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

Trigueiro-Louro, João; Correia, Vanessa; Figueiredo-Nunes, Inês; Gíria, Marta; Rebelo-de-Andrade, Helena

http://hdl.handle.net/10400.18/7608

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Authors

Trigueiro-Louro, João

Correia, Vanessa

Figueiredo-Nunes, Inês

Gíria, Marta

Rebelo-de-Andrade, Helena

Abstract(s)

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.

Highlights: 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.

Keywords

COVID-19 SARS-CoV-2 Therapeutics Betacoronavirus Coronavirus Disease Druggability Prediction Novel Antiviral Targets Sequence Conservation Spike Protein Infecções Respiratórias