Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management DOI Creative Commons
Aganze Gloire-Aimé Mushebenge, Samuel Chima Ugbaja,

Nonjabulo Ntombikhona Magwaza

et al.

Future Pharmacology, Journal Year: 2024, Volume and Issue: 4(4), P. 825 - 852

Published: Nov. 28, 2024

The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and responsible for breaking down releasing vital functional viral proteins crucial virus development transmission. As catalytically active dimer, its dimerization interface has become an attractive target antiviral drug development. Recent research extensively investigated enzymatic activity of Mpro, focusing on role regulating replication complex significance maturation infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond substrate-binding region. Empirical validation through site-directed alanine mutagenesis targeted residues both regions corroborated these predictions. Structural studies can inform therapeutic approaches, with metadynamics simulations shedding light H163 Mpro function providing insights into dynamic equilibrium to wild-type enzyme. Despite efficacy vaccines drugs mitigating SARS-CoV-2 spread, ongoing evolution, selective pressures, continued transmission pose challenges, potentially leading resistant mutations. Phylogenetic analyses indicated existence several variations predating introduction human population, emphasizing likelihood spread. Hydrogen/deuterium-exchange mass spectrometry reveals structural influence mutation. At same time, clinical trials 3CLPro inhibitors underscore reduced offer avenues future exploration. Understanding implications mutations holds promise shaping forthcoming strategies against COVID-19. This review delves factors influencing mutation rates identifies areas warranting further investigation, comprehensive overview mutations, categorization, terminology. Moreover, we examine their associations outcomes, illness severity, unresolved issues, prospects, including impact vaccine targeting.

Language: Английский

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review DOI Creative Commons
Bailey Lubinski, Gary R. Whittaker

Viruses, Journal Year: 2024, Volume and Issue: 16(6), P. 984 - 984

Published: June 19, 2024

Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility infection. Here we review the of proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe various classes present tract, as well elsewhere body, and incorporate targeting these therapeutic drugs for humans. Host are also systemic spread viruses play important roles outside tract; therefore, address how affect across spectrum infections that occur humans, intending understand extrapulmonary

Language: Английский

Citations

2
Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review DOI Open Access
Bailey Lubinski, Gary R. Whittaker

Published: May 15, 2024

Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility infection. Here we review the of proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe various classes present tract, as well elsewhere body, and incorporate targeting these therapeutic drugs for humans. Host are also systemic spread viruses play important roles outside tract; therefore, address how affect across spectrum infections that occur humans, intending understand extrapulmonary

Language: Английский

Citations

1
Antiviral mechanisms of guanylate-binding protein 5: versatile inhibition of multiple viral glycoproteins DOI Creative Commons
Daniel Sauter, Frank Kirchhoff

mBio, Journal Year: 2024, Volume and Issue: 15(11)

Published: Oct. 15, 2024

ABSTRACT Guanylate-binding proteins (GBPs) are interferon-inducible cellular factors known to inhibit a wide variety of pathogens. Humans encode seven GBPs that have functionally diversified provide broad protection against bacteria, protozoa, and viruses. Here, we discuss recent data on the mechanisms underlying antiviral activity GBP5 (H. Veler, C. M. Lun, A. Waheed, E. O. Freed, mBio e02086-24, 2024, https://doi.org/10.1128/mbio.02086-24 ) place them in context previous studies ability this factor impair function numerous viral envelope (Env) glycoproteins. We focus effects glycosylation, proteolytic processing, anterograde transport Env mechanistic interdependencies these maturation steps. Understanding induction action broadly acting immune factors, such as GBP5, may help develop effective immune-based strategies

Language: Английский

Citations

1
The Proteolytic Activity of Neutrophil-Derived Serine Proteases Bound to the Cell Surface Arming Lung Epithelial Cells for Viral Defense DOI Creative Commons

