A screen for novel hepatitis C virus RdRp inhibitor identifies a broad-spectrum antiviral compound

Abhilasha Madhvi,Chandru Subramani,Manjula Kalia,Rajpal Srivastav,Nishant Joshi,Rajagopalan Muthumohan,Shweta Varshney,Renu Khasa,Smita Hingane,Sudhanshu Vrati,Milan Surjit,C T Ranjith-Kumar

doi:10.1038/s41598-017-04449-3

Abstract

Hepatitis C virus (HCV) is a global pathogen and infects more than 185 million individuals worldwide. Although recent development of direct acting antivirals (DAA) has shown promise in HCV therapy, there is an urgent need for the development of more affordable treatment options. We initiated this study to identify novel inhibitors of HCV through screening of compounds from the National Cancer Institute (NCI) diversity dataset. Using cell-based assays, we identified NSC-320218 as a potent inhibitor against HCV with an EC50 of 2.5 μM and CC50 of 75 μM. The compound inhibited RNA dependent RNA polymerase (RdRp) activity of all six major HCV genotypes indicating a pan-genotypic effect. Limited structure-function analysis suggested that the entire molecule is necessary for the observed antiviral activity. However, the compound failed to inhibit HCV NS5B activity in vitro, suggesting that it may not be directly acting on the NS5B protein but could be interacting with a host protein. Importantly, the antiviral compound also inhibited dengue virus and hepatitis E virus replication in hepatocytes. Thus, our study has identified a broad-spectrum antiviral therapeutic agent against multiple viral infections.

Highlights

Hepatitis C virus is one of the leading causes of acute and chronic liver diseases
Dengue virus (DENV) and hepatitis E virus (HEV) infections are a couple of such major global health problems
Similar to Hepatitis C virus (HCV)-1b NS5B, activity of the HCV-3a NS5B cell-based assay was dependent on the catalytically active NS5B and a functional RIG-I (Fig. S1B)[19]. Employing this assay we screened a library of 1363 biologically active small molecule compounds belonging to the diversity set II of National Cancer Institute (NCI) Developmental Therapeutic Program (DTP) to identify novel inhibitor of HCV-3a RNA dependent RNA polymerase (RdRp) (Fig. 1A)

Summary

Introduction

Hepatitis C virus is one of the leading causes of acute and chronic liver diseases. Approximately 4 million new HCV infections occur every year with a fatality rate of more than 50,000 each year. There are no vaccines available to combat HCV and its treatment is highly dependent on antiviral drugs. There are six major genotypes of HCV and response to DAA treatment can vary according to the genotype. Dengue virus (DENV) and hepatitis E virus (HEV) infections are a couple of such major global health problems. HEV causes self-limiting hepatitis with an estimated 20 million infections and 3.3 million acute cases annually worldwide. It causes chronic infection in organ transplant or immunocompromised individuals and a 30% mortality rate is seen in pregnant women in developing countries[13, 14]. Development of dengue vaccines is facing difficulties because of the antibody-dependent enhancement (ADE) phenomena[17]. There is an urgent requirement of antiviral drugs to treat or prevent these viral infections

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Conclusion