Linked Life Data

16984172

Source:http://linkedlifedata.com/resource/pubmed/id/16984172

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
38
pubmed:dateCreated
2006-9-20
pubmed:abstractText
Cysteine proteases are crucial regulatory enzymes in human physiology and disease. Inhibitors are usually designed with reactive electrophiles to covalently bond to the catalytic cysteinyl sulfur, and consequently they also indiscriminately interact with biological thiolates and other nucleophiles, leading to toxic side effects in vivo. Here we describe an alternative to using reactive electrophiles, demonstrating the use of a much less reactive azidomethylene substituent (-CH2-N3) that confers potent inhibition of cysteine proteases. This new approach resulted in potent, reversible, competitive inhibitors of caspase-1 (IC50 < 10 nM), with significant advantages over aldehydes such as high stability in vitro to thiols (10 mM dithiothreitol (pH 7.2), 20 mM glutathione (pH 7.2, 9, 11)) and aqueous media, as well as some highly desirable druglike features. It was also demonstrated that azides can be incorporated into inhibitors of other caspases (e.g. 3, 8) and cathepsins (e.g. K, S, B), indicating the versatility of this valuable new approach to cysteine protease inhibition.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0002-7863
pubmed:author
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
128
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
12396-7
pubmed:dateRevised
2008-1-17
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Organic azide inhibitors of cysteine proteases.
pubmed:affiliation
Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't