Journal
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
Volume 18, Issue -, Pages 2117-2131Publisher
ELSEVIER
DOI: 10.1016/j.csbj.2020.07.017
Keywords
Betacoronavirus; Coronavirus disease; Druggability prediction; Novel antiviral targets; SARS-CoV-2; Sequence conservation; Spike protein
Funding
- FCT - Fundacao para a Ciencia e a Tecnologia, I.P.
- FCT [PTDC/SAU-INF/30729/2017]
- FCT PhD Programme in Medicines and Pharmaceutical Innovation (i3DU) [PD/BD/128402/2017]
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There 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 SDI (S1 sub-unit); 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. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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