| Autor: |
Zhang, Hai-Jun, Ociepa, Michał, Nassir, Molhm, Zheng, Bin, Lewicki, Sarah A., Salmaso, Veronica, Baburi, Helay, Nagel, Jessica, Mirza, Salahuddin, Bueschbell, Beatriz, Al-Hroub, Haneen, Perzanowska, Olga, Lin, Ziqin, Schmidt, Michael A., Eastgate, Martin D., Jacobson, Kenneth A., Müller, Christa E., Kowalska, Joanna, Jemielity, Jacek, Baran, Phil S. |
| Zdroj: |
Nature Chemistry; February 2024, Vol. 16 Issue: 2 p249-258, 10p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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