Glucosamine nucleotide sugars

Abstract

The invention includes methods and compositions for remodeling a peptide molecule, including the addition or deletion of one or more glycosyl groups to a peptide, and/or the addition of a modifying group to a peptide.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein
 X, Y, Z, and A are independently selected linking groups which are members selected from O, NR, S and CH 2 ; 
 wherein
 R is a member selected from H, an acetyl group, a water-soluble polymer, and a linker to a water-soluble polymer; 
 
 R 1 , R 2 , R 3 , and R 4  are members independently selected from H, an acetyl group, a poly(alkylene oxide), and a linker joined to a poly(alkylene oxide); 
 Q is a member selected from H, OH, an acetyl group, and a poly(alkylene oxide); and 
 i +  is a cation. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein A is NH and R 4  is an acetyl group. 
     
     
         3 . The compound according to  claim 1 , wherein at least one of said R, R 1 , R 2 , R 3 , and R 4  is a poly(alkylene oxide). 
     
     
         4 . The compound according to  claim 3 , wherein said poly(alkylene oxide) is a member selected from: acyl-PEG, acyl-PPG, alkyl-PEG, acyl-alkyl-PEG, acyl-alkyl-PEG, carbamoyl-PEG, carbamoyl-PPG, PEG, PPG, acyl-aryl-PEG, acyl-aryl-PPG, aryl-PEG, and aryl-PPG. 
     
     
         5 . The compound according to  claim 1 , wherein said poly(alkylene oxide) is poly(ethylene glycol). 
     
     
         6 . The compound according to  claim 5 , wherein said poly(ethylene glycol) is a member selected from linear poly(ethylene glycol) and branched poly(ethylene glycol). 
     
     
         7 . The compound according to  claim 5 , wherein said poly(ethylene glycol) has a molecular weight distribution that is essentially homodisperse. 
     
     
         8 . A poly(ethylene glycol) molecule having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is a member selected from H, alkyl, aryl, acetal, OHC—, H 2 N—CH 2 CH 2 — and HS—CH 2 CH 2 —; 
 X, Y and W are members independently selected from O, S, NH and N—R′ 
 wherein
 R′ is selected from alkyl and aryl; 
 
 m is an integer from 0 to 20; 
 n is an integer from 1 to 2000; 
 o is an integer from 0 to 20; 
 Z is a member selected from (CH 2 ) p U(CH 2 ) s [C(Y′)] r V, (CH 2 ) p C(Y′)V and (CH 2 ) p U(CH 2 ) s C(Y′)V 
 wherein
 U is a member selected from O, S, NH and N—R″ 
 wherein
 R″ is selected from alkyl and aryl; 
 
 V is UDP-glucosamine; 
 Y′ is a member selected from O, S, NH and N—R′″ 
 wherein
 R′″ is selected from alkyl and aryl; 
 
 r is an integer selected from 0 and 1; 
 p is an integer selected from 0 to 20; and 
 s is an integer selected from 0 to 20. 
 
 
     
     
         9 . The poly(ethylene glycol) molecule according to  claim 8 , wherein
 R is a member selected from H, alkyl, aryl;   X, Y and W are O;   Z is (CH 2 ) p U(CH 2 ) s C(Y′)V   wherein
 U is NH; and 
 Y′ is O. 
   
     
     
         10 . The poly(ethylene glycol) molecule according to  claim 8 , wherein said poly(ethylene glycol) has a molecular weight distribution that is essentially homodisperse. 
     
     
         11 . The poly(ethylene glycol) molecule according to  claim 8 , wherein said poly(ethylene glycol) is monomethoxy-poly(ethylene glycol). 
     
     
         12 . The poly(ethylene glycol) molecule according to  claim 8 , wherein Z is (CH 2 ) p U(CH 2 ) s [C(Y′)] r V; p is 0; s is 0; U is NH and r is a member selected from 0 and 1. 
     
