Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection
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-approved 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 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-susceptible 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.
Authors
- Eun Sun Jang (ORCID: https://orcid.org/0000-0003-4274-2582)
- Inna Ricardo-Lax (ORCID: https://orcid.org/0000-0002-9590-9692)
- Amy Q. Wang (ORCID: https://orcid.org/0000-0001-7368-1917)
- Irving C. Allen (ORCID: https://orcid.org/0000-0001-9573-5250)
- Madeleine Leek (ORCID: https://orcid.org/0000-0003-2452-3861)
- Tracey A. Rouault (ORCID: https://orcid.org/0000-0003-0062-0245)
- Charles M. Rice (ORCID: https://orcid.org/0000-0003-3087-8079)
- Parker Irvin (ORCID: https://orcid.org/0000-0003-2360-5507)
- T. Jake Liang (ORCID: https://orcid.org/0000-0003-3828-702X)
- Wei Zheng (ORCID: https://orcid.org/0000-0003-1034-0757)
- Wenwei Huang (ORCID: https://orcid.org/0000-0002-7727-9287)
- Mohsin Khan (ORCID: https://orcid.org/0000-0001-6090-4966)
- Yihong Ye (ORCID: https://orcid.org/0000-0002-9512-7922)
- Seung Bum Park (ORCID: https://orcid.org/0000-0003-2834-9071)
- Sheryl Coutermarsh‐Ott (ORCID: https://orcid.org/0000-0001-7385-3969)
- Hannah Ivester
- Nunziata Maio (ORCID: https://orcid.org/0000-0002-6225-6058)
- Zongyi Hu (ORCID: https://orcid.org/0000-0002-7048-4683)
- Jian-kang Jiang (ORCID: https://orcid.org/0000-0001-7878-0965)
- Ailis Grieshaber
- Qi Zhang (ORCID: https://orcid.org/0000-0001-5249-0206)
- Yiran Li (ORCID: https://orcid.org/0000-0001-7922-7766)
- Xin Xu (ORCID: https://orcid.org/0000-0003-1163-9304)
Institutions
- Virginia–Maryland College of Veterinary Medicine (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- National Center for Advancing Translational Sciences (US)
- Rockefeller University (US)
- Virginia Tech (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1172/jci.insight.182704
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.39
Funders
- George Mason University
- Leona M. and Harry B. Helmsley Charitable Trust
- Robertson Foundation
- Fast Grants
- National Institutes of Health
- Virginia-Maryland College of Veterinary Medicine
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Child Health and Human Development
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development