Activation Activation of<unk>  into its active triphosphate metabolite<unk>  is a protide (prodrug of nucleotide) able to diffuse into cells, where it is converted to GS-441524 monophosphate via the actions of esterases (CES1 and CTSA) and a phosphoamidase (HINT1); this in turn is further phosphorylated to its active metabolite triphosphate by nucleoside-phosphate kinases. This pathway of bioactivation is meant to occur intracellularly, but a substantial amount of<unk>  is prematurely hydrolyzed in plasma, with GS-441524 being the major metabolite in plasma, and the only metabolite remaining two hours after dosing. Mechanism of action As an adenosine nucleoside triphosphate analog (GS-443902), the active metabolite of<unk>  interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. In some viruses, such as the respiratory syncytial virus, it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain. For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2, arrest of RNA synthesis occurs after incorporation of three additional nucleotides. Hence,<unk>  is classified as a direct-acting antiviral agent that works as a delayed chain terminator. Pharmacokinetics In non-human primates, the plasma half-life of the prodrug is 20 minutes, with the main metabolite being the nucleoside, GS-441524. Two hours post injection, the main metabolite GS-441524 is present at micromolar concentrations, whilst intact<unk>  is no longer detectable. Because of this rapid extracellular conversion to the nucleoside GS-441524, some researchers have questioned whether the active nucleotide triphosphate is truly derived from<unk>  pro-drug removal or whether it occurs by GS-441524 phosphorylation, and whether direct administration of GS-441524 would constitute a cheaper and easier to administer COVID‑19 drug compared to<unk> . The activated nucleotide triphosphate form has sustained intracellular levels in PBMC and presumably in other cells as well. Resistance Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance to<unk>  were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.
Remdesivir
Coronavir
Entecavir
Saquinavir
Letermovir
Odalasvir
Maribavir
Fostemsavir