     
         13 . A poly(ethylene glycol) molecule having the formula: 
       
         
           
           
               
               
           
         
         wherein
 R′ and R″ are members independently selected from H, alkyl, aryl, heteroaryl, NH 2 , CHO, acetal, (CH 2 ) t C(Y′)OH, (CH 2 ) t C(Y′)NH 2 , (CH 2 ) t C(Y′)-halogen-sugar-nucleotide, and protein 
 wherein
 Y′ is a member selected from O, S, NH, N—R i  and CH 2 ; 
 t is an integer from 1 to 20; and 
 R i  is a member selected from alkyl and aryl; 
 
 X, Y, W, A and B are members independently selected from O, S, N—R ii  and CH 2 ; 
 wherein
 R ii  is a member selected from H, alkyl and aryl; 
 
 n and p are integers independently selected from 1 to 2000; 
 m, q, and o are integers independently selected from 0 to 20; 
 Z is a member selected from (CH 2 ) s (CH 2 ) v [C(Y′)] r V, (CH 2 ) s C(Y″)V and (CH 2 ) s U(CH 2 ) v C(Y″)V 
 wherein
 U is a member selected from O, S, and N—R ii    
 wherein
 R ii  is a member selected from H, alkyl and aryl; 
 
 V is UDP-glucosamine; 
 r is an integer selected from 0 and 1; 
 s is an integer selected from 0 to 20; 
 v is an integer selected from 0 to 20; and 
 Y″ is a member selected from O, S, N—R iii  and CH 2    
 wherein
 R iii  is a member selected from alkyl and aryl. 
 
 
 
       
     
     
         14 . The poly(ethylene glycol) molecule according to  claim 13 , wherein said poly(ethylene glycol) has a molecular weight distribution that is essentially homodisperse. 
     
     
         15 . The poly(ethylene glycol) molecule according to  claim 13 , wherein Z is (CH 2 ) s U(CH 2 ) v [C(Y′)] r V; s is 0; v is 0; U is NH and r is a member selected from 0 and 1. 
     
     
         16 . A compound comprising a poly(ethylene glycol) moiety covalently joined to a sugar moiety of UDP-glucosamine. 
     
     
         17 . The compound according to  claim 16 , wherein said poly(ethylene glycol) moiety and said sugar moiety are covalently joined through a linker moiety. 
     
     
         18 . The compound according to  claim 16 , wherein said poly(ethylene glycol) moiety is a member selected from linear and branched poly(ethylene glycol). 
     
     
         19 . The compound according to  claim 16 , wherein said poly(ethylene glycol) moiety is monomethoxy-poly(ethylene glycol). 
     
     
         20 . The compound according to  claim 16 , wherein said poly(ethylene glycol) has a molecular weight distribution that is essentially homodisperse. 
     
     
         21 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein
 X, Y, Z, A and B are independently selected linking groups which are members selected from O, NR, S and CH 2 ; 
 wherein
 R is a member selected from H, an acetyl group, a water-soluble polymer, and a linker to a water-soluble polymer; 
 
 R 1 , R 2 , R 3 , R 4  and R 5  are members independently selected from H, an acetyl group, a poly(alkylene oxide), and a linker joined to a poly(alkylene oxide); 
 R 6  is a member selected from H, OH, an acetyl group, and a poly(alkylene oxide); and 
 i +  is a cation, 
 with the proviso that at least one of R, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  is a water soluble polymer. 
 
       
     
     
         22 . The compound according to  claim 21 , having a formula which is a member selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein
 R 7  is a member selected from a poly(alkylene oxide) and a linker joined to a poly(alkylene oxide), 
 i +  is a member selected from hydrogen, sodium, potassium, lithium, magnesium, manganese and zinc. 
 
       
     
     
         23 . The compound according to  claim 22 , wherein said compound has a structure according to the following formula: 
       
         
           
           
               
               
           
         
         wherein
 R 7  is a member selected from: 
 
       
       
         
           
           
               
               
           
         
       
       and 
       i +  is Na + . 
     
     
         24 . A poly(ethylene glycol) molecule having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is a member selected from H, alkyl, aryl, acetal, OHC—, H 2 N—CH 2 CH 2 — and HS—CH 2 CH 2 —; 
 X, Y and W are members independently selected from O, S, NH and N—R′ wherein
 R′ is selected from alkyl and aryl; 
 
 m is an integer from 0 to 20; 
 n is an integer from 1 to 2000; 
 o is an integer from 0 to 20; 
 Z is a member selected from (CH 2 ) p U(CH 2 ) s [C(Y′)] r V, (CH 2 ) p C(Y′)V and (CH 2 ) p U(CH 2 ) s C(Y′)V 
 wherein
 U is a member selected from O, S, NH and N—R″ 
 wherein
 R″ is selected from alkyl and aryl; 
 
 V is a sugar nucleotide; 
 Y′ is a member selected from O, S, NH and N—R′″ 
 wherein
 R′″ is selected from alkyl and aryl; 
 
 r is an integer selected from 0 and 1; 
 p is an integer selected from 0 to 20; and 
 s is an integer selected from 0 to 20. 
 
