A Novel Inhibitor IDPP Interferes with Entry and Egress of HCV by Targeting Glycoprotein E1 in a Genotype-Specific Manner.
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 (EC5046 ± 26 pM) iminodipyridinopyrimidine (IDPP) drug candidate was selected, and confirmed in primary human hepatocytes (EC500.5 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.
Department of Applied Molecular Virology, Hepatitis Research Laboratory, Institut Pasteur Korea, 696, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.|Department of Biological Science, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, Republic of Korea.
Myungeun
M
Lee
Department of Applied Molecular Virology, Hepatitis Research Laboratory, Institut Pasteur Korea, 696, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
Jaewon
J
Yang
Department of Applied Molecular Virology, Hepatitis Research Laboratory, Institut Pasteur Korea, 696, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
Eunji
E
Jo
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.|German Center for Infection Research, Heidelberg University, Heidelberg, Germany.
Ji-Young
JY
Lee
Department of Applied Molecular Virology, Hepatitis Research Laboratory, Institut Pasteur Korea, 696, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
Hee-Young
HY
Kim
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.|German Center for Infection Research, Heidelberg University, Heidelberg, Germany.
Ralf
R
Bartenschlager
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and engineering, KAIST, Daejeon, Republic of Korea.
Eui-Cheol
EC
Shin
Department of Biological Science, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, Republic of Korea.
Yong-Soo
YS
Bae
Department of Applied Molecular Virology, Hepatitis Research Laboratory, Institut Pasteur Korea, 696, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
Marc P
MP
Windisch
D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002219:Carbamates; D004338:Drug Combinations; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000821:virology; D057166:High-Throughput Screening Assays; D054884:Host-Pathogen Interactions; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D061251:Primary Cell Culture; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011759:Pyrrolidines; D000069474:Sofosbuvir / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*; D057074:Virus Release / Q000187:drug effects*
D000998:Antiviral Agents; D002219:Carbamates; D004338:Drug Combinations; C087035:E1 protein, Hepatitis C virus; D007093:Imidazoles; D016898:Interferon-alpha; D009842:Oligopeptides; D011725:Pyridines; D011743:Pyrimidines; D011759:Pyrrolidines; D014759:Viral Envelope Proteins; C486464:telaprevir; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir