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
Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, Manchester, UK.
Compound Synthesis and Management, Discovery Sciences, BioPharmaceuticals, R&D, AstraZeneca, Gothenburg, Sweden.
Nat Synth. 2025;4(2):156-166. doi: 10.1038/s44160-024-00671-w. Epub 2024 Nov 5.
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.
在2'-位官能化的核苷在治疗中起着关键作用，既作为小分子药物，又作为治疗性寡核苷酸的修饰。然而，这些分子的合成常常面临重大的合成挑战。在此，我们提出一种基于嘌呤核苷补救途径中的酶来合成2'-官能化核苷的方法。首先，生成脱氧核糖-5-磷酸醛缩酶的活性位点变体，用于在2-位高度立体选择性地合成具有广泛官能团的d-核糖-5-磷酸类似物。此后，通过构建一锅多酶级联反应，将这些2-修饰的戊糖磷酸转化为2'-修饰的嘌呤类似物，从而合成鸟苷（2'-OH）和腺苷（2'-OH、2'-Me、2'-F）类似物。这种级联反应能够在控制2-立体化学的同时控制2'-官能团。我们的研究结果表明，这些生物催化级联反应能够从简单的起始原料高效地生成2'-官能化核苷。
