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

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 kn...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2021-11, Vol.16 (11), p.e0260283-e0260283
Main Authors: Mahindra, Amit, Tejeda, Gonzalo, Rossi, Mario, Janha, Omar, Herbert, Imogen, Morris, Caroline, Morgan, Danielle C, Beattie, Wendy, Montezano, Augusto C, Hudson, Brian, Tobin, Andrew B, Bhella, David, Touyz, Rhian M, Jamieson, Andrew G, Baillie, George S, Blair, Connor M
Format: Article
Language:English
Subjects:
A549 Cells
ACE2
Affinity
Amino acids
Angiotensin
Angiotensin converting enzyme
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - immunology
Antibodies
Antiviral activity
Antiviral Agents - pharmacology
Arrays
Binding
Binding sites
Biology
Biology and life sciences
Coronaviruses
Crystal structure
Cytokines
Firing pattern
Fluorescence
Glycoproteins
Health aspects
Humans
Inflammation
Life sciences
Medicine and health sciences
Nanobodies
Peptides
Peptides - pharmacology
Peptidyl-dipeptidase A
Protein Binding - drug effects
Protein Interaction Domains and Motifs
Proteins
Receptors
Research and Analysis Methods
Sequences
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - immunology
Spike protein
Supervision
Trimers
Viral infections
Virulence
Virus attachment
Virus Internalization
Writing
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3
cites cdi_FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3
container_end_page e0260283
container_issue 11
container_start_page e0260283
container_title PloS one
container_volume 16
creator Mahindra, Amit
Tejeda, Gonzalo
Rossi, Mario
Janha, Omar
Herbert, Imogen
Morris, Caroline
Morgan, Danielle C
Beattie, Wendy
Montezano, Augusto C
Hudson, Brian
Tobin, Andrew B
Bhella, David
Touyz, Rhian M
Jamieson, Andrew G
Baillie, George S
Blair, Connor M
description 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.
doi_str_mv 10.1371/journal.pone.0260283
format article
fullrecord <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2599054349</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A683045859</galeid><doaj_id>oai_doaj_org_article_bd3f0fee6eca437982991ad72b197890</doaj_id><sourcerecordid>A683045859</sourcerecordid><originalsourceid>FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3</originalsourceid><addsrcrecordid>eNqNk89u1DAQxiMEoqXwBggsISE4ZLHj_LEvSKtVgUqVilro1XLs8a7bJF5sp2JfhmfF6W6rLuoB5ZB48ptvPJ89Wfaa4BmhDfl05UY_yG62dgPMcFHjgtEn2SHhtMjrAtOnD74PshchXGFcUVbXz7MDWjacVhU9zP58h3W0GgLS4O0NaGS861FcAbqYn1_kC3eZF8iDSpjzqLWDtsMS9S5ac7tC0aH54rhA7RiRdmhwEbWdU9e30bwHbWVMsisXIlLQdQiG6Dcoia29y-1gOtn3MolvkNpEd20HQEl3VNG64WX2zMguwKvd-yj7-eX4x-Jbfnr29WQxP81VzYuY15JQ3SqmG6ZB65K33LS0YjVmJTVaY2bapoGGENOwtoSSAy14rSoFmGij6FH2dqu77lwQO2uDKCrOcVXSkifiZEtoJ6_E2tte-o1w0orbgPNLIX20qgPRamqwAahByZI2nBWcE6mboiW8YRwnrc-7amObDFKTI7LbE93_M9iVWLobkRoiZUGTwIedgHe_RghR9DZM5soB3LjdN2GUNCyh7_5BH-9uRy1laiAdikt11SQq5jWjuKxYNVGzR6j0aOitSvfQ2BTfS_i4l5CYCL_jUo4hiJOL8_9nzy732fcP2BXILq6C68bpyoR9sNyCyrsQPJh7kwkW0xjduSGmMRK7MUppbx4e0H3S3dzQv0TuGRE</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2599054349</pqid></control><display><type>article</type><title>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</title><source>Publicly Available Content Database</source><source>PubMed Central</source><source>Coronavirus Research Database</source><creator>Mahindra, Amit ; Tejeda, Gonzalo ; Rossi, Mario ; Janha, Omar ; Herbert, Imogen ; Morris, Caroline ; Morgan, Danielle C ; Beattie, Wendy ; Montezano, Augusto C ; Hudson, Brian ; Tobin, Andrew B ; Bhella, David ; Touyz, Rhian M ; Jamieson, Andrew G ; Baillie, George S ; Blair, Connor M</creator><contributor>Wang, Tianwen</contributor><creatorcontrib>Mahindra, Amit ; Tejeda, Gonzalo ; Rossi, Mario ; Janha, Omar ; Herbert, Imogen ; Morris, Caroline ; Morgan, Danielle C ; Beattie, Wendy ; Montezano, Augusto C ; Hudson, Brian ; Tobin, Andrew B ; Bhella, David ; Touyz, Rhian M ; Jamieson, Andrew G ; Baillie, George