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Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates
Nature Chemistry ( IF 19.2 ) Pub Date : 2023-10-19 , DOI: 10.1038/s41557-023-01347-2
Hai-Jun Zhang 1 , Michał Ociepa 1 , Molhm Nassir 1 , Bin Zheng 2 , Sarah A Lewicki 3 , Veronica Salmaso 3 , Helay Baburi 4 , Jessica Nagel 4 , Salahuddin Mirza 4 , Beatriz Bueschbell 4 , Haneen Al-Hroub 4 , Olga Perzanowska 5, 6 , Ziqin Lin 2 , Michael A Schmidt 2 , Martin D Eastgate 2 , Kenneth A Jacobson 3 , Christa E Müller 4 , Joanna Kowalska 5 , Jacek Jemielity 6 , Phil S Baran 1
Affiliation  

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeutics has been accomplished by their isosteric replacement with phosphorothioates, no practical methods exist to rapidly and controllably access stereopure di- and triphosphate thioisosteres of both natural and unnatural nucleosides. Here we show how a modular, reagent-based platform can enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates, as well as symmetrical or unsymmetrical dinucleoside thiodiphosphates and thiotriphosphates (including RNA cap reagents). We demonstrate that ligand–receptor interactions can be dramatically influenced by P-stereochemistry, showing that such thioisosteric replacements can have profound effects on the potency and stability of lead candidates.



中文翻译:


对核苷二磷酸和三磷酸的硫代等排体进行立体控制访问



核苷二磷酸和三磷酸几乎影响生物化学的方方面面;然而,使用此类化合物作为核苷酸依赖性酶和受体的工具或药物先导物受到其快速体内代谢的阻碍。尽管已经通过用硫代磷酸酯等构置换解决了寡核苷酸治疗药物中单磷酸基团不稳定性的成功策略,但没有实用的方法可以快速和可控地获得天然和非天然核苷的立体纯二磷酸盐和三磷酸硫代等排体。在这里,我们展示了基于试剂的模块化平台如何实现此类分子库的立体控制和可扩展合成。这种作简单的方法提供了核苷 α-硫代二磷酸和 α-硫代三磷酸的纯立体异构体,以及对称或不对称的二核苷硫代二磷酸和硫代三磷酸(包括 RNA 帽试剂)。我们证明配体-受体相互作用可以受到 P-立体化学的显着影响,表明这种硫等位置换可以对先导候选物的效力和稳定性产生深远影响。

更新日期:2023-10-19
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