Anti-severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) potency of Mefloquine as an entry inhibitor in vitro

  1. Kaho Shionoya
  2. Masako Yamasaki
  3. Shoya Iwanami
  4. Yusuke Ito
  5. Shuetsu Fukushi
  6. Hirofumi Ohashi
  7. Wakana Saso
  8. Tomohiro Tanaka
  9. Shin Aoki
  10. Kouji Kuramochi
  11. Shingo Iwami
  12. Yoshimasa Takahashi
  13. Tadaki Suzuki
  14. Masamichi Muramatsu
  15. Makoto Takeda
  16. Takaji Wakita
  17. Koichi Watashi

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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 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.

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  1. ScreenIT

    SciScore for 10.1101/2020.11.19.389726: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A limitation of our study is the use of antiviral profile data in cell culture assays but without an in vivo infection model. To date, SARS-CoV-2 studies have used models including hACE2-transgenic mice, ferrets, cats, hamsters, nonhuman primates and mice infected with mouse-adapted SARS-CoV-2 (Bao et al., 2020; Jiang et al., 2020; Hassan et al., 2020; Sun et al., 2020; Winkler et al., 2020; Golden et al., 2020; Kim et al., 2020; Shi et al., 2020; Richard et al., 2020; Sia et al., 2020; Imai et al., 2020; Rogers et al., 2020; Rockx et al., 2020; Gao et al., 2020; Yu et al., 2020b; Gu et al., 2020). However, except for antibodies or vaccine candidates, there are very limited reports at present successfully confirming the reduction of SARS-CoV-2 viral load in these models by treatment with drug candidates (Park et al., 2020). At this time, however, proposing an additional treatment choice with significant antiviral evidences is urgently demanded to combat COVID-19. Interestingly, MFQ showed a synergistic effect combined with a replication inhibitor for SARS-associated coronavirus, NFV (Yamamoto et al., 2004; Ohashi et al., 2020) (Fig. 4). These data would prospect better clinical outcomes by combined drugs with different modes of action, as used with antiviral therapy against HIV and HCV (Koizumi et al., 2017; Shen et al., 2008). Given the inhibition of viral entry, MFQ is also expected for prophylactic use. Its long half-life of approximately 20 days is advantageous for achiev...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.11.19.389726 on bioRxiv