Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs

Abstract

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 cells

Remdesivir como tratamiento para COVID-19

“…El 14 de mayo del 2020 se publicó reporte de caso por el Centro de Salud y Ciencia de la Universidad de Tennessee sobre una paciente embarazada positiva para COVID-19 en estado grave, la misma que fue tratada con remdesivir y terapia con plasma obteniéndose una mejoría exitosa a los 5 días de tratamiento, fue extubada con paso a aire ambiente y 24 horas más tarde de finalizar la terapia con remdesivir fue dada de alta (18). La U.S. Food and Drug Administration (FDA) ha emitido una autorización de uso de emergencia de remdesivir para el tratamiento de pacientes hospitalizados con COVID-19, porque este fármaco puede mitigar la morbilidad, mortalidad por CO-VID-19 (2)(10)(14)(17) (23), dicho fármaco debe administrarse por vía intravenosa (24). En un estudio publicado el 11 de junio por The New England Journal of Medicine se trataron con remdesivir 53 pacientes hospitalizados por COVID-19 Carrera de Medicina.…”

Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524)

“…In vivo RDV is converted rapidly to RVn (1,8,11,12), which has 0.5 to 2 log 10 less activity than RDV against most of the viruses tested. In contrast, ODBG-P-RVn is stable in plasma for >24 hours and at therapeutic plasma levels of ODBG-P-Rvn (above EC 90 for SARS-CoV-2) after oral administration of 16.9 mg/kg to Syrian hamsters; furthermore RVn was not observed at virologically significant levels (38). Thus, one would predict sustained in vivo antiviral activity with ODBG-P-RVn without substantial generation in plasma of RVn, the less active metabolite.…”

“…A significant drawback of RDV is the requirement for intravenous administration, which limits its use to hospital contexts. In an attempt to develop an orally bioavailable form of remdesivir, we recently synthesized a 1-O-octadecyl-2-O-benzylsn-glycerylester (ODBG) lipid-modified monophosphate prodrug of RVn (ODBG-P-RVn), which demonstrated more favorable in vitro antiviral activity against SARS-CoV-2 compared to that of RVn and RDV in Vero-E6 cells (18).…”

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

“…Accordingly, other prodrugs of EIDD-1931 may also be assessed for COVID-19 and patented. Similarly, the clinically useful prodrugs of remdesivir are also anticipated [65].…”