Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates

Hai Jun Zhang, Michał Ociepa, Molhm Nassir, Bin Zheng, Sarah A. Lewicki, Veronica Salmaso, Helay Baburi, Jessica Nagel, Salahuddin Mirza, Beatriz Bueschbell, Haneen Al-Hroub, Olga Perzanowska, Ziqin Lin, Michael A. Schmidt, Martin D. Eastgate, Kenneth A. Jacobson, Christa E. Müller, Joanna Kowalska, Jacek Jemielity, Phil S. Baran

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)249-258
Number of pages10
JournalNature Chemistry
Volume16
Issue number2
Early online date19 Oct 2023
DOIs
StatePublished - Feb 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2023.

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