A P(V) platform for oligonucleotide synthesis Huang, Yazhong Knouse, Kyle W. Qiu, Shenjie Hao, Wei Vantourout, Julien C. Zheng, Bin Mercer, Stephen E. Lopez-Ogalla, Javier Narayan, Rohan Olson, Richard E. Blackmond, Donna G. Eastgate, Martin D. Schmidt, Michael A. McDonald, Ivar M. Baran, Phil S. Muñoz Padial, Natalia The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides, by far most of which contain modified phosphate linkages. These unnatural linkages have desirable biological and physical properties but are often accessed with difficulty using phosphoramidite chemistry. We report a flexible and efficient [P(V)]–based platform that can install a wide variety of phosphate linkages at will into oligonucleotides. This approach uses readily accessible reagents and can install not only stereodefined or racemic thiophosphates but any combination of (S, R or rac)–PS with native phosphodiester (PO2) and phosphorodithioate (PS2) linkages into DNA and other modified nucleotide polymers. This platform easily accesses this diversity under a standardized coupling protocol with sustainably prepared, stable P(V) reagents. 2025-01-30T09:36:43Z 2025-01-30T09:36:43Z 2021-09-10 journal article Science, 2021, 373, 1265–1270 https://hdl.handle.net/10481/101157 10.1126/science.abi9727 eng open access American Association for the Advancement of Science: AAAS, USA.