Drug screening identified gemcitabine inhibiting hepatitis E virus by inducing interferon-like response via activation of STAT1 phosphorylation.

Abstract

Exposure to hepatitis E virus (HEV) bears a high risk of developing chronic infection in immunocompromised patients, including organ transplant recipients and cancer patients. We aim to identify effective anti-HEV therapies through screening and repurposing safe-in-human broad-spectrum antiviral agents. In this study, a safe-in-human broad-spectrum antiviral drug library comprising of 94 agents was used. Upon screening, we identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of HEV replication. The antiviral effect was confirmed in a range of cell culture models with genotype 1 and 3 HEV strains. As a cytidine analog, exogenous supplementation of pyrimidine nucleosides effectively reversed the antiviral activity of gemcitabine, but the level of pyrimidine nucleosides per se does not affect HEV replication. Surprisingly, similar to interferon-alpha (IFNα) treatment, gemcitabine activates STAT1 phosphorylation. This subsequently triggers activation of interferon-sensitive response element (ISRE) and transcription of interferon-stimulated genes (ISGs). Cytidine or uridine effectively inhibits gemcitabine-induced activation of ISRE and ISGs. As expected, JAK inhibitor 1 blocked IFNα, but not gemcitabine-induced STAT1 phosphorylation, ISRE/ISG activation, and anti-HEV activity. These effects of gemcitabine were completely lost in STAT1 knockout cells. In summary, gemcitabine potently inhibits HEV replication by triggering interferon-like response through STAT1 phosphorylation but independent of Janus kinases. This represents a non-canonical antiviral mechanism, which utilizes the innate defense machinery that is distinct from the classical interferon response. These results support repurposing gemcitabine for treating hepatitis E, especially for HEV-infected cancer patients, leading to dual anti-cancer and antiviral effects.

• Authors: Yunlong Li, Pengfei Li, Yang Li, Ruyi Zhang, Peifa Yu, Zhongren Ma, Denis E Kainov, Robert A de Man, Maikel P Peppelenbosch, Qiuwei Pan
• Journal: Antiviral research (Antiviral Res) Vol. 184 Pg. 104967 (12 2020) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 33137361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Interferon-alpha
• Pyrimidine Nucleosides
• STAT1 Transcription Factor
• STAT1 protein, human
• Deoxycytidine
• Ribavirin
• Janus Kinases
• Mycophenolic Acid
• Gemcitabine

Topics

• Antiviral Agents (pharmacology)
• Cell Line
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Evaluation, Preclinical
• Drug Repositioning
• Drug Synergism
• Gene Expression Regulation
• Hepatitis E (drug therapy)
• Hepatitis E virus (drug effects, physiology)
• Host Microbial Interactions
• Humans
• Interferon-alpha (pharmacology)
• Janus Kinases (metabolism)
• Mycophenolic Acid (antagonists & inhibitors)
• Phosphorylation (drug effects)
• Pyrimidine Nucleosides (pharmacology)
• Response Elements
• Ribavirin (antagonists & inhibitors)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction
• Virus Replication (drug effects)
• Gemcitabine