Antiviral suppression vs restoration of RIG-I signaling by hepatitis C protease and polymerase inhibitors

Gastroenterology
Yuqiong LiangStanley M Lemon

Abstract

Expression of the nonstructural protein (NS)3/4A protease in cells infected with hepatitis C virus (HCV) results in cleavage of the mitochondrial antiviral-signaling protein (MAVS) and disruption of signaling pathways that lead to viral activation of interferon regulatory factor 3 (IRF-3) and synthesis of type 1 interferons (IFN-alpha/beta). High concentrations of inhibitors of NS3/4A reverse this signaling defect, but quantitative analyses of this potential therapeutic effect are lacking. This study quantitatively assessed the rescue of IRF-3 signaling by NS3/4A inhibitors, compared with in vitro antiviral activity. Antiviral activities of 2 NS3/4A protease inhibitors (TMC435350 and an analog, TMC380765) and a nonnucleoside polymerase inhibitor (Tib-3) were determined in HCV replicon cells and in cells infected with genotype 1a and 2a viruses. The capacity to rescue IRF-3 activation in these cells was assessed by monitoring IFN-beta promoter activity following challenge with Sendai virus. Inhibitor-induced changes in NS3 and MAVS expression were assessed in immunoblots. Both protease inhibitors were capable of rescuing IFN-beta promoter activation but only at concentrations approximately 100-fold the antiviral 50% effective co...Continue Reading

Citations

May 12, 2010·The Journal of Biological Chemistry·Stanley M Lemon
Aug 28, 2009·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Stacy M Horner, Michael Gale
Jan 28, 2009·Antimicrobial Agents and Chemotherapy·Tse-I LinKenneth Simmen
Sep 17, 2010·Journal of Clinical Microbiology·Dimitry GryadunovJacques Izopet
Sep 13, 2011·Expert Review of Anti-infective Therapy·Maria Ripoli, Valerio Pazienza
Apr 1, 2009·Expert Opinion on Drug Metabolism & Toxicology·Emi ShudoAlan S Perelson
Jul 1, 2015·Nature Reviews. Gastroenterology & Hepatology·Alan S Perelson, Jeremie Guedj
Oct 31, 2013·Molecular & Cellular Proteomics : MCP·Marie-Anne GermainDaniel Lamarre
Jul 17, 2010·Liver International : Official Journal of the International Association for the Study of the Liver·Tarik AsselahPatrick Marcellin
Mar 8, 2019·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Yuji IshidaTakeshi Saito
May 6, 2016·Nature Reviews. Gastroenterology & Hepatology·Matthias Götte, Jordan J Feld
Dec 3, 2013·Drugs·Asha Vaidya, Caroline M Perry
Aug 6, 2011·Scandinavian Journal of Gastroenterology·Christian M LangeChristoph Sarrazin
Aug 1, 2013·Expert Review of Gastroenterology & Hepatology·Jeremie GuedjAlan S Perelson
Jan 2, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Pantxika BellecaveMarkus H Heim
Oct 27, 2018·Frontiers in Microbiology·Marcos V S DiasLuis L P daSilva
Aug 6, 2021·Antioxidants & Redox Signaling·Arjun SharmaMarkus Bosmann
Jun 27, 2009·Pharmacology & Therapeutics·Claire GondeauPatrick Maurel

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