SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target.

Abstract

Viruses are obligate intracellular microbes that exploit the host metabolic machineries to meet their biosynthetic demands, making these host pathways potential therapeutic targets. Here, by exploring a lipid library, we show that AM580, a retinoid derivative and RAR-α agonist, is highly potent in interrupting the life cycle of diverse viruses including Middle East respiratory syndrome coronavirus and influenza A virus. Using click chemistry, the overexpressed sterol regulatory element binding protein (SREBP) is shown to interact with AM580, which accounts for its broad-spectrum antiviral activity. Mechanistic studies pinpoint multiple SREBP proteolytic processes and SREBP-regulated lipid biosynthesis pathways, including the downstream viral protein palmitoylation and double-membrane vesicles formation, that are indispensable for virus replication. Collectively, our study identifies a basic lipogenic transactivation event with broad relevance to human viral infections and represents SREBP as a potential target for the development of broad-spectrum antiviral strategies.

• Authors: Shuofeng Yuan, Hin Chu, Jasper Fuk-Woo Chan, Zi-Wei Ye, Lei Wen, Bingpeng Yan, Pok-Man Lai, Kah-Meng Tee, Jingjing Huang, Dongdong Chen, Cun Li, Xiaoyu Zhao, Dong Yang, Man Chun Chiu, Cyril Yip, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Kong-Hung Sze, Jie Zhou, Ivy Hau-Yee Chan, Kin-Hang Kok, Kelvin Kai-Wang To, Richard Yi-Tsun Kao, Johnson Yiu-Nam Lau, Dong-Yan Jin, Stanley Perlman, Kwok-Yung Yuen
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 120 (01 10 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30631056 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Benzoates
• Lipids
• Retinoids
• Sterol Regulatory Element Binding Proteins
• Tetrahydronaphthalenes
• Am 580

Topics

• Antiviral Agents (pharmacology)
• Benzoates (chemistry, metabolism, pharmacology)
• Biosynthetic Pathways (drug effects)
• Influenza A virus (drug effects, physiology)
• Lipid Metabolism (drug effects)
• Lipids (biosynthesis)
• Middle East Respiratory Syndrome Coronavirus (drug effects, physiology)
• Protein Binding
• Retinoids (chemistry, metabolism, pharmacology)
• Sterol Regulatory Element Binding Proteins (metabolism)
• Tetrahydronaphthalenes (chemistry, metabolism, pharmacology)
• Virus Diseases (prevention & control, virology)
• Virus Replication (drug effects)