Glycopeptide analgesics

Excluding insulin, the global market for peptide pharmaceuticals is expected to grow from $350 million in 1999 to over $800 million by 2005 (1). Despite their advantages of potency, specificity and low toxicity, peptides have not gained the rapid acceptance by the pharmaceutical industry that one might have predicted in the 1970s, chiefly due to difficulties in peptide manufacture and poor bioavailability. Results from several studies now demonstrate that O-linked glycosylation of peptides can promote the serum stability of several classes of peptides in vivo, and can promote the transport of enkephalin analogs across the blood-brain barrier (BBB). Recent work with glycosylated enkephalin analogs suggests that the incorporation of a glycosylated serine or threonine residue promotes transport across the BBB, which resulted in an AUC increase of over 30-fold in rats. Antinociception assays with mice demonstrate that glycosylated enkephalins can compete with morphine in efficacy, even when administered peripherally. Proper placement of the glycoside moiety is necessary in order to avoid perturbation of the mu/delta selectivity of the parent peptide pharmacophore.