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

  • iScience. 2026 Aug 6;29(8):117111. doi: 10.1016/j.isci.2026.117111.
Xintian Zhang  1 ,  Tingfu Du  1 ,  Yongjian Wang  2 ,  Wenhai Yu  1 ,  Tanxiu Chen  1 ,  Ruixue Liu  3 ,  Yunpeng Liu  3 ,  Ruimin Zhu  3 ,  Doudou Xu  3 ,  Li Li  3 ,  Bin Yin  4 ,  Shuaiyao Lu  1 ,  Zhuorong Li  2 ,  Xiaozhong Peng  1  4  3
Affiliations
  • 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 Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3. 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.
  • 4. 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.
PMID: 42603033 DOI: 10.1016/j.isci.2026.117111
Abstract

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.

Keywords
SARS-CoV-2; antiviral agent; fatty acid synthase; lipid metabolism; protein degradation; stearoyl-CoA desaturase 1; viral replication.
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