Normal connective tissue remodeling requires a family of enzymes called matrix metalloproteinases (MMPs) such as collagenases, gelatinases, and stromelysins. Excess activity of these proteinases often leads to pathological conditions such as arthritis, neural degenerative diseases, and periodontal diseases by uncontrolled degradation of extracellular matrix components. One of the therapeutical approaches is to develop inhibitors for these enzymes to restore the control on the enzymatic activities. MMPs are homologous enzymes with defined domain structures. We expressed the catalytic domains of human MMPs in E. coil and used these recombinant catalytic domains in MMP inhibitor discovery. We obtained initial inhibitors through random mass screening and demonstrated that inhibitors for the catalytic domains also inhibit corresponding full length MMPs. By combined use of chemical compound library screening, enzyme/inhibitor complex structural analysis, and inhibitor structural modification, we have obtained novel and non-peptidic MMP inhibitors with promising activities in animal diseases models.
|Original language||English (US)|
|State||Published - Dec 1 1997|
ASJC Scopus subject areas
- Molecular Biology