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

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

doi:10.1016/j.csbj.2020.07.017

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

Comput Struct Biotechnol J. 2020 Jul 31:18:2117-2131. doi: 10.1016/j.csbj.2020.07.017. eCollection 2020.

Authors

João Trigueiro-Louro^{1

2}, Vanessa Correia¹, Inês Figueiredo-Nunes², Marta Gíria², Helena Rebelo-de-Andrade^{1

2}

Affiliations

¹ Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016 Lisbon, Portugal.
² Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal.

Abstract

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.

Keywords: ACE2, angiotensin-converting enzyme2; Bat-SL-CoVs, bat SARS-like coronavirus; Beta-CoVs, betacoronavirus; Betacoronavirus; CC, conserved cluster; CD, connector domain; CDP, consensus druggable pocket; CDR, consensus druggable residue; CH, central helix; CP, cytoplasmic domain; CR, connecting region; CS, conservation score; CoVs, coronavirus; Coronavirus disease; DGSS, DoGSiteScorer; DPP4, dipeptidyl peptidase-4; Druggability prediction; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; MERS-CoVs, middle east respiratory syndrome coronavirus; MERSr-CoVs, middle east respiratory syndrome-related coronavirus; MSA, multiple sequence alignment; NTD, N-terminal domain; Novel antiviral targets; PDB, Protein Data Bank; PDS, PockDrug-Server; RBD, Receptor-Binding Domain; S, Spike; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoVs, severe acute respiratory syndrome coronavirus; SARSr-CoVs, severe acute respiratory syndrome-related coronavirus; SD1, subdomain 1; SD2, subdomain 2; SF, SiteFinder from MOE; SP, small pocket; Sequence conservation; Spike protein; Sv, shorter variant; T-RHS, top-ranked hot spots; TMPRSS2, transmembrane protease serine 2; aa, amino acid; hSARSr-CoVs, human Severe acute respiratory syndrome-related coronavirus; nts, nucleotides.