The gelatinases and their inhibitors: the structure-activity relationships

The interest in gelatinases is increased because of their association in diverse human diseases, though the relationship between MMP expression and disease progression is very complex and varies in cell to cell. Targeting gelatinases in disease treatment is complicated by the fact that gelatinases are indispensable for normal development and physiology due to their multifunctionality, possible functional redundancy, context-dependent expression, and activity. They are secreted as inactive zymogens which are processed to become active by removal of N-terminal propeptide. The folded conformation of zymogen is required to keep the gelatinases in its latency. Acting on a broad spectrum of extracellular substrates, the gelatinases (both MMP-2 and MMP-9) are critical to the biological processes. Three-dimensional structures of gelatinase-inhibitor complexes and inhibition profiles of compounds screened on them provide an invaluable source to gain insight into the structural determinants as well as functional selectivity. The quest for selective MMP inhibitors (MMPIs) still remains a challenge in search of successful clinical candidates. An increased understanding of the structure, regulation, and function of the individual MMPs will likely lead to more effective strategies in the development of highly selective inhibitors for any given MMP that can then be exploited to achieve the desired drugs.