Functional Pangenome Analysis Shows Key Features of E Protein Are Preserved in SARS and SARS-CoV-2

Abstract
The 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 and SARS-CoV-2 are similar, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-specific neutralizing antibodies to inhibit SARS-CoV-2. Here we used comparative pangenomic analysis of all sequenced reference Betacoronaviruses, complemented with functional and structural analyses. This analysis reveals that, among all core gene clusters present in these viruses, the envelope protein E shows a variant cluster shared by SARS and SARS-CoV-2 with two completely-conserved key functional features, namely an ion-channel, and a PDZ-binding motif (PBM). These features play a key role in the activation of the inflammasome causing the acute respiratory distress syndrome, the leading cause of death in SARS and SARS-CoV-2 infections. Together with functional pangenomic analysis, mutation tracking, and previous evidence, on E protein as a determinant of pathogenicity in SARS, we suggest E protein as an alternative therapeutic target to be considered for further studies to reduce complications of SARS-CoV-2 infections in COVID-19.

Citation
Alam, I., Kamau, A. K., Kulmanov, M., Arold, S. T., Pain, A. T., Gojobori, T., & Duarte, C. M. (2020). Functional pangenome analysis points to protein E, a pathogenicity determinant in SARS, as a therapeutic target for COVID-19 complications. doi:10.3389/fcimb.2020.00405

Acknowledgements
The research reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST), under award number FCC/1/1976-25-01.
We are thankful to KAUST Supercomputing Laboratory (KSL), KAUST Information Technology (IT) and Muhammad Saif from CBRC, KAUST for providing support in computing resources. We are grateful to all the authors and GSAID for providing access to SARS-CoV-2 isolates for research, contributing labs and authors are clearly shown in the metadata table at https://trackncov.cbrc.kaust.edu.sa.

Publisher
Frontiers Media SA

Journal
Frontiers in Cellular and Infection Microbiology

DOI
10.3389/fcimb.2020.00405
10.1101/2020.02.17.952895

Additional Links
https://www.frontiersin.org/articles/10.3389/fcimb.2020.00405/abstract

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Version History

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VersionDateSummary
4*
2020-07-27 06:44:45
Published in journal
2020-07-01 13:52:24
Accepted for publication
2020-03-09 12:55:31
Updated version deposited to bioRxiv.
2020-03-02 08:57:59
* Selected version