Mefloquine, a Potent Anti-severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Drug as an Entry Inhibitor in vitro

  • Front Microbiol. 2021 Apr 30;12:651403. doi: 10.3389/fmicb.2021.651403.
Kaho Shionoya  1  2 ,  Masako Yamasaki  1  2 ,  Shoya Iwanami  3  4 ,  Yusuke Ito  4 ,  Shuetsu Fukushi  5 ,  Hirofumi Ohashi  1  2 ,  Wakana Saso  1  6  7 ,  Tomohiro Tanaka  8 ,  Shin Aoki  9 ,  Kouji Kuramochi  2 ,  Shingo Iwami  3  4  10  11  12  13  14 ,  Yoshimasa Takahashi  15  16 ,  Tadaki Suzuki  17 ,  Masamichi Muramatsu  1 ,  Makoto Takeda  18 ,  Takaji Wakita  1 ,  Koichi Watashi  1  2  10  16  19
Affiliations
  • 1. Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
  • 2. Department of Applied Biological Science, Tokyo University of Science, Tokyo, Japan.
  • 3. Interdisciplinary Biology Laboratory (iBLab), Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan.
  • 4. Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
  • 5. Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
  • 6. The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 7. AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
  • 8. Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan.
  • 9. Research Institute for Science and Technology, Tokyo University of Science, Tokyo, Japan.
  • 10. MIRAI, JST, Saitama, Japan.
  • 11. Institute of Mathematics for Industry, Kyushu University, Fukuoka, Japan.
  • 12. Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.
  • 13. NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
  • 14. Science Groove Inc., Fukuoka, Japan.
  • 15. Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
  • 16. Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan.
  • 17. Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
  • 18. Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.
  • 19. Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
PMID: 33995308 DOI: 10.3389/fmicb.2021.651403
Abstract

Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the Infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher Antiviral potency, we screened approved Anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 μM, IC90 = 2.31 μM, and IC99 = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic Antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.

Keywords
COVID-19; SARS-CoV-2; coronavirus; malaria; mefloquine; repurposing; severe acute respiratory syndrome-related coronavirus 2.
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