S ; Blair, Connor M ; Wang, Tianwen</creatorcontrib><description>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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0260283</identifier><identifier>PMID: 34793553</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>A549 Cells ; ACE2 ; Affinity ; Amino acids ; Angiotensin ; Angiotensin converting enzyme ; Angiotensin-converting enzyme 2 ; Angiotensin-Converting Enzyme 2 - immunology ; Antibodies ; Antiviral activity ; Antiviral Agents - pharmacology ; Arrays ; Binding ; Binding sites ; Biology ; Biology and life sciences ; Coronaviruses ; Crystal structure ; Cytokines ; Firing pattern ; Fluorescence ; Glycoproteins ; Health aspects ; Humans ; Inflammation ; Life sciences ; Medicine and health sciences ; Nanobodies ; Peptides ; Peptides - pharmacology ; Peptidyl-dipeptidase A ; Protein Binding - drug effects ; Protein Interaction Domains and Motifs ; Proteins ; Receptors ; Research and Analysis Methods ; Sequences ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Spike Glycoprotein, Coronavirus - immunology ; Spike protein ; Supervision ; Trimers ; Viral infections ; Virulence ; Virus attachment ; Virus Internalization ; Writing</subject><ispartof>PloS one, 2021-11, Vol.16 (11), p.e0260283-e0260283</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Mahindra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Mahindra et al 2021 Mahindra et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3</citedby><cites>FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3</cites><orcidid>0000-0002-9834-7402 ; 0000-0003-2096-8310</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2599054349/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2599054349?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,38551,43930,44625,53827,53829,74769,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34793553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wang, Tianwen</contributor><creatorcontrib>Mahindra, Amit</creatorcontrib><creatorcontrib>Tejeda, Gonzalo</creatorcontrib><creatorcontrib>Rossi, Mario</creatorcontrib><creatorcontrib>Janha, Omar</creatorcontrib><creatorcontrib>Herbert, Imogen</creatorcontrib><creatorcontrib>Morris, Caroline</creatorcontrib><creatorcontrib>Morgan, Danielle C</creatorcontrib><creatorcontrib>Beattie, Wendy</creatorcontrib><creatorcontrib>Montezano, Augusto C</creatorcontrib><creatorcontrib>Hudson, Brian</creatorcontrib><creatorcontrib>Tobin, Andrew B</creatorcontrib><creatorcontrib>Bhella, David</creatorcontrib><creatorcontrib>Touyz, Rhian M</creatorcontrib><creatorcontrib>Jamieson, Andrew G</creatorcontrib><creatorcontrib>Baillie, George S</creatorcontrib><creatorcontrib>Blair, Connor M</creatorcontrib><title>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</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>A549 Cells</subject><subject>ACE2</subject><subject>Affinity</subject><subject>Amino acids</subject><subject>Angiotensin</subject><subject>Angiotensin converting enzyme</subject><subject>Angiotensin-converting enzyme 2</subject><subject>Angiotensin-Converting Enzyme 2 - immunology</subject><subject>Antibodies</subject><subject>Antiviral activity</subject><subject>Antiviral Agents - pharmacology</subject><subject>Arrays</subject><subject>Binding</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Biology and life sciences</subject><subject>Coronaviruses</subject><subject>Crystal structure</subject><subject>Cytokines</subject><subject>Firing pattern</subject><subject>Fluorescence</subject><subject>Glycoproteins</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Life sciences</subject><subject>Medicine and health sciences</subject><subject>Nanobodies</subject><subject>Peptides</subject><subject>Peptides - pharmacology</subject><subject>Peptidyl-dipeptidase A</subject><subject>Protein Binding - drug effects</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Research and Analysis