Matrix metalloproteinases, pathological

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

The metalloproteases (MPs) and matrix metalloproteinases (MMPs) are a class of metallohydrolases of particular interest to the pharmaceutical industry due to their role in a number of pathological processes [81-83], The lack of an enzyme-bound nucleophilic residue in the metallohydrolases complicates the design of ABPP probes for this class of enzymes. Rather than mechanism-based and electrophilic probes for ABPP, photoreactive variants of reversible inhibitors of metallohydrolases have been developed [84-86]. These reversible inhibitors usually contain a hydroxamate moiety that is capable of chelating the catalytic zinc ion in a bidentate manner [79, 80]. The hydroxamate moiety was incorporated into the first generation of metallohydrolase ABPP probes along with a benzophenone group capable of covalent bond formation upon UV irradiation (Scheme 4). 

The matrix metalloproteinases (MMPs) are a large family of endopeptidases, responsible for degradation of a variety of extracellular matrix components in both normal tissue remodeling and pathological states [47]. The active site is a cavity spanning the entire enzyme, with three subsites on each side of the scissile bond (S3-S3, see Fig. 3.14). Most of the known MMP inhibitors so far exert their function by coordinating to residues in the primed side [48], only little effort has been put into exploring the unprimed sites [49, 50]. 

Periodontal disease is caused by microorganisms, but host responses are in large part responsible for destruction of the periodontal support structures. In these patients, pathological activity of host-derived matrix metalloproteinases occurs in response to the bacterial infection in the... 

Fini M E, Parks W C, Rinehart W B et al 1996. Role of matrix metalloproteinases In failure to re-epitheliallze after corneal injury. American Journal of Pathology 149 1287-1302... 

Bl. Baker, E. A., and Leaper, D. J., The plasminogen activator and matrix metalloproteinase systems in colorectal cancer Relationship to tumour pathology. Eur. J. Cancer 39, 981-988 (2003). 

Metalloproteinases especially matrix metalloproteinases are a group of endopeptidases that contribute for the extracellular matrix degradation, and several tissue remodeling processes. Improper regulation of these endopeptidases could lead to several severe pathological problems that include cardiac, cartilage, and cancer-related diseases. Until now, many synthetic matrix metalloproteinase inhibitory substances (MMPIs) have been reported however, many of them could not make to the final clinical trials. 

Horwitz, V, Dachir, S., Cohen, M., et al., 2014. The beneficial effects of doxycycline, an inhibitor of matrix metalloproteinases, on sulfur mustard-induced ocular pathologies depend on the injury stage. Curr Eye Res. 

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