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

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.