PerspectiveStructural Biology

Kickstarting a viral RNA polymerase

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Science  13 Feb 2015:
Vol. 347, Issue 6223, pp. 715-716
DOI: 10.1126/science.aaa5980

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RNA viruses are a ubiquitous class of pathogens that cause serious human, animal, and plant disease. To synthesize new viral genomes in infected hosts, RNA viruses encode special enzymes, RNA-dependent RNA polymerases (RdRps), which are thus prime targets for antiviral drug design. A case study is hepatitis C virus (HCV). HCV is a major human pathogen that chronically infects an estimated 170 million people worldwide, greatly increasing risk of developing life-threatening liver disease, including cirrhosis and cancer. New drugs against HCV have recently come to market that are extremely successful compared to the former standard of care and allow cure (that is, eradication of HCV from the patient) in over 95% of cases (1). Foremost among these new drugs is sofosbuvir, a nucleoside inhibitor targeting the active site of the HCV RdRp, NS5B. On page 771 of this issue, Appleby et al. describe new crystal structures of HCV NS5B (2) that are a major advance both in our basic understanding of RdRp activity and in the way sofosbuvir can inhibit HCV replication.