Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.153
Vinyl-Stilbene Inhibits Human Norovirus RNA Replication by Activating Heat-Shock Factor-1
Ahrim Lee1,†, Jieun Sung1,†, Dipesh S. Harmalkar1,2,†, Hyeseul Kang1, Hwayoung Lee1, Kyeong Lee1,* and Choongho Lee1,*
1College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
2Department of Chemistry, Dnyanprassarak Mandal’s College & Research Centre, Bardez, Goa 403507, India
*E-mail: kaylee@dongguk.edu (Lee K), choongholee@dongguk.edu (Lee C)
Tel: +82-31-961-5214 (Lee K), +82-31-961-5223 (Lee C)
Fax: +82-31-961-5206 (Lee K), +82-31-961-5206 (Lee C)
The first three authors contributed equally to this work.
Received: September 28, 2021; Revised: October 19, 2021; Accepted: October 25, 2021; Published online: November 16, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Norovirus (NV) is the most common cause of viral gastroenteritis, with the potential to develop into a fatal disease in those who are immuno-compromised, and effective vaccines and treatments are still non-existent. In this study, we aimed to elucidate the molecular mechanism of the previously identified NV replication inhibitor utilizing a vinyl-stilbene backbone, AC-1858. First, we confirmed the inhibition of the NV RNA replication by a structural analog of AC-1858, AC-2288 with its exclusive cytoplasmic subcellular localization. We further validated the induction of one specific host factor, the phosphorylated form of heat shock factor (HSF)-1, and its increased nuclear localization by AC-1858 treatment. Finally, we verified the positive and negative impact of the siRNA-mediated downregulation and lentivirus-mediated overexpression of HSF-1 on NV RNA replication. In conclusion, these data suggest the restrictive role of the host factor HSF-1 in overall viral RNA genome replication during the NV life cycle.
Keywords: Norovirus, Vinyl-stilbene, RNA replication inhibitor, Heat shock factor-1, Antiviral mechanism of action


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