PT  - JOURNAL ARTICLE
AU  - Robert T. Schooley
AU  - Aaron F. Carlin
AU  - James R. Beadle
AU  - Nadejda Valiaeva
AU  - Xing-Quan Zhang
AU  - Aaron F. Garretson
AU  - Victoria I. Smith
AU  - Joyce Murphy
AU  - Karl Y. Hostetler
TI  - Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity
AID  - 10.1101/2020.08.26.269159
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.26.269159
4099  - http://biorxiv.org/content/early/2020/08/27/2020.08.26.269159.short
4100  - http://biorxiv.org/content/early/2020/08/27/2020.08.26.269159.full
AB  - The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cellsCompeting Interest StatementThe authors have declared no competing interest.