Structure-based screening of drug candidates targeting the SARS-CoV-2 envelope protein

  1. Xin Xia
  2. Yuwei Zhang
  3. Songling Li
  4. Hengwei Lin
  5. Zhiqiang Yan

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Abstract

The COVID-19 (coronavirus disease 2019) pandemic is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 produces a small hydrophobic envelope (E) protein which shares high homology with SARS-CoV E protein. By patch-clamp recording, the E protein is demonstrated to be a cation-selective ion channel. Furthermore, the SARS-CoV-2 E protein can be blocked by a SARS-CoV E protein inhibitor hexamethylene amiloride. Using structural model and virtual screening, another E protein inhibitor AZD5153 is discovered. AZD5153 is a bromodomain protein 4 inhibitor against hematologic malignancies in clinical trial. The E protein amino acids Phe23 and Val29 are key determinants for AZD5153 sensitivity. This study provides two promising lead compounds and a functional assay of SARS-CoV-2 E protein for the future drug candidate discovery.

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  1. ScreenIT

    SciScore for 10.1101/2021.08.25.457645: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Recombinant DNA
    SentencesResources
    Plasmid construct: The SARS-CoV-2 envelope (E) protein gene (NCBI Reference Sequence: NC_045512.2) was synthesized and subcloned to a pcDNA3.1 vector with an IRES-GFP by GENEWIZ.
    pcDNA3.1
    suggested: RRID:Addgene_79663)
    Software and Algorithms
    SentencesResources
    Plasmid construct: The SARS-CoV-2 envelope (E) protein gene (NCBI Reference Sequence: NC_045512.2) was synthesized and subcloned to a pcDNA3.1 vector with an IRES-GFP by GENEWIZ.
    GENEWIZ
    suggested: (GENEWIZ, RRID:SCR_003177)
    Signals were filtered at 1 kHz (low-pass) and digitized using a DigiData 1550 with pClamp 10.5 software (Molecular Devices, USA).
    pClamp
    suggested: (pClamp, RRID:SCR_011323)
    Analyses of data were performed with GraphPad Prism7.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The protein sequence of SARS-CoV-2 E protein (YP_009724392.1) was obtained from NCBI database.
    NCBI
    suggested: (NCBI, RRID:SCR_006472)

    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 did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 16. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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 10.1101/2021.08.25.457645v1 on bioRxiv