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

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, Miss 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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173707Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZInstitute of Cardiovascular & Medical Sciences
305807Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosomeAndrew JamiesonEngineering and Physical Sciences Research Council (EPSRC)EP/N034260/2Chemistry
172865EPSRC DTP 16/17 and 17/18Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/N509668/1Research and Innovation Services
305200DTP 2018-19 University of GlasgowMary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/R513222/1MVLS - Graduate School
190615Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762Institute of Cardiovascular & Medical Sciences
656541Structural studies of human viruses and host interactionsDavid BhellaMedical Research Council (MRC)MC_UU_12014/7MVLS III - CENTRE FOR VIRUS RESEARCH