Polysialic acid derivatives

Abstract

A polysialic acid compound is reacted with a hetero-bifunctional reagent to introduce a pendant functional group for site-specific conjugation to sulfhydryl groups, for instance side chains of cysteine units in drugs, drug delivery systems, proteins or peptides. The functional group is, for instance, an N-maleimide group.

1 . A compound comprising a polysaccharide having at least two sialic acid units linked 2.8 and/or 2.9 to one another, and having reducing and non-reducing terminal units and said polysaccharides having a pendant moiety linked to the non-reducing terminal sialic acid unit which pendant moiety includes a functional group selected from N-maleimide, vinyl sulfone, N-iodoacetamide and orthopyridyl disulfide. 
   
   
       2 . The compound of  claim 1  wherein the pendant moiety further comprises alkylene and/or arylene and/or an oxalkylene and/or oligooxa-alkylene and/or oligopeptide. 
   
   
       3 . The compound of  claim 1  wherein the functional group is N-maleimido. 
   
   
       4 . The compound of  claim 1  wherein the polysaccharide is a polysialic acid. 
   
   
       5 . The compound of  claim 1  wherein the polysaccharide has at least 10 saccharide units. 
   
   
       6 . The compound of  claim 4  wherein said polysaccharide consists essentially of sialic acid units and said pendant moiety. 
   
   
       7 . The compound of  claim 1  wherein the polysaccharide has at least 50 saccharide units. 
   
   
       8 . The compound of  claim 4  wherein the polysaccharide has at least 10 saccharide units. 
   
   
       9 . A polysialylated protein with at least one cysteine unit linked through a thioether bond to at least one non-reducing terminal unit of a polysialic acid. 
   
   
       10 . A process to prepare a polysialylated protein coupled to the non-reducing terminal unit of a polysaccharide which method comprises reacting the compound of  claim 3  with a protein having at least one free unprotected cysteine whereby the N-maleimido group forms a thioether linkage with the thiol group of said cysteine. 
   
   
       11 . A process to prepare a polysialylated protein which comprises reacting the compound of  claim 1  with a protein having at least one cysteine whereby the said functional group forms a thioether linkage with the thiol group of said cysteine.