Methods</subject><subject>Sequences</subject><subject>Severe acute respiratory syndrome</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Spike Glycoprotein, Coronavirus - immunology</subject><subject>Spike protein</subject><subject>Supervision</subject><subject>Trimers</subject><subject>Viral infections</subject><subject>Virulence</subject><subject>Virus attachment</subject><subject>Virus Internalization</subject><subject>Writing</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>COVID</sourceid><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk89u1DAQxiMEoqXwBggsISE4ZLHj_LEvSKtVgUqVilro1XLs8a7bJF5sp2JfhmfF6W6rLuoB5ZB48ptvPJ89Wfaa4BmhDfl05UY_yG62dgPMcFHjgtEn2SHhtMjrAtOnD74PshchXGFcUVbXz7MDWjacVhU9zP58h3W0GgLS4O0NaGS861FcAbqYn1_kC3eZF8iDSpjzqLWDtsMS9S5ac7tC0aH54rhA7RiRdmhwEbWdU9e30bwHbWVMsisXIlLQdQiG6Dcoia29y-1gOtn3MolvkNpEd20HQEl3VNG64WX2zMguwKvd-yj7-eX4x-Jbfnr29WQxP81VzYuY15JQ3SqmG6ZB65K33LS0YjVmJTVaY2bapoGGENOwtoSSAy14rSoFmGij6FH2dqu77lwQO2uDKCrOcVXSkifiZEtoJ6_E2tte-o1w0orbgPNLIX20qgPRamqwAahByZI2nBWcE6mboiW8YRwnrc-7amObDFKTI7LbE93_M9iVWLobkRoiZUGTwIedgHe_RghR9DZM5soB3LjdN2GUNCyh7_5BH-9uRy1laiAdikt11SQq5jWjuKxYNVGzR6j0aOitSvfQ2BTfS_i4l5CYCL_jUo4hiJOL8_9nzy732fcP2BXILq6C68bpyoR9sNyCyrsQPJh7kwkW0xjduSGmMRK7MUppbx4e0H3S3dzQv0TuGRE</recordid><startdate>20211118</startdate><enddate>20211118</enddate><creator>Mahindra, Amit</creator><creator>Tejeda, Gonzalo</creator><creator>Rossi, Mario</creator><creator>Janha, Omar</creator><creator>Herbert, Imogen</creator><creator>Morris, Caroline</creator><creator>Morgan, Danielle C</creator><creator>Beattie, Wendy</creator><creator>Montezano, Augusto C</creator><creator>Hudson, Brian</creator><creator>Tobin, Andrew B</creator><creator>Bhella, David</creator><creator>Touyz, Rhian M</creator><creator>Jamieson, Andrew G</creator><creator>Baillie, George S</creator><creator>Blair, Connor M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>COVID</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-9834-7402</orcidid><orcidid>https://orcid.org/0000-0003-2096-8310</orcidid></search><sort><creationdate>20211118</creationdate><title>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</title><author>Mahindra, Amit ; Tejeda, Gonzalo ; Rossi, Mario ; Janha, Omar ; Herbert, Imogen ; Morris, Caroline ; Morgan, Danielle C ; Beattie, Wendy ; Montezano, Augusto C ; Hudson, Brian ; Tobin, Andrew B ; Bhella, David ; Touyz, Rhian M ; Jamieson, Andrew G ; Baillie, George S ; Blair, Connor M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>A549 Cells</topic><topic>ACE2</topic><topic>Affinity</topic><topic>Amino acids</topic><topic>Angiotensin</topic><topic>Angiotensin converting enzyme</topic><topic>Angiotensin-converting enzyme 2</topic><topic>Angiotensin-Converting Enzyme 2 - immunology</topic><topic>Antibodies</topic><topic>Antiviral activity</topic><topic>Antiviral Agents - pharmacology</topic><topic>Arrays</topic><topic>Binding</topic><topic>Binding sites</topic><topic>Biology</topic><topic>Biology and life sciences</topic><topic>Coronaviruses</topic><topic>Crystal structure</topic><topic>Cytokines</topic><topic>Firing pattern</topic><topic>Fluorescence</topic><topic>Glycoproteins</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Life sciences</topic><topic>Medicine and health sciences</topic><topic>Nanobodies</topic><topic>Peptides</topic><topic>Peptides - pharmacology</topic><topic>Peptidyl-dipeptidase A</topic><topic>Protein Binding - drug effects</topic><topic>Protein Interaction Domains and Motifs</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Research and Analysis Methods</topic><topic>Sequences</topic><topic>Severe acute respiratory syndrome</topic><topic>Severe acute respiratory syndrome coronavirus 2</topic><topic>Spike Glycoprotein, Coronavirus - immunology</topic><topic>Spike protein</topic><topic>Supervision</topic><topic>Trimers</topic><topic>Viral infections</topic><topic>Virulence</topic><topic>Virus attachment</topic><topic>Virus