Akmaral Assylbekova,

Maiya Allayarova,

Moldir Konysbekova

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(18), P. 4449 - 4449

Published: Sept. 19, 2024

The collaboration between cellular proteases and host cells is pivotal in mounting an effective innate immune defense. Of particular interest the synergistic interaction cathepsin G (CatG) neutrophil elastase (NE), which are secreted by activated neutrophils, human alveolar basal epithelial cell line (A549) lung epithelial-like (H1299), because of potential implications for viral infection. Our study aimed to investigate binding capacity CatG NE on surface A549 H1299 through preincubation with purified NE; thereby, proteolytic activity could be detected using activity-based probes. Both were capable exhibited activity, leading increased levels MHC I molecules, crucial displaying endogenous antigenic repertoire. In addition, cleaved S2′ site SARS-CoV-2 spike protein at two specific sites (815RS816 817FI818) as well (813SK814 818IE819), potentially leads destruction fusion peptide. Additionally, furin required presence Ca2+ ions distinct cleavage necessary generate Overall, findings suggest that can fortify target against entry, underscoring significance protecting invasion.

Language: Английский

Citations

0
Global Antiviral Peptide Research: A Bibliometric Analysis from 1951 to 2022 DOI Creative Commons
Wahyu Aristyaning Putri, Jajar Setiawan, Fajar Sofyantoro

et al.

Universitas Scientiarum, Journal Year: 2024, Volume and Issue: 29(3), P. 229 - 251

Published: Oct. 10, 2024

Antiviral peptides (AVPs) are small molecules that inhibit the replication of viruses in living cells. AVPs being investigated as potential alternatives to traditional antiviral drugs. The development novel agents is highest concern because some medications can be ineffective and lead resistant emergence. We conducted a bibliometric study on global distribution AVP research comprehend trends patterns field. For this analysis, we retrieved data from Scopus database AVP-related publications 1951 2022, including number publications, citations, authors. Overall, 10,279 papers were published, with an annual average 146 publications. United States released most documents, followed by China, Germany, Kingdom. Since 2001, there has been substantial increase AVPs, prominent themes virology, genetics, protease inhibitors, polypeptide antimicrobial agents, viral entry. This analysis used guide future

Language: Английский

Citations

0
Mechanistic Insights into the Mutational Landscape of the Main Protease/3CLPro and Its Impact on Long-Term COVID-19/SARS-CoV-2 Management DOI Creative Commons
Aganze Gloire-Aimé Mushebenge, Samuel Chima Ugbaja,

Nonjabulo Ntombikhona Magwaza

et al.

Future Pharmacology, Journal Year: 2024, Volume and Issue: 4(4), P. 825 - 852

Published: Nov. 28, 2024

The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and responsible for breaking down releasing vital functional viral proteins crucial virus development transmission. As catalytically active dimer, its dimerization interface has become an attractive target antiviral drug development. Recent research extensively investigated enzymatic activity of Mpro, focusing on role regulating replication complex significance maturation infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond substrate-binding region. Empirical validation through site-directed alanine mutagenesis targeted residues both regions corroborated these predictions. Structural studies can inform therapeutic approaches, with metadynamics simulations shedding light H163 Mpro function providing insights into dynamic equilibrium to wild-type enzyme. Despite efficacy vaccines drugs mitigating SARS-CoV-2 spread, ongoing evolution, selective pressures, continued transmission pose challenges, potentially leading resistant mutations. Phylogenetic analyses indicated existence several variations predating introduction human population, emphasizing likelihood spread. Hydrogen/deuterium-exchange mass spectrometry reveals structural influence mutation. At same time, clinical trials 3CLPro inhibitors underscore reduced offer avenues future exploration. Understanding implications mutations holds promise shaping forthcoming strategies against COVID-19. This review delves factors influencing mutation rates identifies areas warranting further investigation, comprehensive overview mutations, categorization, terminology. Moreover, we examine their associations outcomes, illness severity, unresolved issues, prospects, including impact vaccine targeting.

Language: Английский

Citations

0