high degree of enantiospecificity for the enzyme-inhibitor reaction, a (+) enantiomer of (5) was determined to be more potent than its (–) counterpart. These compounds all bind to the palm region of the NS5B polymerase in an allosteric pocket. Further developments were made by Burton G in 2007 to optimize the acyl pyrrolidine scaffold to achieve replicon activity. Replacing thiophene with thiazole in N-acyl pyrrolidine scaffold produced analog (6) to achieve great enzyme activity, IC50=40nM. Nonetheless, this series of compounds had low cellular permeability. The most potent analog during the optimization of cellular activity of this series was (7) with IC50 = 5nM and EC50 = 0.61 μM. The problem with this compound (7) was poor oral bioavailability and poor absorption. To achieve a better pharmacokinetic profile, modifications to the structure led to compound (8) with EC50 of 0.39 μM and an oral bioavailability of about 50%. This compound was then selected as a drug candidate for further development as a combination therapy with peginterferon alfa-2a. History Dynamic evolution of drug discovery started in early 1960s after hepatitis A and B types were recognized. Numerous medications have been tested in hopes of positive results. Interferon was one of the first that demonstrated effectiveness. Subsequently, three different variations of interferon alfa, beta and gamma were identified. 1986 – Non-A, non-B hepatitis was identified as hepatitis C, which was the impetus for further researches in drug development. 1990s – The dose and length of treatment with interferon were established. At approximately same time, ribavirin was added to interferon therapy, thereby exceeding a sustained virological response of 50%. 2001 – Pegylated interferon was approved. Pegylation of interferon enhanced its half-life at the same time leading to increase of sustained virological response and reducing injection frequency. Because of the relatively low efficacy and tolerability of interferon and ribavirin, intense investigations in the development of direct-acting antivirals were undertaken. Expression of direct-acting antivirals does not occur in uninfected cells, therefore, improving its tolerability and efficacy in most genotypes of hepatitis C, up to 90%. 2011 – The first direct-acting antiviral or NS3/4A (protease inhibitor) boceprevir was approved. Thereafter other inhibitors in this class telaprevir, simeprevir, asunaprevir, paritaprevir and grazoprevir were approved. 2013 – The first NS5B polymerase inhibitor sofosbuvir approved. Dasabuvir was approved in 2014. 2014 – The first NS5A inhibitor ledipasvir was approved. Four other NS5A inhibitors of this class—daclatasvir, ombitasvir, elbasvir and velpatasvir—have