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

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 and Kwok-Yung Yuen ()
Additional contact information
Shuofeng Yuan: The University of Hong Kong
Hin Chu: The University of Hong Kong
Jasper Fuk-Woo Chan: The University of Hong Kong
Zi-Wei Ye: The University of Hong Kong
Lei Wen: The University of Hong Kong
Bingpeng Yan: The University of Hong Kong
Pok-Man Lai: The University of Hong Kong
Kah-Meng Tee: The University of Hong Kong
Jingjing Huang: The University of Hong Kong
Dongdong Chen: The University of Hong Kong
Cun Li: The University of Hong Kong
Xiaoyu Zhao: The University of Hong Kong
Dong Yang: The University of Hong Kong
Man Chun Chiu: The University of Hong Kong
Cyril Yip: The University of Hong Kong
Vincent Kwok-Man Poon: The University of Hong Kong
Chris Chung-Sing Chan: The University of Hong Kong
Kong-Hung Sze: The University of Hong Kong
Jie Zhou: The University of Hong Kong
Ivy Hau-Yee Chan: The University of Hong Kong
Kin-Hang Kok: The University of Hong Kong
Kelvin Kai-Wang To: The University of Hong Kong
Richard Yi-Tsun Kao: The University of Hong Kong
Johnson Yiu-Nam Lau: The University of Hong Kong
Dong-Yan Jin: The University of Hong Kong
Stanley Perlman: University of Iowa
Kwok-Yung Yuen: The University of Hong Kong

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08015-x

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