Thiol proteases: inhibitors and potential therapeutic targets.
A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.
Leung-Toung
Regis
R
Medicinal Chemistry Department, Apotex Research Inc., 400 Ormont Drive, Toronto, Ontario M9L 1N9, Canada. rleung@apotex.ca.
Zhao
Yanqing
Y
Li
Wanren
W
Tam
Tim F
TF
Karimian
Khashayar
K
Spino
Michael
M
D017322:Clinical Trials, Phase II as Topic; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids; D003546:Cysteine Endopeptidases