Abstract
Despite recent advances in curing chronic hepatitis C (CHC), the high economic burden to therapy, viral drug resistance, difficult to treat hepatitis C virus (HCV) genotypes and patient groups are still of concern. To address this unmet medical needs, we devised strategies to identify novel viral interventions through target-free high-throughput screening of small molecules utilizing a phenotypic-based HCV infection assay. Thereby, a very potent (EC50 46 ± 26 pM) iminodipyridinopyrimidine (IDPP) drug candidate was selected, and confirmed in primary human hepatocytes (EC50 0.5 nM). IDPP mainly targets a post-attachment step of HCV without affecting endosomal acidification, prevents the secretion of infectious particles and viral cell-to-cell spread. The putative molecular target of IDPP is glycoprotein E1, as revealed by selection for viral drug resistance (Gly-257-Arg). IDPP was synergistic in combination with FDA-approved HCV drugs and inhibited pre-existing resistant HCV strains induced by today’s therapies. Interestingly, IDPP exclusively inhibited HCV genotype 2. However, we identified the genotype-specificity determining region in E1 and generated HCV genotype 1 susceptible to IDPP by changing one amino acid in E1 (Gln-257-Gly). Together, our results indicate an opportunity to provide an alternative treatment option for CHC and will shed light on the poorly understood function of HCV glycoprotein E1.
Highlights
Since its discovery in 19891, hepatitis C virus (HCV) has been recognized as a major global health problem that causes chronic liver diseases including cirrhosis and hepatocellular carcinoma (HCC)[2]
RNA replication was not affected by IDPP as determined with a subgenomic replicon, while it was significantly inhibited by sofosbuvir (Fig. 1E), suggesting that IDPP interferes with HCV entry and/or viral production rather than genome replication
Similar potencies have been observed with NS5A inhibitors inhibiting HCV RNA replication and RNA encapsidation[6]
Summary
Since its discovery in 19891, hepatitis C virus (HCV) has been recognized as a major global health problem that causes chronic liver diseases including cirrhosis and hepatocellular carcinoma (HCC)[2]. A new drug application was submitted to the U.S Food and Drug Administration (FDA) for the approval of a Sofosbuvir/Velpatasvir/Voxilaprevir combinatorial therapy (http://hepatitiscnewdrugresearch.com/) This therapy will be the first once-daily single tablet regimen available for patients infected with HCV genotypes 1–6. The discovery of the infectious HCV cell culture (HCVcc) system[9,10] has enabled researchers to monitor the entire viral life cycle This allows the discovery of drugs that target, in addition to RNA replication, early and late steps such as viral attachment and entry as well as assembly and egress of HCV particles[11,12]. Using the HCVcc system, small molecules, including ferroquine[13], HCV II-114, curcumin[15] and green-tea polyphenolepigallocatechin -3-gallate (EGCG)[16], have been identified as HCV entry inhibitors Those molecules have been shown to target the viral glycoproteins E1 and E2.
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