A review of the ADAMTS family, pharmaceutical targets of the future.
The 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.
Tortorella
Micky D
MD
Pfizer Global Research and Development, St. Louis, MO 63017, USA. micky.d.tortorella@gmail.com
Malfait
Fransiska
F
Barve
Ruteja A
RA
Shieh
Huey-Sheng
HS
Malfait
Anne-Marie
AM
D051722:ADAM Proteins / Q000737:chemistry / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D000595:Amino Acid Sequence; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D051722:ADAM Proteins