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While treatments have been developed to reduce morbidity and mortality of COVID-19, more antivirals with broad-spectrum activities are still needed. Here, we identified lonafarnib (LNF), a Food and Drug Administration\u2013approved inhibitor of cellular farnesyltransferase (FTase), as an effective anti\u2013SARS-CoV-2 agent. LNF inhibited SARS-CoV-2 infection and acted synergistically with known anti-SARS antivirals. LNF was equally active against diverse SARS-CoV-2 variants. Mechanistic studies suggested that LNF targeted multiple steps of the viral life cycle. Using other structurally diverse FTase inhibitors and a LNF-resistant FTase mutant, we demonstrated a key role of FTase in the SARS-CoV-2 life cycle. To demonstrate in vivo efficacy, we infected SARS-CoV-2\u2013susceptible humanized mice expressing human angiotensin-converting enzyme 2 (ACE2) and treated them with LNF. LNF at a clinically relevant dose suppressed the viral titer in the respiratory tract and improved pulmonary pathology and clinical parameters. Our study demonstrated that LNF, an approved oral drug with excellent human safety data, is a promising antiviral against SARS-CoV-2 that warrants further clinical assessment for treatment of COVID-19 and potentially other viral infections.<\/jats:p>","DOI":"10.1172\/jci.insight.182704","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T12:00:33Z","timestamp":1733227233000},"source":"Crossref","is-referenced-by-count":1,"title":["Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection"],"prefix":"10.1172","volume":"10","author":[{"given":"Mohsin","family":"Khan","sequence":"first","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parker","family":"Irvin","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney 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