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This study evaluated the<jats:italic>in vitro<\/jats:italic>activity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC<jats:sub>50<\/jats:sub>s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC<jats:sub>50<\/jats:sub>shift in the presence of 40% human serum in the genotype 1b replicon. The EC<jats:sub>90<\/jats:sub>\/EC<jats:sub>50<\/jats:sub>ratio was low (2.6). A 50% cytotoxic concentration (CC<jats:sub>50<\/jats:sub>) of &gt;100 \u03bcM provided a selectivity index of &gt;5 \u00d7 10<jats:sup>7<\/jats:sup>. Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-\u03b1), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replication<jats:italic>in vitro<\/jats:italic>and is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.<\/jats:p>","DOI":"10.1128\/aac.02777-13","type":"journal-article","created":{"date-parts":[[2014,5,28]],"date-time":"2014-05-28T07:08:08Z","timestamp":1401260888000},"page":"4431-4442","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":29,"title":["<i>In Vitro<\/i>Activity and Resistance Profile of Samatasvir, a Novel NS5A Replication Inhibitor of Hepatitis C Virus"],"prefix":"10.1128","volume":"58","author":[{"given":"J. P.","family":"Bilello","sequence":"first","affiliation":[{"name":"Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. 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