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

Dolan, Jonathan P; Keenan, Tessa; Cheallaigh, Aisling Ni; Fascione, Martin A.; Miller, Gavin J

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.

Citation

Dolan, J. P., Keenan, T., Cheallaigh, A. N., Fascione, M. A., & Miller, G. J. (2025). 3′-O-β-Glucosylation of nucleoside analogues using a promiscuous bacterial glycosyltransferase. RSC Chemical Biology, https://doi.org/10.1039/D5CB00026B

• Journal Article Type: Article
• Acceptance Date: Mar 22, 2025
• Online Publication Date: Mar 25, 2025
• Publication Date: Mar 25, 2025
• Deposit Date: Mar 26, 2025
• Publicly Available Date: Mar 26, 2025
• Journal: RSC Chemical Biology
• Print ISSN: 2633-0679
• Electronic ISSN: 2633-0679
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1039/D5CB00026B
• Public URL: https://keele-repository.worktribe.com/output/1111541
• Publisher URL: https://doi.org/10.1039/D5CB00026B
• PMID: 40176969