Abstract
The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteases consists of 19 members. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis and atherosclerosis. Unlike other metalloproteinases, ADAMTS members demonstrate a narrow substrate specificity due to the various exosites located in the C-terminal regions of the enzymes, which influence protein recognition and matrix localization. The tight substrate specificity exhibited by ADAMTS enzymes makes them potentially safe pharmaceutical targets, as selective inhibitors designed for each member will result in the inhibition or cleavage of only a limited number of proteins. With the recent elucidation of crystal structures for ADAMTS-1, -4 and -5, the design of potent and selective small molecule inhibitors is underway and will lead to drug candidates for evaluation in clinical trials in the next 5-10 years.
Keywords: ADAMTS, metalloproteinase, aggrecanase
Current Pharmaceutical Design
Title: A Review of the ADAMTS Family, Pharmaceutical Targets of the Future
Volume: 15 Issue: 20
Author(s): Micky D. Tortorella, Fransiska Malfait, Ruteja A Barve, Huey-Sheng Shieh and Anne-Marie Malfait
Affiliation:
Keywords: ADAMTS, metalloproteinase, aggrecanase
Abstract: The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteases consists of 19 members. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis and atherosclerosis. Unlike other metalloproteinases, ADAMTS members demonstrate a narrow substrate specificity due to the various exosites located in the C-terminal regions of the enzymes, which influence protein recognition and matrix localization. The tight substrate specificity exhibited by ADAMTS enzymes makes them potentially safe pharmaceutical targets, as selective inhibitors designed for each member will result in the inhibition or cleavage of only a limited number of proteins. With the recent elucidation of crystal structures for ADAMTS-1, -4 and -5, the design of potent and selective small molecule inhibitors is underway and will lead to drug candidates for evaluation in clinical trials in the next 5-10 years.
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Tortorella D. Micky, Malfait Fransiska, Barve A Ruteja, Shieh Huey-Sheng and Malfait Anne-Marie, A Review of the ADAMTS Family, Pharmaceutical Targets of the Future, Current Pharmaceutical Design 2009; 15 (20) . https://dx.doi.org/10.2174/138161209788682433
DOI https://dx.doi.org/10.2174/138161209788682433 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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