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Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

2020-07-31Journal article Open access
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dc.contributor.authorTrigueiro-Louro, João
dc.contributor.authorCorreia, Vanessa
dc.contributor.authorFigueiredo-Nunes, Inês
dc.contributor.authorGíria, Marta
dc.contributor.authorRebelo-de-Andrade, Helena
dc.date.accessioned2021-03-31T15:03:43Z
dc.date.available2021-03-31T15:03:43Z
dc.date.issued2020-07-31
dc.description.abstractThere are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved druggable regions resulting from a comprehensive large-scale sequence analysis and structural characterization of Spike domains across SARSr- and MERSr-CoVs. We have disclosed 28 main consensus druggable pockets within the Spike. The RBD and SD1 (S1 subunit); and the CR, HR1 and CH (S2 subunit) represent the most promising conserved druggable regions. Additionally, we have identified 181 new potential hot spot residues for the hSARSr-CoVs and 72 new hot spot residues for the SARSr- and MERSr-CoVs, which have not been described before in the literature. These sites/residues exhibit advantageous structural features for targeted molecular and pharmacological modulation. This study establishes the Spike as a promising anti-CoV target using an approach with a potential higher resilience to resistance development and directed to a broad spectrum of Beta-CoVs, including the new SARS-CoV-2 responsible for COVID-19. This research also provides a structure-based rationale for the design and discovery of chemical inhibitors, antibodies or other therapeutic modalities successfully targeting the Beta-CoV Spike protein.pt_PT
dc.description.abstractHighlights: Human SARSr-CoV Spike protein is highly conserved in both S1 and S2 subunits; The S1-RBD, -SD1; S2-CR, -HR1 and -CH are the most promising druggable S regions; 28 main consensus druggable pockets were found with high druggabbility score; New hot spots were identified for hSARSr-CoVs (n = 181) and Beta-CoVs (n = 72); A structure-based rationale is disclosed for drug design and discovery.pt_PT
dc.description.sponsorshipThis work is funded by National Funds through the FCT - Fundação para a Ciência e a Tecnologia, I.P., by the FCT project PTDC/SAU-INF/30729/2017; and supported by the PhD grant PD/BD/128402/2017 from FCT PhD Programme in Medicines and Pharmaceutical Innovation (i3DU).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationComput Struct Biotechnol J. 2020 Jul 31;18:2117-2131. doi: 10.1016/j.csbj.2020.07.017. eCollection 2020.pt_PT
dc.identifier.doi10.1016/j.csbj.2020.07.017pt_PT
dc.identifier.issn2001-0370
dc.identifier.urihttp://hdl.handle.net/10400.18/7608
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevier/ Research Network of Computational and Structural Biotechnologypt_PT
dc.relationReverse Genetics Vaccine Seeds for Influenza: Mechanisms that drive the co-segregation of PB1 with antigenic proteins
dc.relationNS1 como alvo terapêutico emergente: na procura de novos fármacos contra o vírus influenza
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S2001037020303494?via%3Dihubpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCOVID-19pt_PT
dc.subjectSARS-CoV-2pt_PT
dc.subjectTherapeuticspt_PT
dc.subjectBetacoronaviruspt_PT
dc.subjectCoronavirus Diseasept_PT
dc.subjectDruggability Predictionpt_PT
dc.subjectNovel Antiviral Targetspt_PT
dc.subjectSequence Conservationpt_PT
dc.subjectSpike Proteinpt_PT
dc.subjectInfecções Respiratóriaspt_PT
dc.titleUnlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spikept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleReverse Genetics Vaccine Seeds for Influenza: Mechanisms that drive the co-segregation of PB1 with antigenic proteins
oaire.awardTitleNS1 como alvo terapêutico emergente: na procura de novos fármacos contra o vírus influenza
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-INF%2F30729%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128402%2F2017/PT
oaire.citation.endPage2131pt_PT
oaire.citation.startPage2117pt_PT
oaire.citation.titleComputational and Structural Biotechnology Journalpt_PT
oaire.citation.volume18pt_PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationa0e83cc0-de48-4e03-b202-2e61313186f5
relation.isProjectOfPublication7ea88733-a953-4463-97e1-5a85fe025637
relation.isProjectOfPublication.latestForDiscoverya0e83cc0-de48-4e03-b202-2e61313186f5

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