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

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??M and CC₅₀ of 75??M. 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.

SUBMITTER: Madhvi A

PROVIDER: S-EPMC5517564 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Madhvi Abhilasha A Hingane Smita S Srivastav Rajpal R Joshi Nishant N Subramani Chandru C Muthumohan Rajagopalan R Khasa Renu R Varshney Shweta S Kalia Manjula M Vrati Sudhanshu S Surjit Milan M Ranjith-Kumar C T CT

Scientific reports 20170719 1

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 inhibit ...[more]

PMID: 28725041

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Project description:Diseases caused by new viruses costs thousands if not millions of human lives and trillions of dollars in damage to the global economy. Despite the rapid development of vaccines for SARS-CoV-2, the lack of small molecule antiviral drugs that work against multiple viral families (broad-spectrum antivirals; BSAs) has left the entire worldâ€™s human population vulnerable to the infection between the beginning of the outbreak and the widespread availability of vaccines. Developing BSAs is an attractive, yet challenging, approach that could prevent the next, inevitable, viral outbreak from becoming a global catastrophe. To explore whether historical medicinal chemistry efforts suggest the possibility of discovering novel BSAs, we (i) identified, collected, curated, and integrated all chemical bioactivity data available in ChEMBL for molecules tested in respective assays for 13 emerging viruses that, based on published literature, hold the greatest potential threat to global human health; (ii) identified and solved the challenges related to data annotation accuracy including assay description ambiguity, missing cell or target information, and incorrect BioAssay Ontology (BAO) annotations; (iii) developed a highly curated and thoroughly annotated database of compounds tested in both phenotypic (21,392 entries) and target-based (11,123 entries) assays for these viruses; and (iv) identified a subset of compounds showing BSA activity. For the latter task, we eliminated inconclusive and annotated duplicative entries by checking the concordance between multiple assay results and identified eight compounds active against 3-4 viruses from the phenotypic data, 16 compounds active against two viruses from the target-based data, and 35 compounds active in at least one phenotypic and one target-based assay. The pilot version of our SMACC (Small Molecule Antiviral Compound Collection) database contains over 32,500 entries for 13 viruses. Our analysis indicates that previous research yielded very small number of BSA compounds. We posit that focused and coordinated efforts strategically targeting the discovery of such agents must be established and maintained going forward. The SMACC database publicly available at https://smacc.mml.unc.edu may serve as a reference for virologists and medicinal chemists working on the development of novel BSA agents in preparation for future viral outbreaks.

Dataset Information

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

Publications

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

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