peptide comprising a linker amino acid U and at least one other amino acid: 
       
         
           
           
               
               
           
         
       
       wherein the surfactant X is 
       
         
           
           
               
               
           
         
         wherein:
 A is a hydrophobic group which is 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; and 
 B is a hydrophilic group which is a saccharide and is covalently attached to the peptide via the linker amino acid U; 
 
       
       and wherein the peptide product displays arrestin-biased agonism or antagonism compared to the unmodified peptide not covalently attached to the surfactant X. 
     
     
         49 . The peptide product of  claim 48 , wherein the saccharide is a monosaccharide or disaccharide. 
     
     
         50 . The peptide product of  claim 49 , wherein the saccharide is glucose, galactose, mannose, melibiose, maltose, sucrose, glucuronic acid, galacturonic acid, mannouronic acid, diglucuronic acid, melibiouronic acid or maltouronic acid. 
     
     
         51 . The peptide product of  claim 48 , wherein the hydrophobic group is a substituted or unsubstituted C 8 -C 20  alkyl group. 
     
     
         52 . The peptide product of  claim 48 , wherein the surfactant X is a 1-alkyl glycoside. 
     
     
         53 . The peptide product of  claim 52 , wherein the 1-alkyl glycoside is 1-eicosyl beta-D-glucuronic acid, 1-octadecyl beta-D-glucuronic acid, 1-hexadecyl beta-D-glucuronic acid, 1-tetradecyl beta-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, 1-eicosyl beta-D-melibiouronic acid, 1-octadecyl beta-D-melibiouronic acid, 1-hexadecyl beta-D-melibiouronic acid, 1-tetradecyl beta-D-melibiouronic acid, 1-dodecyl beta-D-melibiouronic acid, 1-decyl beta-D-melibiouronic acid or 1-octyl beta-D-melibiouronic acid, or functionalized 1-eicosyl 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-tetradecyl beta-D-maltoside, 1-dodecyl beta-D-maltoside, 1-decyl beta-D-maltoside, 1-octyl beta-D-maltoside, 1-eicosyl beta-D-melibiose, 1-octadecyl beta-D-melibiose, 1-hexadecyl beta-D-melibiose, 1-tetradecyl beta-D-melibiose, 1-dodecyl beta-D-melibiose, 1-decyl beta-D-melibiose or 1-octyl beta-D-melibiose, or the corresponding alpha-anomer. 
     
     
         54 . The peptide product of  claim 48 , wherein the peptide is an opioid peptide, a PTH peptide, a PTHrP peptide, a glucagon peptide or a GLP-1 peptide, each having a native or non-native amino acid sequence or structure. 
     
     
         55 . The peptide product of  claim 48 , wherein the saccharide group of the surfactant is attached to the peptide via an amide bond. 
     
     
         56 . A pharmaceutical composition comprising a therapeutically effective amount of a peptide product of  claim 48  or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         57 . A method of modulating signal transduction mediated by an arrestin, comprising contacting a cell with a peptide product of  claim 48 . 
     
     
         58 . A method of modulating signal transduction mediated by a G protein-coupled receptor (GPCR), comprising contacting a cell with a peptide product of  claim 48 .