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.
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Conference Article|
February 01 2004
Matrix metalloprotease inhibitors: design from structure
N. Borkakoti
N. Borkakoti
1
Chemical Technologies, Roche Products Ltd, Broadwater Road, Welwyn Garden City, Herts. AL7 3AY, U.K.
1Present address: Biology and Molecular Sciences, Medivir UK Ltd, Peterhouse Technology Park, 100 Fulbourn Road, Cambridge CB1 9PT, U.K. (e-mail Neera.Borkakoti@medivir.com).
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 Biochemical Society
2004
Biochem Soc Trans (2004) 32 (1): 17–20.
Citation
N. Borkakoti; Matrix metalloprotease inhibitors: design from structure. Biochem Soc Trans 1 February 2004; 32 (1): 17–20. doi: https://doi.org/10.1042/bst0320017
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