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A Novel Inhibitor IDPP Interferes with Entry and Egress of HCV by Targeting Glycoprotein E1 in a Genotype-Specific Manner.


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.

SUBMITTER: Lee M 

PROVIDER: S-EPMC5363083 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A Novel Inhibitor IDPP Interferes with Entry and Egress of HCV by Targeting Glycoprotein E1 in a Genotype-Specific Manner.

Lee Myungeun M   Yang Jaewon J   Jo Eunji E   Lee Ji-Young JY   Kim Hee-Young HY   Bartenschlager Ralf R   Shin Eui-Cheol EC   Bae Yong-Soo YS   Windisch Marc P MP  

Scientific reports 20170323


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 (EC<sub>50</sub> 46 ± 26 pM) iminodipyridinopyrimi  ...[more]

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