Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

Abstract

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

• Authors: Shuofeng Yuan, Xin Yin, Xiangzhi Meng, Jasper Fuk-Woo Chan, Zi-Wei Ye, Laura Riva, Lars Pache, Chris Chun-Yiu Chan, Pok-Man Lai, Chris Chung-Sing Chan, Vincent Kwok-Man Poon, Andrew Chak-Yiu Lee, Naoko Matsunaga, Yuan Pu, Chun-Kit Yuen, Jianli Cao, Ronghui Liang, Kaiming Tang, Li Sheng, Yushen Du, Wan Xu, Chit-Ying Lau, Ko-Yung Sit, Wing-Kuk Au, Runming Wang, Yu-Yuan Zhang, Yan-Dong Tang, Thomas Mandel Clausen, Jessica Pihl, Juntaek Oh, Kong-Hung Sze, Anna Jinxia Zhang, Hin Chu, Kin-Hang Kok, Dong Wang, Xue-Hui Cai, Jeffrey D Esko, Ivan Fan-Ngai Hung, Ronald Adolphus Li, Honglin Chen, Hongzhe Sun, Dong-Yan Jin, Ren Sun, Sumit K Chanda, Kwok-Yung Yuen
• Journal: Nature (Nature) Vol. 593 Issue 7859 Pg. 418-423 (05 2021) ISSN: 1476-4687 [Electronic] England
• PMID: 33727703 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antiviral Agents
• Spike Glycoprotein, Coronavirus
• remdesivir
• Adenosine Monophosphate
• Clofazimine
• DNA Helicases
• Alanine

Topics

• Adenosine Monophosphate (analogs & derivatives, pharmacology, therapeutic use)
• Alanine (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacokinetics, pharmacology, therapeutic use)
• Antiviral Agents (pharmacokinetics, pharmacology, therapeutic use)
• Biological Availability
• Cell Fusion
• Cell Line
• Clofazimine (pharmacokinetics, pharmacology, therapeutic use)
• Coronavirus (classification, drug effects, growth & development, pathogenicity)
• Cricetinae
• DNA Helicases (antagonists & inhibitors)
• Drug Synergism
• Female
• Humans
• Life Cycle Stages (drug effects)
• Male
• Mesocricetus
• Pre-Exposure Prophylaxis
• SARS-CoV-2 (drug effects, growth & development)
• Species Specificity
• Spike Glycoprotein, Coronavirus (antagonists & inhibitors)
• Transcription, Genetic (drug effects, genetics)