Discovery of Clioquinol and Analogues as Novel Inhibitors of Severe Acute Respiratory Syndrome Coronavirus 2 Infection, ACE2 and ACE2 - Spike Protein Interaction In Vitro

  1. Omonike A. Olaleye
  2. Manvir Kaur
  3. Collins Onyenaka
  4. Tolu Adebusuyi

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Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for coronavirus disease 2019 (COVID-19), has emerged as an ongoing global pandemic. Presently, there are no clinically approved vaccines nor drugs for COVID-19. Hence, there is an urgent need to accelerate the development of effective antivirals. Here in, we discovered Clioquinol (5-chloro-7-iodo-8-quinolinol (CLQ)), a FDA approved drug and two of its analogues (7-bromo-5-chloro-8-hydroxyquinoline (CLBQ14); and 5, 7-Dichloro-8-hydroxyquinoline (CLCQ)) as potent inhibitors of SARS-CoV-2 infection induced cytopathic effect in vitro . In addition, all three compounds showed potent anti-exopeptidase activity against recombinant human angiotensin converting enzyme 2 (rhACE2) and inhibited the binding of rhACE2 with SARS-CoV-2 Spike (RBD) protein. CLQ displayed the highest potency in the low micromolar range, with its antiviral activity showing strong correlation with inhibition of rhACE2 and rhACE2-RBD interaction. Altogether, our findings provide a new mode of action and molecular target for CLQ and validates this pharmacophore as a promising lead series for clinical development of potential therapeutics for COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.08.14.250480: (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:
    However, our study has some limitations such as the use of Vero E6 cells that were selected for high expression of ACE2 in the antiviral assay, a HTS designed to rapidly screen for inhibitors of infection induced CPE. An additional limitation is that, the amount of zinc in the purified rhACE2 supplied from BPS and RayBiotech assays were unknown. Future metal dependent studies with apoenzymes will be required to determine the amount of zinc. Considering that CLQ is a known zinc chelator and ionophore, an understanding of the physiologic amount of zinc required for inhibition will be critical for optimal efficacy. Therefore, for these two limitations, the measured IC50 values for the compounds may not be representative of the actual in vitro IC50, which may be lower. However, the remarkable consistency in the observed strong correlation between CLQ and its congener’s antiviral activity, in vitro rhACE2 inhibition and disruption of ACE2-RBD protein interaction, reduces these concerns.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    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 10.1101/2020.08.14.250480v1 on bioRxiv