An engineered aldolase enables the biocatalytic synthesis of 2′-functionalized nucleoside analogues

Willmott, Matthew; Finnigan, William; Birmingham, William R.; Derrington, Sasha R.; Heath, Rachel S.; Schnepel, Christian; Hayes, Martin A.; Smith, Peter D.; Falcioni, Francesco; Turner, Nicholas J.

Abstract

Nucleosides functionalized at the 2′-position play a crucial role in therapeutics, serving as both small-molecule drugs and modifications in therapeutic oligonucleotides. However, the synthesis of these molecules often presents substantial synthetic challenges. Here we present an approach to the synthesis of 2′-functionalized nucleosides based on enzymes from the purine nucleoside salvage pathway. Initially, active-site variants of deoxyribose-5-phosphate aldolase were generated for the highly stereoselective synthesis of d-ribose-5-phosphate analogues with a broad range of functional groups at the 2-position. Thereafter, these 2-modified pentose phosphates were converted into 2′-modified purine analogues by construction of one-pot multienzyme cascade reactions, leading to the synthesis of guanosine (2′-OH) and adenosine (2′-OH, 2′-Me, 2′-F) analogues. This cascade allows for the control of the 2′-functional group alongside 2-stereochemistry. Our findings demonstrate the capability of these biocatalytic cascades to efficiently generate 2′-functionalized nucleosides, starting from simple starting materials.

Citation

Willmott, M., Finnigan, W., Birmingham, W. R., Derrington, S. R., Heath, R. S., Schnepel, C., Hayes, M. A., Smith, P. D., Falcioni, F., & Turner, N. J. (online). An engineered aldolase enables the biocatalytic synthesis of 2′-functionalized nucleoside analogues. Nature Synthesis, https://doi.org/10.1038/s44160-024-00671-w

• Journal Article Type: Article
• Acceptance Date: Sep 20, 2024
• Online Publication Date: Nov 5, 2024
• Deposit Date: Jan 1, 2025
• Journal: Nature Synthesis
• Print ISSN: 2731-0582
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s44160-024-00671-w
• Public URL: https://durham-repository.worktribe.com/output/3262875