Home
Deutsch
Advanced Search
Browse by ...
Publication overview
Contact persons
Help
Postprint
DOI
PMC
 |
Open Access Green |
as soon as is submitted to ZB.
Exploiting the S4-S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis.
J. Med. Chem. 61, 1858-1870 (2018)
The neutrophilic serine protease proteinase 3 (PR3) is involved in inflammation and immune response and thus appears as a therapeutic target for a variety of infectious and inflammatory diseases. Here we combined kinetic and molecular docking studies to increase the potency of peptidyl-diphenyl phosphonate PR3 inhibitors. Occupancy of the S1 subsite of PR3 by a nVal residue and of the S4-S5 subsites by a biotinylated Val residue as obtained in biotin-VYDnV(O-CH-4-Cl) enhanced the second-order inhibition constant k/[I] toward PR3 by more than 10 times ( k/[I] = 73000 ± 5000 M s) as compared to the best phosphonate PR3 inhibitor previously reported. This inhibitor shows no significant inhibitory activity toward human neutrophil elastase and resists proteolytic degradation in sputa from cystic fibrosis patients. It also inhibits macaque PR3 but not the PR3 from rodents and can thus be used for in vivo assays in a primate model of inflammation.
Altmetric
Additional Metrics?
Edit extra informations
Login
Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Serine Proteases; Irreversible Inhibition; Human-diseases; Cathepsin-g; Substrate-specificity; Crystal-structure; Diphenyl Esters; Human-leukocyte; Ligand Docking; Elastase
ISSN (print) / ISBN
0022-2623
e-ISSN
1520-4804
Journal
Journal of Medicinal Chemistry
Quellenangaben
Volume: 61,
Issue: 5,
Pages: 1858-1870
Publisher
American Chemical Society (ACS)
Publishing Place
Washington
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Lung Health and Immunity (LHI)