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Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo
Journal article   Open access   Peer reviewed

Enhancing the antiviral potency of ER α-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo

Julia Ma, Xuexiang Zhang, Veronica Soloveva, Travis Warren, Fang Guo, Shuo Wu, Huagang Lu, Jia Guo, Qing Su, Helen Shen, …
Antiviral research, v 150, pp 112-122
Feb 2018
DOI: https://doi.org/10.1016/j.antiviral.2017.12.008
PMID: 29253498
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/j.antiviral.2017.12.008View
Accepted (AM)Maybe Open Access (Publisher Bronze),  Open

Abstract

alpha-Glucosidases - genetics alpha-Glucosidases - metabolism Animals Antiviral Agents - pharmacokinetics Antiviral Agents - pharmacology Cell Line Cells, Cultured Disease Models, Animal Dose-Response Relationship, Drug Drug Synergism Ebolavirus - drug effects Glycoside Hydrolase Inhibitors - pharmacokinetics Glycoside Hydrolase Inhibitors - pharmacology Hemorrhagic Fever, Ebola - drug therapy Hemorrhagic Fever, Ebola - metabolism Hemorrhagic Fever, Ebola - virology Humans Mice Virus Replication - drug effects
Targeting host functions essential for viral replication has been considered as a broad spectrum and resistance-refractory antiviral approach. However, only a few host functions have, thus far, been validated as broad-spectrum antiviral targets in vivo. ER α-glucosidases I and II have been demonstrated to be essential for the morphogenesis of many enveloped viruses, including members from four families of viruses causing hemorrhagic fever. In vivo antiviral efficacy of various iminosugar-based ER α-glucosidase inhibitors has been reported in animals infected with Dengue, Japanese encephalitis, Ebola, Marburg and influenza viruses. Herein, we established Huh7.5-derived cell lines with ER α-glucosidase I or II knockout using CRISPR/Cas9 and demonstrated that the replication of Dengue, Yellow fever and Zika viruses was reduced by only 1-2 logs in the knockout cell lines. The results clearly indicate that only a partial suppression of viral replication can possibly be achieved with a complete inhibition of ER-α-glucosidases I or II by their inhibitors. We therefore explore to improve the antiviral efficacy of a lead iminosugar IHVR-19029 through combination with another broad-spectrum antiviral agent, favipiravir (T-705). Indeed, combination of IHVR-19029 and T-705 synergistically inhibited the replication of Yellow fever and Ebola viruses in cultured cells. Moreover, in a mouse model of Ebola virus infection, combination of sub-optimal doses of IHVR-19029 and T-705 significantly increased the survival rate of infected animals. We have thus proved the concept of combinational therapeutic strategy for the treatment of viral hemorrhagic fevers with broad spectrum host- and viral- targeting antiviral agents.

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28 citations in Web of Science
27 citations in Scopus

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Collaboration types
Industry collaboration
Domestic collaboration
Web of Science research areas
Pharmacology & Pharmacy
Virology
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