Internalization</topic><topic>Writing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mahindra, Amit</creatorcontrib><creatorcontrib>Tejeda, Gonzalo</creatorcontrib><creatorcontrib>Rossi, Mario</creatorcontrib><creatorcontrib>Janha, Omar</creatorcontrib><creatorcontrib>Herbert, Imogen</creatorcontrib><creatorcontrib>Morris, Caroline</creatorcontrib><creatorcontrib>Morgan, Danielle C</creatorcontrib><creatorcontrib>Beattie, Wendy</creatorcontrib><creatorcontrib>Montezano, Augusto C</creatorcontrib><creatorcontrib>Hudson, Brian</creatorcontrib><creatorcontrib>Tobin, Andrew B</creatorcontrib><creatorcontrib>Bhella, David</creatorcontrib><creatorcontrib>Touyz, Rhian M</creatorcontrib><creatorcontrib>Jamieson, Andrew G</creatorcontrib><creatorcontrib>Baillie, George S</creatorcontrib><creatorcontrib>Blair, Connor M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Science in Context</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing &amp; Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Coronavirus Research Database</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mahindra, Amit</au><au>Tejeda, Gonzalo</au><au>Rossi, Mario</au><au>Janha, Omar</au><au>Herbert, Imogen</au><au>Morris, Caroline</au><au>Morgan, Danielle C</au><au>Beattie, Wendy</au><au>Montezano, Augusto C</au><au>Hudson, Brian</au><au>Tobin, Andrew B</au><au>Bhella, David</au><au>Touyz, Rhian M</au><au>Jamieson, Andrew G</au><au>Baillie, George S</au><au>Blair, Connor M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-11-18</date><risdate>2021</risdate><volume>16</volume><issue>11</issue><spage>e0260283</spage><epage>e0260283</epage><pages>e0260283-e0260283</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Competing Interests: The authors declare no competing interests.</notes><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34793553</pmid><doi>10.1371/journal.pone.0260283</doi><tpages>e0260283</tpages><orcidid>https://orcid.org/0000-0002-9834-7402</orcidid><orcidid>https://orcid.org/0000-0003-2096-8310</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1932-6203
ispartof PloS one, 2021-11, Vol.16 (11), p.e0260283-e0260283
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_2599054349
source Publicly Available Content Database; PubMed Central; Coronavirus Research Database
subjects A549 Cells
ACE2
Affinity
Amino acids
Angiotensin
Angiotensin converting enzyme
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - immunology
Antibodies
Antiviral activity
Antiviral Agents - pharmacology
Arrays
Binding
Binding sites
Biology
Biology and life sciences
Coronaviruses
Crystal structure
Cytokines
Firing pattern
Fluorescence
Glycoproteins
Health aspects
Humans
Inflammation
Life sciences
Medicine and health sciences
Nanobodies
Peptides
Peptides - pharmacology
Peptidyl-dipeptidase A
Protein Binding - drug effects
Protein Interaction Domains and Motifs
Proteins
Receptors
Research and Analysis Methods
Sequences
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - immunology
Spike protein
Supervision
Trimers
Viral infections
Virulence
Virus attachment
Virus Internalization
Writing
title 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
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T19%3A58%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Peptides%20derived%20from%20the%20SARS-CoV-2%20receptor%20binding%20motif%20bind%20to%20ACE2%20but%20do%20not%20block%20ACE2-mediated%20host%20cell%20entry%20or%20pro-inflammatory%20cytokine%20induction&rft.jtitle=PloS%20one&rft.au=Mahindra,%20Amit&rft.date=2021-11-18&rft.volume=16&rft.issue=11&rft.spage=e0260283&rft.epage=e0260283&rft.pages=e0260283-e0260283&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0260283&rft_dat=%3Cgale_plos_%3EA683045859%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c692t-6a13dbc8d78dedd49b9fb35860843fdd08fb77e711f78b4e49e3296c5ce01dfc3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2599054349&rft_id=info:pmid/34793553&rft_galeid=A683045859&rfr_iscdi=true