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

Autor:	Trigueiro-Louro J; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal.; Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal., Correia V; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal., Figueiredo-Nunes I; Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal., Gíria M; Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal., Rebelo-de-Andrade H; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal.; Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2020 Jul 31; Vol. 18, pp. 2117-2131. Date of Electronic Publication: 2020 Jul 31 (Print Publication: 2020).
DOI:	10.1016/j.csbj.2020.07.017
Abstrakt:	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 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. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2020 The Authors.)
Databáze:	MEDLINE
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