Graphical abstract 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. 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.
【저자키워드】 coronavirus disease, SARS-CoV-2, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, RBD, receptor-binding domain, Betacoronavirus, Spike protein, S, spike, Sequence conservation, NTD, N-terminal domain, PDB, Protein Data Bank, DPP4, dipeptidyl peptidase-4, TMPRSS2, Transmembrane Protease Serine 2, FP, fusion peptide, HR1, heptad repeat 1, CH, central helix, CD, connector domain, aa, amino acid, ACE2, angiotensin-converting enzyme2, Bat-SL-CoVs, bat SARS-like coronavirus, Beta-CoVs, betacoronavirus, CC, conserved cluster, CDR, consensus druggable residue, CDP, consensus druggable pocket, CoVs, coronavirus, CP, cytoplasmic domain, CR, connecting region, CS, conservation score, DGSS, DoGSiteScorer, HR2, heptad repeat 2, hSARSr-CoVs, human Severe acute respiratory syndrome-related coronavirus, MERS-CoVs, middle east respiratory syndrome coronavirus, MERSr-CoVs, middle east respiratory syndrome-related coronavirus, MSA, multiple sequence alignment, nts, nucleotides, PDS, PockDrug-Server, SARS-CoVs, severe acute respiratory syndrome coronavirus, SARSr-CoVs, severe acute respiratory syndrome-related coronavirus, SD1, subdomain 1, SD2, subdomain 2, Sv, shorter variant, SF, SiteFinder from MOE, SP, small pocket, T-RHS, top-ranked hot spots, Druggability prediction, Novel antiviral targets, 【초록키워드】 COVID-19, Resilience, Pathogenesis, spike, drug design, antibody, Human, Infection, inhibitors, Protein, Region, Features, RBD, therapeutic, Research, Sequence analysis, molecular, Critical, S2 subunit, SARSr-CoV, Consensus, Abstract, modulation, residue, domain, subunits, beta-CoVs, pharmacological, regions, approach, feature, new SARS-CoV-2, responsible, resulting, described, S1 and S2, performed, conserved, approved, provide, in viral, New, the Spike, 【제목키워드】 spike, SARS-CoV, MERS-CoV, COVID, therapeutic,