Matrix metalloprotease inhibitors: design from structure

Abstract

The zinc- and calcium-dependent family of proteins called the MMPs (matrix metalloproteases) are collectively responsible for the degradation of the extracellular matrix. The enzymes are synthesized as zymogens, and under physiological conditions are selectively regulated by endogenous inhibitors. An imbalance between the active enzymes and their natural inhibitors leads to the accelerated destruction of connective tissue associated with the pathology of diseases such as arthritis, cancer, multiple sclerosis and cardiovascular diseases. The potential for using specific enzyme inhibitors as therapeutic agents to redress this balance has led to intensive research focused on the design, synthesis and molecular deciphering of low-molecular-mass inhibitors of this family of proteins. The design of early MMP inhibitors was based on the scissile site sequence of peptide substrates, with moieties customized to chelate the critical zinc ion at the enzymes' active site. These initial efforts were supported by X-ray and NMR data on MMP complexes, exploiting sequence and structural differences in the principal specificity pocket of the enzymes, leading to subtype-selective MMP inhibitors. This review will provide a critical appraisal of the design principles that have been utilized in generating molecules that inhibit MMPs, and explore issues relevant to obtaining clinical efficacy of MMP inhibitor-based therapies.

Expression of extracellular matrix proteins in ameloblastomas and adenomatoid odontogenic tumors

“…The highest expression of tenascin is observed in unstable environments such as during cell migration, in active areas of epithelialmesenchymal interactions, and in neoplastic stroma [14,16,18,24]. Type I collagen is found throughout the connective tissue and is one of the most abundant components of the interstitial ECM [5,23,25], being highly resistant to proteases due to its unique supercoiled triple helix structure [26][27][28].…”

Overexpression of Human Matrix Metalloproteinase-12 Enhances the Development of Inflammatory Arthritis in Transgenic Rabbits

“…In this aspect, several MMP inhibitors have been developed and it will be interesting to test the efficacy of these inhibitors. 35 In conclusion, the increased expression of MMP-12 in Tg rabbits dramatically exacerbated synovial hyperplasia, pannus formation, and the degeneration of articular cartilage in an experimentally induced inflammatory arthritis. These results provide evidence for a potential role of MMP-12 in the pathogenesis of RA and imply that the inhibition of MMP-12 may be potentially therapeutic for the treatment of inflammatory joint diseases.…”

Snapshots of the Reaction Mechanism of Matrix Metalloproteinases

“…[16] The interest in MMPs has grown again because of the need for inhibitors that are as specific as possible for each of the 23 human proteins. [17][18][19][20][21][22] We have now solved a series of X-ray crystal structures under a variety of conditions in an attempt to obtain models of the various steps of the reaction mechanism of MMPs. The protein tends to digest itself, so crystallization is always carried out in the presence of an inhibitor.…”