دورية أكاديمية
Molecules targeting a novel homotrimer cavity of Spike protein attenuate replication of SARS-CoV-2.
| العنوان: | Molecules targeting a novel homotrimer cavity of Spike protein attenuate replication of SARS-CoV-2. |
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| المؤلفون: | Daniels A; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Padariya M; International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, 80-822 Gdańsk, Poland., Fletcher S; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom., Ball K; University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom., Singh A; University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom., Carragher N; University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom., Hupp T; International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, 80-822 Gdańsk, Poland; University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom., Tait-Burkard C; The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom. Electronic address: christine.burkard@roslin.ed.ac.uk., Kalathiya U; International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, 80-822 Gdańsk, Poland. Electronic address: umesh.kalathiya@ug.edu.pl. |
| المصدر: | Antiviral research [Antiviral Res] 2024 Aug; Vol. 228, pp. 105949. Date of Electronic Publication: 2024 Jun 26. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8109699 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9096 (Electronic) Linking ISSN: 01663542 NLM ISO Abbreviation: Antiviral Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Amsterdam : Elsevier Original Publication: [Amsterdam ; New York : Elsevier/North-Holland Biomedical Press, c1981- |
| مواضيع طبية MeSH: | Spike Glycoprotein, Coronavirus*/metabolism , Spike Glycoprotein, Coronavirus*/chemistry , Spike Glycoprotein, Coronavirus*/genetics , Spike Glycoprotein, Coronavirus*/antagonists & inhibitors , SARS-CoV-2*/drug effects , SARS-CoV-2*/physiology , Virus Replication*/drug effects , Antiviral Agents*/pharmacology , Antiviral Agents*/chemistry, Humans ; Chlorocebus aethiops ; Vero Cells ; Animals ; Binding Sites ; Virus Internalization/drug effects ; COVID-19/virology ; Protein Multimerization/drug effects ; COVID-19 Drug Treatment ; Small Molecule Libraries/pharmacology |
| مستخلص: | The SARS-CoV-2 Spike glycoprotein (S) utilizes a unique trimeric conformation to interact with the ACE2 receptor on host cells, making it a prime target for inhibitors that block viral entry. We have previously identified a novel proteinaceous cavity within the Spike protein homotrimer that could serve as a binding site for small molecules. However, it is not known whether these molecules would inhibit, stimulate, or have no effect on viral replication. To address this, we employed structural-based screening to identify small molecules that dock into the trimer cavity and assessed their impact on viral replication. Our findings show that a cohort of identified small molecules binding to the Spike trimer cavity effectively reduces the replication of various SARS-CoV-2 variants. These molecules exhibited inhibitory effects on B.1 (European original, D614G, EDB2) and B.1.617.2 (δ) variants, while showing moderate activity against the B.1.1.7 (α) variant. We further categorized these molecules into distinct groups based on their structural similarities. Our experiments demonstrated a dose-dependent viral replication inhibitory activity of these compounds, with some, like BCC0040453 exhibiting no adverse effects on cell viability even at high concentrations. Further investigation revealed that pre-incubating virions with compounds like BCC0031216 at different temperatures significantly inhibited viral replication, suggesting their specificity towards the S protein. Overall, our study highlights the inhibitory impact of a diverse set of chemical molecules on the biological activity of the Spike protein. These findings provide valuable insights into the role of the trimer cavity in the viral replication cycle and aid drug discovery programs aimed at targeting the coronavirus family. Competing Interests: Declaration of competing interest 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. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: ACE2; ARS-CoV-2; Coronavirus; Homotrimer cavity; Infection; Ligand screening; Spike glycoprotein |
| المشرفين على المادة: | 0 (Spike Glycoprotein, Coronavirus) 0 (spike protein, SARS-CoV-2) 0 (Antiviral Agents) 0 (Small Molecule Libraries) |
| SCR Organism: | SARS-CoV-2 variants |
| تواريخ الأحداث: | Date Created: 20240628 Date Completed: 20240715 Latest Revision: 20240813 |
| رمز التحديث: | 20240813 |
| DOI: | 10.1016/j.antiviral.2024.105949 |
| PMID: | 38942150 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1872-9096 |
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| DOI: | 10.1016/j.antiviral.2024.105949 |