Abstract

The SARS-CoV-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARS-CoV-2 bind in the mRNA entry channel of the 40S ribosomal subunit and blocks mRNA entry, thereby shutting down host protein synthesis. Nsp1 suppresses host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics. In this study, we have in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter. Among the top hits obtained, montelukast sodium hydrate binds to Nsp1 with a binding affinity (KD) of 10.8±0.2 µM in vitro. It forms a stable complex with Nsp1-C-ter in simulation runs with -95.8±13.3 kJ/mol binding energy. Montelukast sodium hydrate also rescues the inhibitory effect of Nsp1 in host protein synthesis, as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, it shows antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells. We, therefore, propose montelukast sodium hydrate can be used as a lead molecule to design potent inhibitors to help combat SARS-CoV-2 infection.

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All data generated or analyzed during this study are included in the manuscript and supporting file.

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Author details

  1. Mohammad Afsar

    Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Rohan Narayan

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Md Noor Akhtar

    Department of Biochemistry, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4669-1543
  4. Deepakash Das

    Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Huma Rahil

    Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  6. Santhosh Kambaiah Nagaraj

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  7. Sandeep M Eswarappa

    BiochemistryDepartment of Biochemistry, Indian Institute of Science Bangalore, Bengaluru, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7903-5198
  8. Shashank Tripathi

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  9. Tanweer Hussain

    Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science Bangalore, Bangalore, India
    For correspondence
    hussain@iisc.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4735-2380

Funding

DBT-Wellcome Trust India Alliance (IA/I/17/2/503313)

  • Tanweer Hussain

IRPHA (IPA/2020/000094)

  • Tanweer Hussain

DBT-Wellcome Trust India Alliance (IA/I/18/1/503613)

  • Shashank Tripathi

Swarnajayanti Fellowship (SB/SJF/2020-21/18)

  • Sandeep M Eswarappa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Shozeb Haider, University College London, United Kingdom

Version history

  1. Received: October 20, 2021
  2. Preprint posted: November 3, 2021 (view preprint)
  3. Accepted: March 23, 2022
  4. Accepted Manuscript published: March 24, 2022 (version 1)
  5. Version of Record published: April 19, 2022 (version 2)

Copyright

© 2022, Afsar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mohammad Afsar
  2. Rohan Narayan
  3. Md Noor Akhtar
  4. Deepakash Das
  5. Huma Rahil
  6. Santhosh Kambaiah Nagaraj
  7. Sandeep M Eswarappa
  8. Shashank Tripathi
  9. Tanweer Hussain
(2022)
Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2
eLife 11:e74877.
https://doi.org/10.7554/eLife.74877

Share this article

https://doi.org/10.7554/eLife.74877

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    This work was supported by Youth Medical Talents – Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).