Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management
The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and is responsible for breaking down and releasing vital functional viral proteins crucial for virus development and transmission. As a catalytically active dimer...
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2024-11-01
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| author | Aganze Gloire-Aimé Mushebenge Samuel Chima Ugbaja Nonjabulo Ntombikhona Magwaza Nonkululeko Avril Mbatha Tambwe Willy Muzumbukilwa Mukanda Gedeon Kadima Fave Yohanna Tata Mthokosizi Bongani Nxumalo Riziki Ghislain Manimani Ntabaza Ndage Bakari Salvius Amuri Kahumba Byanga Manimbulu Nlooto Rene B. Khan Hezekiel M. Kumalo |
| author_facet | Aganze Gloire-Aimé Mushebenge Samuel Chima Ugbaja Nonjabulo Ntombikhona Magwaza Nonkululeko Avril Mbatha Tambwe Willy Muzumbukilwa Mukanda Gedeon Kadima Fave Yohanna Tata Mthokosizi Bongani Nxumalo Riziki Ghislain Manimani Ntabaza Ndage Bakari Salvius Amuri Kahumba Byanga Manimbulu Nlooto Rene B. Khan Hezekiel M. Kumalo |
| author_sort | Aganze Gloire-Aimé Mushebenge |
| collection | DOAJ |
| description | The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and is responsible for breaking down and releasing vital functional viral proteins crucial for virus development and transmission. As a catalytically active dimer, its dimerization interface has become an attractive target for antiviral drug development. Recent research has extensively investigated the enzymatic activity of Mpro, focusing on its role in regulating the coronavirus replication complex and its significance in virus maturation and infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond the substrate-binding region. Empirical validation through site-directed alanine mutagenesis has targeted residues in both the active and allosteric regions and corroborated these predictions. Structural studies of drug target proteins can inform therapeutic approaches, with metadynamics simulations shedding light on the role of H163 in regulating Mpro function and providing insights into its dynamic equilibrium to the wild-type enzyme. Despite the efficacy of vaccines and drugs in mitigating SARS-CoV-2 spread, its ongoing viral evolution, selective pressures, and continued transmission pose challenges, potentially leading to resistant mutations. Phylogenetic analyses have indicated the existence of several resistant variations predating drug introduction to the human population, emphasizing the likelihood of drug spread. Hydrogen/deuterium-exchange mass spectrometry reveals the structural influence of the mutation. At the same time, clinical trials on 3CLPro inhibitors underscore the clinical significance of reduced enzymatic activity and offer avenues for future therapeutic exploration. Understanding the implications of 3CLPro mutations holds promise for shaping forthcoming therapeutic strategies against COVID-19. This review delves into factors influencing mutation rates and identifies areas warranting further investigation, providing a comprehensive overview of Mpro mutations, categorization, and terminology. Moreover, we examine their associations with clinical outcomes, illness severity, unresolved issues, and future research prospects, including their impact on vaccine efficacy and potential therapeutic targeting. |
| format | Article |
| id | doaj-art-603aa73517c74f55bb82d8278e6afcea |
| institution | DOAJ |
| issn | 2673-9879 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-603aa73517c74f55bb82d8278e6afcea2025-08-20T02:53:19ZengMDPI AGFuture Pharmacology2673-98792024-11-014482585210.3390/futurepharmacol4040044Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 ManagementAganze Gloire-Aimé Mushebenge0Samuel Chima Ugbaja1Nonjabulo Ntombikhona Magwaza2Nonkululeko Avril Mbatha3Tambwe Willy Muzumbukilwa4Mukanda Gedeon Kadima5Fave Yohanna Tata6Mthokosizi Bongani Nxumalo7Riziki Ghislain Manimani8Ntabaza Ndage9Bakari Salvius Amuri10Kahumba Byanga11Manimbulu Nlooto12Rene B. Khan13Hezekiel M. Kumalo14Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaAfrica Health Research Institute, Durban 4000, South AfricaDiscipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaDiscipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDepartment of Internal Medicine, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaFaculty of Pharmaceutical Sciences, University of Lubumbashi, Lubumbashi 1825, Democratic Republic of the CongoFaculty of Pharmaceutical Sciences, University of Lubumbashi, Lubumbashi 1825, Democratic Republic of the CongoFaculty of Pharmaceutical Sciences, University of Lubumbashi, Lubumbashi 1825, Democratic Republic of the CongoDiscipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaThe main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and is responsible for breaking down and releasing vital functional viral proteins crucial for virus development and transmission. As a catalytically active dimer, its dimerization interface has become an attractive target for antiviral drug development. Recent research has extensively investigated the enzymatic activity of Mpro, focusing on its role in regulating the coronavirus replication complex and its significance in virus maturation and infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond the substrate-binding region. Empirical validation through site-directed alanine mutagenesis has targeted residues in both the active and allosteric regions and corroborated these predictions. Structural studies of drug target proteins can inform therapeutic approaches, with metadynamics simulations shedding light on the role of H163 in regulating Mpro function and providing insights into its dynamic equilibrium to the wild-type enzyme. Despite the efficacy of vaccines and drugs in mitigating SARS-CoV-2 spread, its ongoing viral evolution, selective pressures, and continued transmission pose challenges, potentially leading to resistant mutations. Phylogenetic analyses have indicated the existence of several resistant variations predating drug introduction to the human population, emphasizing the likelihood of drug spread. Hydrogen/deuterium-exchange mass spectrometry reveals the structural influence of the mutation. At the same time, clinical trials on 3CLPro inhibitors underscore the clinical significance of reduced enzymatic activity and offer avenues for future therapeutic exploration. Understanding the implications of 3CLPro mutations holds promise for shaping forthcoming therapeutic strategies against COVID-19. This review delves into factors influencing mutation rates and identifies areas warranting further investigation, providing a comprehensive overview of Mpro mutations, categorization, and terminology. Moreover, we examine their associations with clinical outcomes, illness severity, unresolved issues, and future research prospects, including their impact on vaccine efficacy and potential therapeutic targeting.https://www.mdpi.com/2673-9879/4/4/44SARS-CoV-2main protease/3CLPromutationsvaccine efficacyenzymatic activitytherapeutic targeting |
| spellingShingle | Aganze Gloire-Aimé Mushebenge Samuel Chima Ugbaja Nonjabulo Ntombikhona Magwaza Nonkululeko Avril Mbatha Tambwe Willy Muzumbukilwa Mukanda Gedeon Kadima Fave Yohanna Tata Mthokosizi Bongani Nxumalo Riziki Ghislain Manimani Ntabaza Ndage Bakari Salvius Amuri Kahumba Byanga Manimbulu Nlooto Rene B. Khan Hezekiel M. Kumalo Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management Future Pharmacology SARS-CoV-2 main protease/3CLPro mutations vaccine efficacy enzymatic activity therapeutic targeting |
| title | Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management |
| title_full | Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management |
| title_fullStr | Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management |
| title_full_unstemmed | Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management |
| title_short | Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management |
| title_sort | mechanistic insights into the mutational landscape of the main protease 3clpro and its impact on long term covid 19 sars cov 2 management |
| topic | SARS-CoV-2 main protease/3CLPro mutations vaccine efficacy enzymatic activity therapeutic targeting |
| url | https://www.mdpi.com/2673-9879/4/4/44 |
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