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Abstract
The hepatitis C virus (HCV) and norovirus (NoV) are significant human pathogens posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of these viruses through the development of both vaccines and antivirals has proven to be difficult, partly because of the refractoriness in growing these viruses in cell culture. The current standard treatment for HCV is expensive, poorly tolerated, has a long duration, and is only partly effective. Although new direct-acting antivirals (DAA) are entering clinical treatment, these emerging molecules have been mainly targeted against one of six HCV genotypes, namely G1. Conversely, there are no antivirals for the treatment of chronic NoV infections, or for use as a prophylactic measure in an outbreak setting, which typically affects hospitals, nursing homes and other enclosed environments. The viral RNA-dependent RNA polymerases (RdRp) of HCV and NoV are prime targets for antiviral development, given their crucial role for the viral replication, and the absence of a homologous human enzyme. This study describes the discovery and characterisation of the first non-nucleoside inhibitors (NNI) specifically targeted against the RdRp of HCV G3a, a neglected but increasingly important genotype of HCV. Chemical scaffolds and derivatives were identified with low micromolar inhibitory activity against recombinant RdRp, and the HCV replicon cell culture model. Furthermore, the efficacy of previously identified inhibitors against the HCV G3a RdRp was examined, and a novel mechanism of enhancement of de novo transcription was discovered for a subclass of these antivirals; the T2 and P-β binding NNIs. This study also describes the high-throughput identification of the first four NoV-directed NNI scaffolds, which provide a strong platform for future rational drug design for antivirals against another pathogen with thus far limited control measures