Sofosbuvir

Sofosbuvir[1] (brand name Sovaldi) is a nucleotide analog used in combination with other drugs for the treatment of hepatitis C virus (HCV) infection. It has been marketed since 2013. Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to four-fold reduced duration of therapy.[2][3][4] Sofosbuvir allows most patients to be treated successfully without the use of peginterferon,[5] an injectable drug with severe side effects[6] that is a key component of older drug combinations for the treatment of HCV.

Sofosbuvir inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.[7]

Medical uses[edit]
Sofosbuvir is used for the treatment of chronic hepatitis C, genotypes 1, 2, 3, and 4, in combination with pegylated interferon and ribavirin, or with ribavirin alone. It is also used in combination with the viral NS5a inhibitor ledipasvir in an interferon-free combination for the treatment of genotype 1 hepatitis C infection.[10] Sofosbuvir is also used in HCV patients with an HIV coinfection.[16] The treatment is based on a number of clinical trials, for example the ELECTRON trial which showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.

Mechanism of action[edit]
Sofosbuvir is a prodrug using the ProTide biotechnology strategy. It is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis.[26] Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as antihepatitis C treatments, but these exhibited relatively low potency. This low potency arises in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir, based on the protide approach, avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell.[27][28] The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle.