Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV‑2 Activity

COVID-19 patients with severe symptoms still lack antiviral
treatment
options. Although remdesivir is the only FDA-approved drug for those
patients, its efficacy is limited by premature hydrolysis to nucleoside
(NUC), low accumulation in the disease-targeted tissue (lungs), and
low antiviral potency. In this study, we synthesized a new series
of remdesivir analogues by modifying the ProTide moiety. In comparison
with remdesivir, the lead compound MMT5-14 showed 2- to 7-fold higher
antiviral activity in four variants of SARS-CoV-2. By reducing premature
hydrolysis in hamsters, MMT5-14 increased the prodrug concentration
by 200- to 300-fold in the plasma and lungs but also enhanced lung
accumulation of the active metabolite triphosphate nucleosides (NTP)
by 5-fold. Compared to remdesivir, MMT5-14 also increased the intracellular
uptake and activation in lung epithelial cells by 4- to 25-fold. These
data suggest that MMT5-14 could be a potential antiviral drug to treat
COVID-19 patients with severe symptoms.