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Drug platforms

Crystal structures of HCV NS3/4A protease complex with HCV protease inhibitors

Crystal structures of HCV NS3/4A proteases complexed with HCV protease inhibitors could aid the development of new therapeutics against drug-resistant HCV strains. Researchers generated crystal structures of wild-type HCV NS3/4A protease and three common drug-resistant variants in complex with four small molecule protease inhibitors. The structures showed that Incivek telaprevir, danoprevir, vaniprevir and MK-5172 interact at sites on the wild-type protease that are mutated in drug-resistant variants, such as R155, A156 and D168. Next steps include characterizing additional drug-resistant variants of the HCV NS3/4A protease complex and conducting studies to better understand the role of the protease's helicase domain.
Vertex Pharmaceuticals Inc., Johnson & Johnson and Mitsubishi Tanabe Pharma Corp. market Incivek to treat HCV.
Merck & Co. Inc.'s vaniprevir is in Phase III testing and MK-5172 is in Phase II testing for HCV.
Roche's danoprevir is in Phase II testing to treat HCV.

SciBX 5(32); doi:10.1038/scibx.2012.853
Published online Aug. 16, 2012

Unpatented; licensing status not applicable; available for partnering and collaborations

Romano, K.P. et al. PLoS Pathog.; published online July 26, 2012;
doi:10.1371/journal.ppat.1002832
Contact: Celia A. Schiffer, University of Massachusetts Medical School, Worcester, Mass.
e-mail:

celia.schiffer@umassmed.edu