Objective: Cathepsin G (CatG) is a cationic serine protease with wide substrate specificity. CatG is reported to play a role in several inflammatory pathologies. Thus, we aimed at identifying a potent and allosteric inhibitor of CatG to be used as a platform in further drug development opportunities.
Methods: Chromogenic substrate hydrolysis assays were used to evaluate the inhibition potency and selectivity of SPGG towards CatG. Salt-dependent studies, Michaelis-Menten kinetics and SDS-PAGE were exploited to decipher the mechanism of CatG inhibition by SPGG. Molecular modelling was also used to identify a plausible binding site.
Key Findings: SPGG displayed an inhibition potency of 57 nM against CatG, which was substantially selective over other proteases. SPGG protected fibronectin and laminin against CatG-mediated degradation. SPGG reduced V of CatG hydrolysis of a chromogenic substrate without affecting K, suggesting an allosteric mechanism. Resolution of energy contributions indicated that non-ionic interactions contribute ~91% of binding energy, suggesting a substantial possibility of specific recognition. Molecular modelling indicated that SPGG plausibly binds to an anion-binding sequence of SRRVRRNRN.
Conclusion: We present the discovery of SPGG as the first small molecule, potent, allosteric glycosaminoglycan mimetic inhibitor of CatG. SPGG is expected to open a major route to clinically relevant allosteric CatG anti-inflammatory agents.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942669 | PMC |
| http://dx.doi.org/10.1093/rpsppr/rqad001 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Sulfonated Penta-Galloyl Glucose (SPGG): The Pharmacological Effects of Promiscuous Glycosaminoglycan Small Molecule Mimetic.
Mini Rev Med Chem
November 2024
Division of Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana 70125, USA.
Sulfated glycosaminoglycans (SGAGs), such as heparin, are complex linear polysaccharides attached to core proteins via covalent bonds to form proteoglycans. SGAGs are crucial in assembling extracellular matrix, the regulation of cell signaling and cell behavior, hemostasis, development, and various diseases, including thrombosis, cancer, infectious diseases, and neurodegenerative disorders, through their binding with diverse proteins. Despite the abundant SGAG-protein interactions provided by nature, the development of small SGAG-like molecules remains underexplored.
View Article and Find Full Text PDFInfluenza vaccination in older adults and patients with chronic disorders: A position paper from the Portuguese Society of Pulmonology, the Portuguese Society of Cardiology, the Portuguese Society of Diabetology, the Portuguese Society of Infectious Diseases and Clinical Microbiology, the Portuguese Society of Geriatrics and Gerontology, and the Study Group of Geriatrics of the Portuguese Society of Internal Medicine.
Pulmonology
September 2024
Portuguese Society of Pulmonology (SPP), Portugal; Pulmonology Department, Hospital de São João, Centro Hospitalar Universitário São João, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal; i3S - Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal. Electronic address:
Influenza affects millions of people worldwide each year and can lead to severe complications, hospitalizations, and even death, especially among vulnerable populations such as older adults and those with chronic medical conditions. Annual vaccination is considered the most effective measure for preventing influenza and its complications. Despite the widespread availability of influenza vaccines, however, vaccination coverage rates remain suboptimal in several countries.
View Article and Find Full Text PDFThe Straw Pressure Gradient and Gravity (SPGG) Technique: A Safe and Cost-Effective Technique for Laparoscopic Suction.
Cureus
April 2023
Department of General and Emergency Surgery, Kingston Hospital NHS Foundation Trust, London, GBR.
Suction devices are frequently used during laparoscopic surgery. However, their cost and limitations can be significant, depending on the clinical case, theatre setting and national health system. Furthermore, the continuous need to reduce the costs of the consumables in minimally invasive surgical procedures and their environmental burden creates extra pressure on the healthcare systems globally.
View Article and Find Full Text PDFSulphated penta-galloyl glucopyranoside (SPGG) is glycosaminoglycan mimetic allosteric inhibitor of cathepsin G.
RPS Pharm Pharmacol Rep
January 2023
Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, USA.
Objective: Cathepsin G (CatG) is a cationic serine protease with wide substrate specificity. CatG is reported to play a role in several inflammatory pathologies. Thus, we aimed at identifying a potent and allosteric inhibitor of CatG to be used as a platform in further drug development opportunities.
View Article and Find Full Text PDFInhibition of Human Cytomegalovirus Entry into Host Cells Through a Pleiotropic Small Molecule.
Int J Mol Sci
February 2020
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!