Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection.

Autor:	Khan M; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Irvin P; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Park SB; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Ivester HM; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America., Ricardo-Lax I; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America., Leek M; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Grieshaber A; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Jang ES; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Coutermarsh-Ott SL; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America., Zhang Q; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Maio N; Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America., Jiang JK; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Li B; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Huang W; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Wang AQ; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Xu X; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Hu Z; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Zheng W; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America., Ye Y; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America., Rouault T; Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America., Rice CM; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America., Allen IC; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America., Liang TJ; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Dec 03. Date of Electronic Publication: 2024 Dec 03.
DOI:	10.1172/jci.insight.182704
Abstrakt:	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), has emerged as a global pandemic pathogen with high mortality. 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 (FDA)-approved drug inhibitor of cellular farnesyltransferase (FTase), as an effective anti-SARS-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 viral life cycle. Using other structurally diverse FTase inhibitors and LNF-resistant FTase mutant, we demonstrated a key role of FTase in SARS-CoV-2 life cycle. To demonstrate in vivo efficacy, we infected SARS-CoV-2 susceptible humanized mice expressing human angiotensin-converting enzyme 2 (ACE2) and treated them with LNF. LNF at clinically relevant dose suppressed 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.
Databáze:	MEDLINE
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