Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function DOI Open Access
Juan Fernando Padín, José Manuel Pérez‐Ortiz, Francisco Javier Redondo Calvo

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7553 - 7553

Published: July 10, 2024

Proteases are produced and released in the mucosal cells of respiratory tract have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism severe acute syndrome coronavirus type 2 (SARS-CoV-2), which causes disease 2019 (COVID-19), takes advantage host proteases two ways: change spatial conformation spike (S) protein via endoproteolysis (e.g., transmembrane serine protease (TMPRSS2)) as a target anchor epithelial angiotensin-converting enzyme (ACE2)). This process leads an imbalance mucosa between release action versus regulation by anti-proteases, contributes exacerbation inflammatory prothrombotic response COVID-19. In this article, we describe most that affected COVID-19, how their overactivation affects three main systems they participate: complement system kinin–kallikrein (KKS), both form part contact innate immunity, renin–angiotensin–aldosterone (RAAS). We aim elucidate pathophysiological bases COVID-19 context anti-proteases understand aprotinin (a panprotease inhibitor). second-part review, titled “Aprotinin (II): Inhalational Administration Treatment Other Viral Conditions”, explain depth pharmacodynamics, pharmacokinetics, toxicity, use antiviral drug.

Language: Английский

From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants DOI
Gabriel Lemieux, Jimena Pérez‐Vargas, Antoine Désilets

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

The worldwide spread of new SARS-CoV-2 variants emphasizes the need to diversify existing therapeutic strategies. TMPRSS2, a host protease crucial for entry, has garnered significant research attention as potential target intervention. Here, we optimized N-0385, previously reported TMPRSS2 ketobenzothiazole-based peptidomimetic inhibitor, by screening 135 derivatives affinity and antiviral potency. Among top candidates, N-0695 exhibited low nanomolar Ki values against three TTSPs associated with respiratory virus entry: matriptase, TMPRSS13. Notably, N-0920 demonstrated exceptional potency in reducing EG.5.1 JN.1 entry Calu-3 cells, representing first cellulo picomolar inhibitor EC50 300 90 pM, respectively. Additionally, molecular modeling provided insights into binding interactions between compounds their targets. This study underscores effectiveness our approach refining an scaffold enhance selectivity activity.

Language: Английский

Citations

0
Advancements in Serine Protease Inhibitors: From Mechanistic Insights to Clinical Applications DOI Open Access
Wei Yang,

Mingdong Huang,

Longguang Jiang

et al.

Catalysts, Journal Year: 2024, Volume and Issue: 14(11), P. 787 - 787

Published: Nov. 5, 2024

Serine proteases, a significant class of enzymes comprising approximately one-third known human are ubiquitously present across various organisms. These typically exhibit highly conserved catalytic domain structures, and their activity is stringently regulated within the body, playing pivotal role in numerous physiological processes. Dysregulation serine protease can result severe consequences, including excessive inflammation, heightened risk thrombosis cancer, even mortality. inhibitors have emerged as critical regulators, offering broad range functions such maintaining coagulation–fibrinolysis balance, modulating inflammatory responses, accelerating wound healing, promoting apoptosis, providing antitumor antiviral effects. As result, development has become increasingly vital. In recent years, progress study proteases led to clinical diagnosis treatment. This review explores fundamental mechanisms inhibitors, summarizes those that been successfully integrated into practice, discusses challenges encountered along with partial solutions. advancements lay groundwork for further refinement innovation inhibitor therapeutics.

Language: Английский

Citations

3
Liposome-encapsulated aprotinin biodistribution in mice: side-by-side comparison with free drug formulation DOI
Elizaveta N. Mochalova, Vladimir K. Cherkasov,

Artem A. Sizikov

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2024, Volume and Issue: 734, P. 150636 - 150636

Published: Aug. 31, 2024

Language: Английский

Citations

1
Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function DOI Open Access
Juan Fernando Padín, José Manuel Pérez‐Ortiz, Francisco Javier Redondo Calvo

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7553 - 7553

Published: July 10, 2024

Proteases are produced and released in the mucosal cells of respiratory tract have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism severe acute syndrome coronavirus type 2 (SARS-CoV-2), which causes disease 2019 (COVID-19), takes advantage host proteases two ways: change spatial conformation spike (S) protein via endoproteolysis (e.g., transmembrane serine protease (TMPRSS2)) as a target anchor epithelial angiotensin-converting enzyme (ACE2)). This process leads an imbalance mucosa between release action versus regulation by anti-proteases, contributes exacerbation inflammatory prothrombotic response COVID-19. In this article, we describe most that affected COVID-19, how their overactivation affects three main systems they participate: complement system kinin–kallikrein (KKS), both form part contact innate immunity, renin–angiotensin–aldosterone (RAAS). We aim elucidate pathophysiological bases COVID-19 context anti-proteases understand aprotinin (a panprotease inhibitor). second-part review, titled “Aprotinin (II): Inhalational Administration Treatment Other Viral Conditions”, explain depth pharmacodynamics, pharmacokinetics, toxicity, use antiviral drug.

Language: Английский

Citations

1