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

• Published in: Nature communications Vol. 10; no. 1; pp. 120 - 15
• Main Authors: Yuan, Shuofeng, Chu, Hin, Chan, Jasper Fuk-Woo, Ye, Zi-Wei, Wen, Lei, Yan, Bingpeng, Lai, Pok-Man, Tee, Kah-Meng, Huang, Jingjing, Chen, Dongdong, Li, Cun, Zhao, Xiaoyu, Yang, Dong, Chiu, Man Chun, Yip, Cyril, Poon, Vincent Kwok-Man, Chan, Chris Chung-Sing, Sze, Kong-Hung, Zhou, Jie, Chan, Ivy Hau-Yee, Kok, Kin-Hang, To, Kelvin Kai-Wang, Kao, Richard Yi-Tsun, Lau, Johnson Yiu-Nam, Jin, Dong-Yan, Perlman, Stanley, Yuen, Kwok-Yung
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 14/19; 14/28; 49/31; 49/91; 49/98; 631/154/555; 631/326/596/1296; 631/45/608; 64/110; 692/699/255/2514; 96/1; Antiviral activity; Antiviral Agents - pharmacology; Antiviral drugs; Benzoates - chemistry; Benzoates - metabolism; Benzoates - pharmacology; Biosynthesis; Biosynthetic Pathways - drug effects; Chemical synthesis; Coronaviridae; Coronaviruses; Humanities and Social Sciences; Influenza A; Influenza A virus - drug effects; Influenza A virus - physiology; Life cycle engineering; Life cycles; Lipid Metabolism - drug effects; Lipids; Lipids - biosynthesis; Membrane proteins; Membrane vesicles; Middle East Respiratory Syndrome Coronavirus - drug effects; Middle East Respiratory Syndrome Coronavirus - physiology; multidisciplinary; Organic chemistry; Palmitoylation; Protein Binding; Proteins; Proteolysis; Retinoids - chemistry; Retinoids - metabolism; Retinoids - pharmacology; Science; Science (multidisciplinary); Sterol Regulatory Element Binding Proteins - metabolism; Sterol regulatory element-binding protein; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - metabolism; Tetrahydronaphthalenes - pharmacology; Therapeutic applications; Viral infections; Virus Diseases - prevention & control; Virus Diseases - virology; Virus Replication - drug effects; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08015-x

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. Viruses rely on host cell metabolism for replication, making these pathways potential therapeutic targets. Here, the authors show that AM580, a retinoid derivative and RAR-α agonist, affects replication of several RNA viruses by interfering with the activity of SREBP.