ABSTRACT
Remdesivir, a monophosphate prodrug of nucleoside analog GS-441524, is widely used for the treatment of moderate to severe COVID-19. It has been suggested to use GS-441524 instead of remdesivir in the clinic and in new inhalation formulations. Thus, we compared the anti-SARS-CoV-2 activity of remdesivir and GS-441524 in Vero E6, Vero CCL-81, Calu-3, Caco-2 âcells, and anti-HCoV-OC43 activity in Huh-7 âcells. We also compared the cellular pharmacology of these two compounds in Vero E6, Vero CCL-81, Calu-3, Caco-2, Huh-7, 293T, BHK-21, 3T3 and human airway epithelial (HAE) cells. Overall, remdesivir exhibited greater potency and superior intracellular metabolism than GS-441524 except in Vero E6 and Vero CCL-81 âcells.
ABSTRACT
A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-(E)-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j, a hexadecyloxypropyl (HDP)/(isopropyloxycarbonyl-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 µM, without significant cytotoxicity (IC50 = 66.4 µM in HepG2 cells, IC50 = 43.1 µM in HepG2 cells) at 10 µM.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Azo Compounds/chemistry , Nucleosides/chemistry , Organophosphonates/chemistry , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Alkenes/chemistry , Animals , Cell Line, Tumor , Chlorocebus aethiops , HIV-1/drug effects , Hepatitis B virus/drug effects , Humans , Magnetic Resonance Spectroscopy , Methylation , SARS-CoV-2/drug effects , Structure-Activity Relationship , Triazoles/chemistry , Vero CellsABSTRACT
Coronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase.