Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity
<b>Background</b>, <b>Aims</b>, <b>Methods</b>, <b>Results</b>, <b>Conclusions:</b> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/2/309 |
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| author | Harry Ridgway Charalampos Ntallis Christos T. Chasapis Konstantinos Kelaidonis Minos-Timotheos Matsoukas Panagiotis Plotas Vasso Apostolopoulos Graham Moore Sotirios Tsiodras Dimitrios Paraskevis Thomas Mavromoustakos John M. Matsoukas |
| author_facet | Harry Ridgway Charalampos Ntallis Christos T. Chasapis Konstantinos Kelaidonis Minos-Timotheos Matsoukas Panagiotis Plotas Vasso Apostolopoulos Graham Moore Sotirios Tsiodras Dimitrios Paraskevis Thomas Mavromoustakos John M. Matsoukas |
| author_sort | Harry Ridgway |
| collection | DOAJ |
| description | <b>Background</b>, <b>Aims</b>, <b>Methods</b>, <b>Results</b>, <b>Conclusions:</b> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CL<sup>pro</sup>) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants’ distribution data for SARS-CoV-2 across EU/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2′ (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19. |
| first_indexed | 2024-03-11T08:01:03Z |
| format | Article |
| id | doaj.art-bf4a94437923467e81a13e8f6ce5ed80 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T08:01:03Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-bf4a94437923467e81a13e8f6ce5ed802023-11-16T23:47:18ZengMDPI AGViruses1999-49152023-01-0115230910.3390/v15020309Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and InfectivityHarry Ridgway0Charalampos Ntallis1Christos T. Chasapis2Konstantinos Kelaidonis3Minos-Timotheos Matsoukas4Panagiotis Plotas5Vasso Apostolopoulos6Graham Moore7Sotirios Tsiodras8Dimitrios Paraskevis9Thomas Mavromoustakos10John M. Matsoukas11Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne 8001, VIC, AustraliaInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceNewDrug PC, Patras Science Park, 26504 Patras, GreeceDepartment of Biomedical Engineering, University of West Attica, Egaleo, 12210 Athens, GreeceLaboratory of Primary Health Care, School of Health Rehabilitation Sciences, University of Patras, 26504 Patras, GreeceInstitute for Health and Sport, Victoria University, Melbourne 3030, VIC, AustraliaPepmetics Inc., 772 Murphy Place, Victoria, BC V6Y 3H4, Canada4th Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Chemistry, National and Kapodistrian University of Athens, 11571 Athens, GreeceNewDrug PC, Patras Science Park, 26504 Patras, Greece<b>Background</b>, <b>Aims</b>, <b>Methods</b>, <b>Results</b>, <b>Conclusions:</b> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CL<sup>pro</sup>) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants’ distribution data for SARS-CoV-2 across EU/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2′ (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19.https://www.mdpi.com/1999-4915/15/2/309SARS-CoV-2COVID-19epidemiologymutationsACE2ARBs |
| spellingShingle | Harry Ridgway Charalampos Ntallis Christos T. Chasapis Konstantinos Kelaidonis Minos-Timotheos Matsoukas Panagiotis Plotas Vasso Apostolopoulos Graham Moore Sotirios Tsiodras Dimitrios Paraskevis Thomas Mavromoustakos John M. Matsoukas Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity Viruses SARS-CoV-2 COVID-19 epidemiology mutations ACE2 ARBs |
| title | Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity |
| title_full | Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity |
| title_fullStr | Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity |
| title_full_unstemmed | Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity |
| title_short | Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity |
| title_sort | molecular epidemiology of sars cov 2 the dominant role of arginine in mutations and infectivity |
| topic | SARS-CoV-2 COVID-19 epidemiology mutations ACE2 ARBs |
| url | https://www.mdpi.com/1999-4915/15/2/309 |
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