POLYSIALIC ACID DERIVATIVES
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.