Targeting host lipogenesis with a diarylamide inhibitor disrupts SARS-CoV-2 replication

Zhang et al., iScience, doi:10.1016/j.isci.2026.117111, Aug 2026
In vitro and in vivo study of a diarylamide clofoctol derivative, showing potent inhibition of SARS-CoV-2 replication by targeting host lipogenesis.
Zhang et al., 31 Aug 2026, China, peer-reviewed, 14 authors. Contact: lushuaiyao-km@163.com (corresponding author), lushuaiyao-km@163.com (corresponding author), lizhuorong@imb.pumc.edu.cn, pengxiaozhong@pumc.edu.cn.
Abstract: ## iScience Cytoplasm Targeting host lipogenesis with a diarylamide inhibitor disrupts SARS-CoV-2 replication FASN SCD1) Graphical abstract Replication organelles SARS-CoV-2 Highlights - Compound 10 is a diarylamide chemotype that potently inhibits SARS-CoV-2 replication - Compound 10 disrupts replication organelles via suppression of FASN/SCD1-mediated lipogenesis - The host transcriptional coactivator NCOA1 is identified as a target of compound 10 - Intranasal compound 10 reduces lung viral load and pathology in SARS-CoV-2-infected hamsters Acetyl-CoA Authors Xintian Zhang, Tingfu Du, Yongjian Wang, ..., Shuaiyao Lu, Zhuorong Li, Xiaozhong Peng Correspondence lushuaiyao-km@163.com (S.L.), lizhuorong@imb.pumc.edu.cn (Z.L.), pengxiaozhong@pumc.edu.cn (X.P.) In brief Pharmacology; Virology Article Targeting host lipogenesis with a diarylamide inhibitor disrupts SARS-CoV-2 replication Xintian Zhang, 1,5 Tingfu Du, 1,5 Yongjian Wang, 3 Wenhai Yu, 1 Tanxiu Chen, 1 Ruixue Liu, 4 Yunpeng Liu, 4 Ruimin Zhu, 4 Doudou Xu, 4 Li Li, 4 Bin Yin, 2 Shuaiyao Lu, 1, * Zhuorong Li, 3, * and Xiaozhong Peng 1,2,4,6, * 1 State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China 2 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Medical Primate Research Center, Neuroscience Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China 4 National Center of Technology Innovation for Animal Model, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China 5 These authors contributed equally 6 Lead contact *Correspondence: lushuaiyao-km@163.com (S.L.), lizhuorong@imb.pumc.edu.cn (Z.L.), pengxiaozhong@pumc.edu.cn (X.P.) https://doi.org/10.1016/j.isci.2026.117111 SUMMARY The vulnerability of direct-acting antivirals to resistance has motivated interest in host-directed strategies that target conserved cellular pathways essential for viral replication. Here, we report a diarylamide molecule, compound 10 (compd. 10), which inhibits SARS-CoV-2 more potently than the parent clofoctol. Mechanistic studies revealed that it is associated with suppression of host lipogenesis, evidenced by downregulation of fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), and partial reversal of antiviral activity upon fatty acid supplementation. Compd. 10 was found to bind to and promote degradation of nuclear receptor coactivator 1 (NCOA1, also known as SRC-1), which suppressed transcription of these lipogenic enzymes. In vivo , intranasal compd. 10 reduced pulmonary viral loads and attenuated lung histopathology in SARS-CoV-2-infected hamsters, confirming its antiviral efficacy. These findings identify compd. 10 as a promising antiviral candidate that disrupts SARS-CoV-2 replication by targeting lipogenesis, providing a chemotype for host-directed antiviral development.
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