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Article Abstract
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.
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| http://dx.doi.org/10.1021/acs.jmedchem.2c00758 | DOI Listing |
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