Brilacidin, a COVID-19 Drug Candidate, Exhibits Potent In Vitro Antiviral Activity Against SARS-CoV-2

  1. Allison Bakovic
  2. Kenneth Risner
  3. Nishank Bhalla
  4. Farhang Alem
  5. Theresa L. Chang
  6. Warren Weston
  7. Jane A. Harness
  8. Aarthi Narayanan

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Abstract

Summary

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than one million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin—a de novo designed synthetic small molecule that captures the biological properties of HDPs—on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is primarily a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin has demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 and thus supports brilacidin as a promising COVID-19 drug candidate.

Highlights

  • Brilacidin potently inhibits SARS-CoV-2 in an ACE2 positive human lung cell line.

  • Brilacidin achieved a high Selectivity Index of 426 (CC 50 =241μM/IC 50 =0.565μM).

  • Brilacidin’s main mechanism appears to disrupt viral integrity and impact viral entry.

  • Brilacidin and remdesivir exhibit excellent synergistic activity against SARS-CoV-2.

Significance Statement

SARS-CoV-2, the emergent novel coronavirus, has led to the current global COVID-19 pandemic, characterized by extreme contagiousness and high mortality rates. There is an urgent need for effective therapeutic strategies to safely and effectively treat SARS-CoV-2 infection. We demonstrate that brilacidin, a synthetic small molecule with peptide-like properties, is capable of exerting potent in vitro antiviral activity against SARS-CoV-2, both as a standalone treatment and in combination with remdesivir, which is currently the only FDA-approved drug for the treatment of COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.29.352450: (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.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Toxicity Screens: Cells were seeded in 96-well white plates 24h prior as follows: Vero and Caco-2 cells at 5×104 cells per well, Calu-3 cells at 1.3×105 cells per well.
    Caco-2
    suggested: None
    Calu-3
    suggested: None
    Pseudovirus Spike Neutralization Assay: Vero cells were seeded in a black 96-well plate at 5×104 cells per well and incubated for 24h.
    Vero
    suggested: RRID:CVCL_ZW93)
    Software and Algorithms
    SentencesResources
    Vero cells were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM, Quality Biological, 112-013-101CS) supplemented with 4.5g/L glucose, 2mM L-glutamine (FisherSci, MT2005CI), 5% heat-inactivated fetal bovine essence (FBE) (VWR, 10805-184) for Vero cells, 10ug/mL streptomycin and 10U/mL penicillin (VWR, 45000-652).
    Quality Biological
    suggested: None
    Statistical analyses and significance was determined using One-Way ANOVA with Dunnett’s Post Test in Prism 7 (Graph Pad) unless otherwise stated.
    Prism
    suggested: (PRISM, RRID:SCR_005375)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.10.29.352450v1 on bioRxiv