3'- O-β-Glucosylation of nucleoside analogues using a promiscuous bacterial glycosyltransferase

Abstract

Nucleoside analogue therapeutics have a proven capability within drug discovery as antiviral and antineoplastic agents. However, their efficacy can be limited by poor cellular uptake, off target toxicity and low bioavailability. Glycosylation of pharmaceutical agents/natural products represents a strategically simple method to modulate pharmacological profiles. Herein, we explore biocatalytic glycosylation of nucleoside analogues. The activity of the nucleoside-specific 3'-O-glycosyltransferase AvpGT from Streptomyces sp. AVP053U2 is investigated toward a panel of both natural and clinically relevant purine and pyrimidine nucleoside analogues. AvpGT demonstrates broad substrate promiscuity, with glycosylation observed by HILIC-MS for 15 of 21 nucleosides tested. Of these, 12 nucleosides were successfully glycosylated on ≥25 μmol scale in 39-91% isolated yields, including four current therapeutics.

Fig. 1. ¹H–¹³C HMBC of 3′-O-β-glucosyl-tubercidin (2a) in D₂O at 400 MHz showing correlation between the H1′′ on glucose and C3′ on ribose.