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dc.contributor.authorAlam, Intikhab
dc.contributor.authorKamau, Allan K
dc.contributor.authorKulmanov, Maxat
dc.contributor.authorArold, Stefan T.
dc.contributor.authorPain, Arnab
dc.contributor.authorGojobori, Takashi
dc.contributor.authorDuarte, Carlos M.
dc.date.accessioned2020-03-09T13:00:35Z
dc.date.available2020-03-02T08:57:59Z
dc.date.available2020-03-09T13:00:35Z
dc.date.issued2020-03-06
dc.identifier.citationAlam, I., Kamau, A. K., Kulmanov, M., Arold, S. T., Pain, A. T., Gojobori, T., & Duarte, C. M. (2020). Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019. doi:10.1101/2020.02.17.952895
dc.identifier.doi10.1101/2020.02.17.952895
dc.identifier.urihttp://hdl.handle.net/10754/661831
dc.description.abstractThe spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells. The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-2. Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS), the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection. However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride) or the PBM (SB203580), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.
dc.description.sponsorshipThis research was funded by the King Abdullah University of Science and Technology (KAUST) through funding allocated to Computational Bioscience Research Center (CBRC) and another KAUST award under the award number FCC/1/1976-25-01.
dc.publisherbioRxiv
dc.relation.urlhttp://biorxiv.org/lookup/doi/10.1101/2020.02.17.952895
dc.rightsArchived with thanks to Cold Spring Harbor Laboratory
dc.titleFunctional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019.
dc.typePreprint
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentComputer Science Program
dc.contributor.departmentBioscience Program
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentMarine Science Program
dc.contributor.departmentRed Sea Research Center (RSRC)
dc.eprint.versionPre-print
dc.contributor.institutionCentre de Biochimie Structurale, CNRS, INSERM, Université de Montpellier, 34090 Montpellier, France
kaust.personAlam, Intikhab
kaust.personKamau, Allan K
kaust.personKulmanov, Maxat
kaust.personArold, Stefan T.
kaust.personGojobori, Takashi
kaust.personDuarte, Carlos M.
dc.relation.issupplementedbyURL:https://pangenomedb.cbrc.kaust.edu.sa/
refterms.dateFOA2020-03-02T08:59:01Z
display.relations<b> Is Supplemented By:</b> <br/> <ul><li><i>[Database]</i> <br/> Betacoronavirus PanGenome DB. URL: <a href="https://pangenomedb.cbrc.kaust.edu.sa/">https://pangenomedb.cbrc.kaust.edu.sa/</a></li></ul>
kaust.acknowledged.supportUnitCBRC
kaust.acknowledged.supportUnitInformation Technology
kaust.acknowledged.supportUnitKAUST Supercomputing Laboratory (KSL)


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