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ACE-2-Derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2

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    ACE-2-Derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2
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    • Saroj Kumar Panda
      Saroj Kumar Panda
      Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Berhampur 760010 Odisha, India
      More by Saroj Kumar Panda
    • Parth Sarthi Sen Gupta
      Parth Sarthi Sen Gupta
      Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Berhampur 760010 Odisha, India
      More by Parth Sarthi Sen Gupta
      Orcidhttp://orcid.org/0000-0002-3083-3957
    • Satyaranjan Biswal
      Satyaranjan Biswal
      Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Berhampur 760010 Odisha, India
      More by Satyaranjan Biswal
    • Abhik Kumar Ray
      Abhik Kumar Ray
      Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Berhampur 760010 Odisha, India
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    • Malay Kumar Rana*
      Malay Kumar Rana
      Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Berhampur 760010 Odisha, India
      *Email: [email protected]
      More by Malay Kumar Rana
      Orcidhttp://orcid.org/0000-0002-1713-8220
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    Journal of Proteome Research

    Cite this: J. Proteome Res. 2021, 20, 2, 1296–1303
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    https://doi.org/10.1021/acs.jproteome.0c00686
    Published January 20, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    SARS-CoV-2, a novel coronavirus causing overwhelming death and infection worldwide, has emerged as a pandemic. Compared to its predecessor SARS-CoV, SARS-CoV-2 is more infective for being highly contagious and exhibiting tighter binding with host angiotensin-converting enzyme 2 (hACE-2). The entry of the virus into host cells is mediated by the interaction of its spike protein with hACE-2. Thus, a peptide that has a resemblance to hACE-2 but can overpower the spike protein–hACE-2 interaction will be a potential therapeutic to contain this virus. The non-interacting residues in the receptor-binding domain of hACE-2 have been mutated to generate a library of 136 new peptides. Out of this library, docking and virtual screening discover seven peptides that can exert a stronger interaction with the spike protein than hACE-2. A peptide derived from simultaneous mutation of all the non-interacting residues of hACE-2 yields almost three-fold stronger interaction than hACE-2 and thus turns out here to be the best peptide inhibitor of the novel coronavirus. The binding of the best peptide inhibitor with the spike protein is explored further by molecular dynamics, free energy, and principal component analysis, which demonstrate its efficacy compared to hACE-2. The delivery of the screened inhibitors with nanocarriers like metal–organic frameworks will be worthy of further consideration to boost their efficacy.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    • Docking score of 136 peptide library, contribution (in kJ/mol) of each residue present in the α-1 helix and the designed peptide inhibitor 13 to binding to the spike protein estimated by the MMPBSA method, docking energy of a number of mutations performed at each selected location of the α-1 helix, peptide 13 inhibitor designed comprise mutations with the lowest docking energy highlighted by connecting through red line, RMSD and RMSF and Rg along with standard deviations, RMSD of the spike protein (black) bound α-1 helix (red) and spike protein (black) bound the best peptide inhibitor 13 (red) plotted as a function of simulation time, RMSF of amino acid residues in α-1 helix (black) and the designed peptide inhibitor 13 (red) and the spike protein bound to α-1 helix (black) and to the designed peptide inhibitor 13 (red) plotted as a function of simulation time, fluctuating residues (380–390) of the spike protein, radius of gyration (Rg) of the spike protein bound to α-1 helix (black) and the designed peptide inhibitor 13 (red) and the Rg of the α-1 helix (black) and the peptide inhibitor 13 (red) bound to the spike protein plotted as a function of simulation time, number of hydrogen bonds formed by the α-1 helix (black) and the peptide inhibitor 13 (red) with the spike protein in different time instants, 2D scatter plots of the α-1 helix (black) and the designed peptide inhibitor 13 (red), projecting the motion in phase space for the first two principal components (EV1 and EV2 are eigenvectors 1 and 2, respectively) (PDF)

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    Journal of Proteome Research

    Cite this: J. Proteome Res. 2021, 20, 2, 1296–1303
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jproteome.0c00686
    Published January 20, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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