A Novel Inhibitor IDPP Interferes with Entry and Egress of HCV by Targeting Glycoprotein E1 in a Genotype-Specific Manneropen access
- Authors
- Lee, M.[Lee, M.]; Yang, J.[ Yang, J.]; Jo, E.[ Jo, E.]; Lee, J.-Y.[ Lee, J.-Y.]; Kim, H.-Y.[ Kim, H.-Y.]; Bartenschlager, R.[ Bartenschlager, R.]; Shin, E.-C.[ Shin, E.-C.]; Bae, Y.-S.[Bae, Y.-S.]; Windisch, M.P.[ Windisch, M.P.]
- Issue Date
- 23-Mar-2017
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- SCIENTIFIC REPORTS, v.7
- Indexed
- SCIE
SCOPUS
- Journal Title
- SCIENTIFIC REPORTS
- Volume
- 7
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/29730
- DOI
- 10.1038/srep44676
- ISSN
- 2045-2322
- 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 phenotypicbased 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.
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- Appears in
Collections - Science > Department of Biological Science > 1. Journal Articles
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