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Tytuł pozycji:

Key genetic elements, single and in clusters, underlying geographically dependent SARS-CoV-2 genetic adaptation and their impact on binding affinity for drugs and immune control.

Tytuł :
Key genetic elements, single and in clusters, underlying geographically dependent SARS-CoV-2 genetic adaptation and their impact on binding affinity for drugs and immune control.
Autorzy :
Salpini R; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Alkhatib M; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Costa G; Dipartimento di Scienze della Salute, Università 'Magna Græcia', Catanzaro, Italy.; Net4Science srl, Università 'Magna Græcia', Catanzaro, Italy.
Piermatteo L; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Ambrosio FA; Dipartimento di Scienze della Salute, Università 'Magna Græcia', Catanzaro, Italy.
Di Maio VC; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Scutari R; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Duca L; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Berno G; Laboratory of Virology, National Institute for Infectious Diseases 'Lazzaro Spallanzani'-IRCCS, Rome, Italy.
Fabeni L; Laboratory of Virology, National Institute for Infectious Diseases 'Lazzaro Spallanzani'-IRCCS, Rome, Italy.
Alcaro S; Dipartimento di Scienze della Salute, Università 'Magna Græcia', Catanzaro, Italy.; Net4Science srl, Università 'Magna Græcia', Catanzaro, Italy.
Ceccherini-Silberstein F; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Artese A; Dipartimento di Scienze della Salute, Università 'Magna Græcia', Catanzaro, Italy.; Net4Science srl, Università 'Magna Græcia', Catanzaro, Italy.
Svicher V; Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
Pokaż więcej
Źródło :
The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2021 Jan 19; Vol. 76 (2), pp. 396-412.
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Publication: 1997- : London : Oxford University Press
Original Publication: London, New York, Academic Press.
MeSH Terms :
Adaptation, Biological/*genetics
Antiviral Agents/*metabolism
COVID-19/*immunology
Coronavirus 3C Proteases/*genetics
Coronavirus Protease Inhibitors/*metabolism
Coronavirus RNA-Dependent RNA Polymerase/*genetics
SARS-CoV-2/*genetics
Americas ; Amino Acid Sequence ; Antigens, Viral/blood ; Antiviral Agents/therapeutic use ; Asia ; COVID-19/drug therapy ; COVID-19/epidemiology ; Computer Simulation ; Coronavirus 3C Proteases/metabolism ; Coronavirus Protease Inhibitors/therapeutic use ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Europe ; Evolution, Molecular ; Humans ; Molecular Docking Simulation ; Multigene Family ; Mutation/genetics ; Mutation Rate ; Oceania ; Protein Binding ; SARS-CoV-2/enzymology ; Topography, Medical
References :
Int J Infect Dis. 2020 Jul;96:459-460. (PMID: 32464271)
PLoS One. 2020 Nov 10;15(11):e0240345. (PMID: 33170902)
Pathogens. 2020 Apr 26;9(5):. (PMID: 32357545)
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Substance Nomenclature :
0 (Antigens, Viral)
0 (Antiviral Agents)
0 (Coronavirus Protease Inhibitors)
EC 2.7.7.48 (Coronavirus RNA-Dependent RNA Polymerase)
EC 3.4.22.- (3C-like protease, SARS coronavirus)
EC 3.4.22.28 (Coronavirus 3C Proteases)
Entry Date(s) :
Date Created: 20201130 Date Completed: 20210202 Latest Revision: 20210202
Update Code :
20210210
PubMed Central ID :
PMC7799093
DOI :
10.1093/jac/dkaa444
PMID :
33254234
Czasopismo naukowe
Objectives: To define key genetic elements, single or in clusters, underlying SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) evolutionary diversification across continents, and their impact on drug-binding affinity and viral antigenicity.
Methods: A total of 12 150 SARS-CoV-2 sequences (publicly available) from 69 countries were analysed. Mutational clusters were assessed by hierarchical clustering. Structure-based virtual screening (SBVS) was used to select the best inhibitors of 3-chymotrypsin-like protease (3CL-Pr) and RNA-dependent RNA polymerase (RdRp) among the FDA-approved drugs and to evaluate the impact of mutations on binding affinity of these drugs. The impact of mutations on epitope recognition was predicted following Grifoni et al. (Cell Host Microbe 2020.
27: 671-80.).
Results: Thirty-five key mutations were identified (prevalence: ≥0.5%), residing in different viral proteins. Sixteen out of 35 formed tight clusters involving multiple SARS-CoV-2 proteins, highlighting intergenic co-evolution. Some clusters (including D614GSpike + P323LRdRp + R203KN + G204RN) occurred in all continents, while others showed a geographically restricted circulation (T1198KPL-Pr + P13LN + A97VRdRp in Asia, L84SORF-8 + S197LN in Europe, Y541CHel + H504CHel + L84SORF-8 in America and Oceania). SBVS identified 20 best RdRp inhibitors and 21 best 3CL-Pr inhibitors belonging to different drug classes. Notably, mutations in RdRp or 3CL-Pr modulate, positively or negatively, the binding affinity of these drugs. Among them, P323LRdRp (prevalence: 61.9%) reduced the binding affinity of specific compounds including remdesivir while it increased the binding affinity of the purine analogues penciclovir and tenofovir, suggesting potential hypersusceptibility. Finally, specific mutations (including Y541CHel + H504CHel) strongly hampered recognition of Class I/II epitopes, while D614GSpike profoundly altered the structural stability of a recently identified B cell epitope target of neutralizing antibodies (amino acids 592-620).
Conclusions: Key genetic elements reflect geographically dependent SARS-CoV-2 genetic adaptation, and may play a potential role in modulating drug susceptibility and hampering viral antigenicity. Thus, a close monitoring of SARS-CoV-2 mutational patterns is crucial to ensure the effectiveness of treatments and vaccines worldwide.
(© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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