Phosphoramidate Prodrugs Continue to Deliver, The Journey of Remdesivir (GS-5734) from RSV to SARS-CoV-2

[Image: see text] Remdesivir (GS-5734) is a monophenol, 2-ethylbutylalanine phosphoramidate prodrug of a 1′-cyano-4-aza-7,9-dideazaadenosine C-nucleoside (GS-441524) that is FDA approved for the treatment of hospitalized patients with COVID-19. The prodrug, initially invented for respiratory syncytial virus, was later found to have activity toward emerging RNA viruses, including Ebola and coronaviruses. Remdesivir is among the first examples of a phosphoramidate prodrug aimed at delivering a nucleoside monophosphate into lung cells to efficiently generate the nucleoside triphosphate inhibitor of viral RNA polymerases. With remdesivir as the central case study, the present work describes the antiviral potency and in vitro metabolism evidence for lung cell activation of phosphoramidates, together with their in vivo pharmacokinetics, lung distribution, and antiviral efficacy toward respiratory viruses. The lung delivery of nucleoside monophosphate analogs using prodrugs warrants further investigation toward the development of novel respiratory antivirals.