Unlocking COVID therapeutic targets : A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike
© 2020 The Authors..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
Computational and structural biotechnology journal - 18(2020) vom: 28., Seite 2117-2131 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Trigueiro-Louro, João [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 12.11.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.csbj.2020.07.017 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM314857702 |
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| 100 | 1 | |a Trigueiro-Louro, João |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unlocking COVID therapeutic targets |b A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 12.11.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2020 The Authors. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ACE2, angiotensin-converting enzyme2 | |
| 650 | 4 | |a Bat-SL-CoVs, bat SARS-like coronavirus | |
| 650 | 4 | |a Beta-CoVs, betacoronavirus | |
| 650 | 4 | |a Betacoronavirus | |
| 650 | 4 | |a CC, conserved cluster | |
| 650 | 4 | |a CD, connector domain | |
| 650 | 4 | |a CDP, consensus druggable pocket | |
| 650 | 4 | |a CDR, consensus druggable residue | |
| 650 | 4 | |a CH, central helix | |
| 650 | 4 | |a CP, cytoplasmic domain | |
| 650 | 4 | |a CR, connecting region | |
| 650 | 4 | |a CS, conservation score | |
| 650 | 4 | |a CoVs, coronavirus | |
| 650 | 4 | |a Coronavirus disease | |
| 650 | 4 | |a DGSS, DoGSiteScorer | |
| 650 | 4 | |a DPP4, dipeptidyl peptidase-4 | |
| 650 | 4 | |a Druggability prediction | |
| 650 | 4 | |a FP, fusion peptide | |
| 650 | 4 | |a HR1, heptad repeat 1 | |
| 650 | 4 | |a HR2, heptad repeat 2 | |
| 650 | 4 | |a MERS-CoVs, middle east respiratory syndrome coronavirus | |
| 650 | 4 | |a MERSr-CoVs, middle east respiratory syndrome-related coronavirus | |
| 650 | 4 | |a MSA, multiple sequence alignment | |
| 650 | 4 | |a NTD, N-terminal domain | |
| 650 | 4 | |a Novel antiviral targets | |
| 650 | 4 | |a PDB, Protein Data Bank | |
| 650 | 4 | |a PDS, PockDrug-Server | |
| 650 | 4 | |a RBD, Receptor-Binding Domain | |
| 650 | 4 | |a S, Spike | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 | |
| 650 | 4 | |a SARS-CoVs, severe acute respiratory syndrome coronavirus | |
| 650 | 4 | |a SARSr-CoVs, severe acute respiratory syndrome-related coronavirus | |
| 650 | 4 | |a SD1, subdomain 1 | |
| 650 | 4 | |a SD2, subdomain 2 | |
| 650 | 4 | |a SF, SiteFinder from MOE | |
| 650 | 4 | |a SP, small pocket | |
| 650 | 4 | |a Sequence conservation | |
| 650 | 4 | |a Spike protein | |
| 650 | 4 | |a Sv, shorter variant | |
| 650 | 4 | |a T-RHS, top-ranked hot spots | |
| 650 | 4 | |a TMPRSS2, transmembrane protease serine 2 | |
| 650 | 4 | |a aa, amino acid | |
| 650 | 4 | |a hSARSr-CoVs, human Severe acute respiratory syndrome-related coronavirus | |
| 650 | 4 | |a nts, nucleotides | |
| 700 | 1 | |a Correia, Vanessa |e verfasserin |4 aut | |
| 700 | 1 | |a Figueiredo-Nunes, Inês |e verfasserin |4 aut | |
| 700 | 1 | |a Gíria, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Rebelo-de-Andrade, Helena |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:18 |g year:2020 |g day:28 |g pages:2117-2131 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.csbj.2020.07.017 |3 Volltext |
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