In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 11 ( 2021-11-18), p. e0260283-
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 (S RBD )–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): S 443 KVGGNYNYLYRLFRK 458 , RBM2A (25mer): E 484 GFNCYFPLQSYGFQPTNGVGYQPY 508 , RBM2B (20mer): F 456 NCYFPLQSYGFQPTNGVGY 505 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 (K d = 0.207–1.206 μM). However, the RBM peptides demonstrated only modest effects in preventing S RBD 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0260283
DOI:
10.1371/journal.pone.0260283.g001
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10.1371/journal.pone.0260283.g002
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10.1371/journal.pone.0260283.g003
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10.1371/journal.pone.0260283.g004
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10.1371/journal.pone.0260283.g005
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10.1371/journal.pone.0260283.g006
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10.1371/journal.pone.0260283.g007
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10.1371/journal.pone.0260283.t001
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10.1371/journal.pone.0260283.t002
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10.1371/journal.pone.0260283.s001
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10.1371/journal.pone.0260283.s002
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10.1371/journal.pone.0260283.s003
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10.1371/journal.pone.0260283.s004
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10.1371/journal.pone.0260283.s005
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10.1371/journal.pone.0260283.s006
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10.1371/journal.pone.0260283.s007
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10.1371/journal.pone.0260283.s008
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10.1371/journal.pone.0260283.s009
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10.1371/journal.pone.0260283.s011
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10.1371/journal.pone.0260283.s012
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10.1371/journal.pone.0260283.s013
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10.1371/journal.pone.0260283.s014
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10.1371/journal.pone.0260283.s015
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10.1371/journal.pone.0260283.s016
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10.1371/journal.pone.0260283.s017
DOI:
10.1371/journal.pone.0260283.r001
DOI:
10.1371/journal.pone.0260283.r002
DOI:
10.1371/journal.pone.0260283.r003
DOI:
10.1371/journal.pone.0260283.r004
DOI:
10.1371/journal.pone.0260283.r005
DOI:
10.1371/journal.pone.0260283.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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