 
     
     
         25 . The poly(ethylene glycol) molecule according to  claim 24 , wherein
 R is a member selected from H, alkyl, aryl;   X, Y and W are O;   Z is (CH 2 ) p U(CH 2 ) s C(Y′)V   wherein
 U is NH; and 
 Y′ is O. 
   
     
     
         26 . The poly(ethylene glycol) molecule according to  claim 24 , where said sugar nucleotide is a member selected from UDP-glycoside, CMP-glycoside, and GDP-glycoside. 
     
     
         27 . The poly(ethylene glycol) molecule according to  claim 26 , where said sugar nucleotide is a member selected from UDP-galactose, UDP-galactosamine, UDP-glucose, UDP-glucosamine, GDP-mannose, GDP-fucose, CMP-sialic acid, and CMP-NeuAc. 
     
     
         28 . A poly(ethylene glycol) molecule having the formula: 
       
         
           
           
               
               
           
         
         wherein
 R′ and R″ are members independently selected from H, alkyl, aryl, heteroaryl, NH 2 , CHO, acetal, (CH 2 ) t C(Y′)OH, (CH 2 ) t C(Y′)NH 2 , (CH 2 ) t C(Y′)-halogen-sugar-nucleotide, and protein 
 wherein
 Y′ is a member selected from O, S, NH, N—R i  and CH 2 ; 
 t is an integer from 1 to 20; and 
 R i  is a member selected from alkyl and aryl; 
 
 X, Y, W, A and B are members independently selected from O, S, N—R ii  and CH 2 ; 
 wherein
 R ii  is a member selected from H, alkyl and aryl; 
 
 n and p are integers independently selected from 1 to 2000; 
 m, q, and o are integers independently selected from 0 to 20; 
 Z is a member selected from (CH 2 ) s U(CH 2 ) v [C(Y′)] r V, (CH 2 ) s C(Y″)V and (CH 2 ) s U(CH 2 ) v C(Y″)V 
 wherein
 U is a member selected from O, S, and N—R ii    
 wherein
 R ii  is a member selected from H, alkyl and aryl; 
 
 V is a sugar nucleotide; 
 r is an integer selected from 0 and 1; 
 s is an integer selected from 0 to 20; 
 v is an integer selected from 0 to 20; and 
 Y″ is a member selected from O, S, N—R iii  and CH 2    
 wherein
 R iii  is a member selected from alkyl and aryl. 
 
 
 
       
     
     
         29 . The poly(ethylene glycol) molecule according to  claim 28 , where said sugar nucleotide is a member selected from UDP-glycoside, CMP-glycoside, and GDP-glycoside. 
     
     
         30 . The poly(ethylene glycol) molecule according to  claim 29 , where said sugar nucleotide is a member selected from UDP-galactose, UDP-galactosamine, UDP-glucose, UDP-glucosamine, GDP-mannose, GDP-fucose, CMP-sialic acid, and CMP-NeuAc. 
     
     
         31 . A compound comprising a poly(ethylene glycol) moiety covalently joined to a sugar moiety of a nucleotide sugar. 
     
     
         32 . The compound according to  claim 31 , wherein said poly(ethylene glycol) moiety and said sugar moiety are covalently joined through a linker moiety. 
     
     
         33 . The compound according to  claim 32 , where said sugar nucleotide is a member selected from UDP-glycoside, CMP-glycoside, and GDP-glycoside. 
     
     
         34 . The compound according to  claim 33 , where said sugar nucleotide is a member selected from UDP-galactose, UDP-galactosamine, UDP-glucose, UDP-glucosamine, GDP-mannose, GDP-fucose, CMP-sialic acid, and CMP-NeuAc. 
     
     
         35 . The compound according to  claim 31 , wherein said poly(ethylene glycol) moiety is a member selected from linear and branched poly(ethylene glycol). 
     
     
         36 . The compound according to  claim 31 , wherein said poly(ethylene glycol) moiety is monomethoxy-poly(ethylene glycol). 
     
     
         37 . The poly(ethylene glycol) molecule according to  claim 28 , wherein
 Z is (CH 2 ) s U(CH 2 ) v [C(Y′)] r V; s is 0; v is 0; U is NH and r is a member selected from 0 and 1.