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ResearchIn-Press PreviewCOVID-19Virology Open Access | 10.1172/jci.insight.182704

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

Mohsin Khan,1 Parker Irvin,1 Seung Bum Park,1 Hannah M. Ivester,2 Inna Ricardo-Lax,3 Madeleine Leek,1 Ailis Grieshaber,1 Eun Sun Jang,1 Sheryl L. Coutermarsh-Ott,2 Qi Zhang,4 Nunziata Maio,5 Jian-Kang Jiang,4 Bing Li,4 Wenwei Huang,4 Amy Q. Wang,4 Xin Xu,4 Zongyi Hu,1 Wei Zheng,4 Yihong Ye,6 Tracey Rouault,5 Charles M. Rice,3 Irving C. Allen,2 and T. Jake Liang1

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Khan, M. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

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1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Park, S. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Ivester, H. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Ricardo-Lax, I. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Leek, M. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

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1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Jang, E. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Coutermarsh-Ott, S. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Zhang, Q. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Maio, N. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Jiang, J. in: JCI | PubMed | Google Scholar |

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Li, B. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Huang, W. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Wang, A. in: JCI | PubMed | Google Scholar |

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Xu, X. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Hu, Z. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Zheng, W. in: JCI | PubMed | Google Scholar |

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Ye, Y. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Rouault, T. in: JCI | PubMed | Google Scholar |

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Rice, C. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Allen, I. in: JCI | PubMed | Google Scholar

1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, United States of America

3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America

4Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

5Eunice Kennedy Shriver National Institute of Child Health and Human Develop, NIH, Bethesda, United States of America

6Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

Find articles by Liang, T. in: JCI | PubMed | Google Scholar |

Published December 3, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.182704.
Copyright © 2024, Khan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 3, 2024 - Version history
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Abstract

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.

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  • Version 1 (December 3, 2024): In-Press Preview
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