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

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

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 IC(50) = 1.28 μM, IC(90) = 2.31 μM, and IC(99) = 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.