Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding

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Authors
Li, Yi
Dou, Dengfeng
He, Guijia
Lushington, Gerald H.
Groutas, William C.
Advisors
Issue Date
2009-05-15
Type
Article
Keywords
Research Support, N.I.H., Extramural
Research Projects
Organizational Units
Journal Issue
Citation
Bioorganic & medicinal chemistry. 2009 May 15; 17(10): 3536-42.
Abstract

A series of mechanism-based inhibitors designed to interact with the S' subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibitors of HNE and were devoid of any inhibitory activity toward PR 3. The results suggest that highly selective inhibitors of serine proteases whose primary substrate specificity and active sites are similar can be identified by exploiting differences in their S' subsites. The best inhibitor (compound 16) had a k(inact)/K(I) value of 4580 M(-1)s(-1).

Table of Contents
Description
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Publisher
Elsevier
Journal
Book Title
Series
Bioorganic & medicinal chemistry
Bioorg. Med. Chem.
PubMed ID
DOI
ISSN
1464-3391
0968-0896
EISSN