Development of a robust virus-based assay for determination of 50% effective concentration and analysis of drug resistance in the hepatitis C virus

Taylor, Nathan Gary Arthur (2016) Development of a robust virus-based assay for determination of 50% effective concentration and analysis of drug resistance in the hepatitis C virus. Masters thesis, Memorial University of Newfoundland.

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Abstract

Hepatitis C virus affects 170 million people worldwide and until recently, therapeutic options have been limited. Novel and effective protease inhibitors (PI) became available in the clinic in 2011, and a plethora of new compounds and classes of compounds have been developed since. Due to the HCV polymerase lacking a proofreading mechanism, resistance to these compounds arises and decreases the success rate of treatment. Classically, drug resistance has been studied in the context of a system that does not recapitulate the entire HCV life cycle. With an established cell culture model of HCV infection in our lab we developed a novel assay for characterization of mutations conferring resistance to direct-acting antiviral compounds. We designed, improved and validated the assay with compounds stemming from different chemical classes including an NS3/4A inhibitor, NS5A inhibitors and NS5B inhibitors. Herein we present the development and implementation of the assay. With this assay in hand a more comprehensive understanding of HCV drug resistance can be realized and used as a tool for future drug development, both in HCV and in other related viruses.

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