Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus NS5B polymerase - the key enzyme mediating HCV RNA replication. Sofosbuvir is a prodrug and after ingestion it is rapidly converted to GS-331007, the predominant circulating drug that accounts for greater than 90% of the systemically active drug. The compound GS-331007 is efficiently taken up by hepatocytes, whereby cellular kinases convert GS-331007 to its pharmacologically active uridine analog 5’-triphosphate form (GS-461203). This triphosphate compound mimics the natural cellular uridine nucleotide and is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination. The active form GS-461203 targets the NS5B catalytic site and acts as a non-obligate chain terminator. The active compound (GS-461203) does not inhibit host DNA polymerases, RNA polymerases, or mitochondrial RNA polymerase. Sofosbuvir (alone or in in combination with other medications) is used to treat Hepatitis C.

GS-9851 (formerly PSI 7851) is an orally available, second generation uridine nucleoside analog polymerase inhibitor of hepatitis C treatment. GS-9851 is a nucleotide prodrug of the nucleoside analog GS-331007 (formerly PSI-6206). GS-9851 potently inhibits HCV NS5B polymerase and has demonstrated pan-genotypic activity in vitro. Preclinical studies of GS-9851 demonstrated a favorable profile in terms of antiviral potency, distribution, and metabolism. GS-9851 is first hydrolyzed to the intermediate GS-566500 (formerly PSI-352707), which is then metabolized to either the inactive metabolite, GS-331007, or the monophosphate GS-606965 (formerly PSI-7411). Inside the hepatocyte, GS-606965 is further phosphorylated by a series of enzymatic steps to an active triphosphate metabolite, GS-461203 (formerly PSI-7409), that selectively inhibits recombinant NS5B. A first-time-in-human study demonstrated that GS-9851 (25 to 800 mg) is generally safe and well tolerated in patients chronically infected with HCV. GS-9851 has a pharmacokinetic profile consistent with once-daily dosing. Administration of GS-9851 led to significant reductions in plasma HCV RNA levels without the evolution of known resistance mutations.