Development of anti-viral compounds effective against various genotypes and resistance-associated variants of hepatitis C virus

Abstract

Approximately 71 million people suffer from hepatitis C virus (HCV) infection worldwide. Persistent HCV infection causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, resulting in approximately 400,000 deaths annually. Effective direct-acting antiviral agents (DAAs) have been developed and are currently used for HCV treatment targeting the following three proteins: NS3/4A proteinase, which cleaves the HCV polyprotein into various functional proteins; RNA-dependent RNA polymerase (designated as NS5B), and NS5A, which is required for the formation of double membrane vesicles serving as RNA replication organelles. At least one compound inhibiting NS5A is included in current HCV treatment regimens because of high efficacy and low toxicity of the drugs targeting NS5A. Here we report novel anti-HCV compounds showing strong inhibitory effects on GT 1b and 3a of HCV. Moreover, some compounds were effective against resistance-associated variants (RAVs) to DAAs. The structure-activity relationships of the compounds were analyzed. Furthermore, we investigated the molecular bases of the inhibitory activities of some compounds by the molecular docking method. Here, we have been developing new series of NS5A inhibitors for years and the process of development was described in chapter 2, 3, and 4. In chapter 2, we report the discovery of the benzidine and diaminofluorene prolinamide derivatives. Through the modification of these compounds, we found several inhibitors, which have high efficacy and low toxicity. In chapter 3, we report on our effort to find desirable core structure to inhibit HCV by using a biaryl sulfate-based structure, and the possibility of the sulfate core structure as a possible core building block for potent NS5A inhibitor. In chapter 4, we described the structure-activity relationship studies of NS5A inhibitor against various genotypic strains of HCV. We modified the compound structures based on compound 43, which was developed in chapter 2, and discovered that a specific region of fluorene based NS5A inhibitors was highly relevant to inhibiting resistance-associated variants (RAVs) of HCV. Furthermore, we investigated the molecular basis of the inhibitory activities of some compounds by the molecular docking method.