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

Kaho Shionoya; Masako Yamasaki; Shoya Iwanami; Yusuke Ito; Shuetsu Fukushi; Hirofumi Ohashi; Wakana Saso; Tomohiro Tanaka; Shin Aoki; Kouji Kuramochi; Shingo Iwami; Yoshimasa Takahashi; Tadaki Suzuki; Masamichi Muramatsu; Makoto Takeda; Takaji Wakita; Koichi Watashi

doi:10.3389/fmicb.2021.651403

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. eCollection 2021.

Authors

Kaho Shionoya^{1

2}, Masako Yamasaki^{1

2}, Shoya Iwanami^{3

4}, Yusuke Ito⁴, Shuetsu Fukushi⁵, Hirofumi Ohashi^{1

2}, Wakana Saso^{1

6

7}, Tomohiro Tanaka⁸, Shin Aoki⁹, Kouji Kuramochi², Shingo Iwami^{3

4

10

11

12

13

14}, Yoshimasa Takahashi^{15

16}, Tadaki Suzuki¹⁷, Masamichi Muramatsu¹, Makoto Takeda¹⁸, Takaji Wakita¹, 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.

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.