In silico rational design of novel inhibitors to Hepatitis C virus (HCV) non-structural proteins (360G-Wellcome-093786_Z_10_Z)

Around 3% of the world population is currently infected with hepatitis C virus (HCV). Chronic infection will develop in 85% of cases and is a prerequisite to liver cirrhosis and hepatocellular carcinoma1-3. Response rates and toleration to current treatments vary between the viral genotypes, placing an emphasis on identifying novel ways to treat infection. Several viral polymerase and protease inhibitors are currently in clinical trials2,4, though the inaccuracy of the viral polymerase leads to rapid development of resistance mutations5, suggesting a combination therapy approach may be required. This project will utilise available structural information, virtual high-throughput screening (vHTS) and rational drug design to identify and optimise novel inhibitor compounds targeted to the viral protease NS2, and to other non-structural proteins involved in viral replication such as NS5A. Identified active compounds will be purchased or synthesised, analysed and optimised to produce new anti-virals against both existing and novel viral protein targets. This project will involve a combination of structural biology, virtual high-throughput screening, rational drug design and chemical synthesis, and as such will take advantage of the interdisciplinary nature of the Astbury Centre at Leeds University.