Mahindra, A. et al. (2021) Peptides derived from the SARS-CoV-2 receptor binding motif bind to ACE2 but do not block ACE2-mediated host cell entry or pro-inflammatory cytokine induction. PLoS ONE, 16(11), e0260283. (doi: 10.1371/journal.pone.0260283) (PMID:34793553) (PMCID:PMC8601423)
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Abstract
SARS-CoV-2 viral attachment and entry into host cells is mediated by a direct interaction between viral spike glycoproteins and membrane bound angiotensin-converting enzyme 2 (ACE2). The receptor binding motif (RBM), located within the S1 subunit of the spike protein, incorporates the majority of known ACE2 contact residues responsible for high affinity binding and associated virulence. Observation of existing crystal structures of the SARS-CoV-2 receptor binding domain (SRBD)–ACE2 interface, combined with peptide array screening, allowed us to define a series of linear native RBM-derived peptides that were selected as potential antiviral decoy sequences with the aim of directly binding ACE2 and attenuating viral cell entry. RBM1 (16mer): S443KVGGNYNYLYRLFRK458, RBM2A (25mer): E484GFNCYFPLQSYGFQPTNGVGYQPY508, RBM2B (20mer): F456NCYFPLQSYGFQPTNGVGY505 and RBM2A-Sc (25mer): NYGLQGSPFGYQETPYPFCNFVQYG. Data from fluorescence polarisation experiments suggested direct binding between RBM peptides and ACE2, with binding affinities ranging from the high nM to low μM range (Kd = 0.207–1.206 μM). However, the RBM peptides demonstrated only modest effects in preventing SRBD internalisation and showed no antiviral activity in a spike protein trimer neutralisation assay. The RBM peptides also failed to suppress S1-protein mediated inflammation in an endogenously expressing ACE2 human cell line. We conclude that linear native RBM-derived peptides are unable to outcompete viral spike protein for binding to ACE2 and therefore represent a suboptimal approach to inhibiting SARS-CoV-2 viral cell entry. These findings reinforce the notion that larger biologics (such as soluble ACE2, ‘miniproteins’, nanobodies and antibodies) are likely better suited as SARS-CoV-2 cell-entry inhibitors than short-sequence linear peptides.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Rossi, Dr Mario and Mahindra, Dr Amit and Hudson, Dr Brian and Morgan, Dr Danielle and Jamieson, Professor Andrew and Touyz, Professor Rhian and Tobin, Andrew and Baillie, Professor George and Janha, Dr Omar and Blair, Dr Connor and Herbert, Miss Imogen and Montezano, Dr Augusto and Beattie, Mrs Wendy and Bhella, Professor David and Morris, Dr Caroline and Tejeda, Dr Gonzalo |
| Creator Roles: | Mahindra, A.Formal analysis, Investigation, Methodology, Project administration, Writing – review and editing Tejeda, G.Formal analysis, Investigation, Methodology, Writing – review and editing Rossi, M.Formal analysis, Investigation, Methodology, Writing – review and editing Janha, O.Formal analysis, Investigation, Methodology Herbert, I.Formal analysis, Investigation, Methodology Morris, C.Formal analysis, Investigation, Methodology, Writing – review and editing Morgan, D. C.Formal analysis, Investigation, Methodology, Writing – review and editing Beattie, W.Formal analysis, Investigation, Methodology Montezano, A. C.Formal analysis, Investigation, Methodology Hudson, B.Formal analysis, Investigation, Methodology Tobin, A. B.Supervision, Writing – review and editing Bhella, D.Supervision, Writing – review and editing Touyz, R. M.Supervision, Writing – review and editing Jamieson, A. G.Supervision, Writing – review and editing Baillie, G. S.Supervision, Writing – review and editing Blair, C. M.Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Writing – original draft, Writing – review and editing |
| Authors: | Mahindra, A., Tejeda, G., Rossi, M., Janha, O., Herbert, I., Morris, C., Morgan, D. C., Beattie, W., Montezano, A. C., Hudson, B., Tobin, A. B., Bhella, D., Touyz, R. M., Jamieson, A. G., Baillie, G. S., and Blair, C. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Science and Engineering > School of Chemistry College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | PLoS ONE |
| Publisher: | Public Library of Science |
| ISSN: | 1932-6203 |
| ISSN (Online): | 1932-6203 |
| Copyright Holders: | Copyright © 2021 Mahindra et al. |
| First Published: | First published in PLoS ONE 16(11): e0260283 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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