Salihovic Admir, Ascham Alex, Rosenqvist Petja S, Taladriz-Sender Andrea, Hoskisson Paul A, Hodgson David R W, Grogan Gideon, Burley Glenn A
Department of Pure & Applied Chemistry, University of Strathclyde 295 Cathedral Street Glasgow G1 1XL UK
Strathclyde Centre for Molecular Bioscience, University of Strathclyde Glasgow UK.
Chem Sci. 2024 Dec 11;16(3):1302-1307. doi: 10.1039/d4sc07521h. eCollection 2025 Jan 15.
Ribonucleosides are essential building blocks used extensively in antiviral and oligonucleotide therapeutics. A major challenge in the further development of nucleoside analogues for therapeutic applications is access to scalable and environmentally sustainable synthetic strategies. This study uses the type II nucleoside 2'-deoxyribosyltransferase from (NDT-2) to prepare a suite of ribonucleoside analogues using naturally-occurring uridine and cytidine sugar donors. Crystal structure and mutational analyses are used to define the substrate tolerance of the nucleobase exchange and the 2'-substituent of the nucleoside sugar donor. Nucleobase profiling identified acceptance of both purine and pyrimidine nucleobases. Finally, the scalability of the approach is showcased, enabling the preparation of ribonucleosides on millimolar scales. This biocatalytic strategy opens up opportunities to establish chemoenzymatic routes to prepare nucleoside analogues incorporating 2' modifications that are of therapeutic importance.
核糖核苷是广泛用于抗病毒和寡核苷酸治疗的重要组成部分。核苷类似物在治疗应用的进一步发展中的一个主要挑战是获得可扩展且环境可持续的合成策略。本研究使用来自[具体来源未给出]的II型核苷2'-脱氧核糖基转移酶（NDT-2），利用天然存在的尿苷和胞苷糖供体来制备一系列核糖核苷类似物。晶体结构和突变分析用于确定核苷酸碱基交换的底物耐受性以及核苷糖供体的2'-取代基。核苷酸碱基分析确定了嘌呤和嘧啶核苷酸碱基均被接受。最后，展示了该方法的可扩展性，能够以毫摩尔规模制备核糖核苷。这种生物催化策略为建立化学酶促路线以制备包含具有治疗重要性的2'修饰的核苷类似物开辟了机会。
