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2000
Volume 9, Issue 1
  • ISSN: 1389-2010
  • E-ISSN: 1873-4316

Abstract

Extensive research has gone into the area of metalloproteinases since the introduction of captopril as an inhibitor of angiotensin converting enzyme for the treatment of hypertension. Matrix metalloproteinases were favorite targets of pharmaceutical companies, with over 2,000 patents issued. Many of the MMPs are required for normal physiological processes such as bone growth, tissue remodeling, morphogenesis and regeneration. In some instances, however, production of active MMPs can lead to disease states that include cancer, arteriosclerosis, osteoarthritis, osteoporosis, chronic obstructive pulmonary disease, and multiple sclerosis. For cancer, MMP inhibition has been met mostly with failures, as the clinical candidates either caused unwanted side effects such as fibroplasias, or were ineffective. Knockout experiments done after the clinical failures, indicate that MMP activities can both promote and inhibit cancer and they have demonstrated that certain MMPs should not be targeted such as MT1-MMP; this MMP has an arthritis like phenotype in the knockout mice. The studies have paved the way for the future which is to develop selective inhibitors of MMPs for therapeutic use. MMP13, for example, is a target for osteoarthritis and/or osteoporosis. Selective inhibitors have been made and tested in preclinical trials. However, none have so far entered the clinic. This is principally due to the fact that MMP13 inhibitors are not selective enough and still cause tendonitis. MMP9 inhibition is also being considered for treating diseases such as multiple sclerosis and chronic obstructive pulmonary disorder. Knockout mice for MMP9 have been characterized, and used in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. The severity of disease was reduced in young MMP9 knockout mice, suggesting that targeting of MMP9 could be beneficial. Other metalloproteinases such as members of the disintegrin and metalloproteinase family (ADAM family) could make excellent pharmaceutical targets as they are associated with disease states such as cancer, arthritis, asthma, and obesity. Knockout experiments have also been done with ADAMs and the closely related ADAMs containing a thrombospondin motif (ADAM TSs). These studies have confirmed that targeting members of both families can be of therapeutic value. ADAM10 is currently being investigated as a target for cancer while ADAM TS 4 and 5 are aggrecanases and therefore make excellent targets for osteoarthritis. In addition since most of the transgenic animals have been made, it has become clear as to which metalloproteinases to investigate for intervention and which to avoid. Finally, other metalloproteinases that are of bacterial origin are also popular, as compounds can be made that are selective over mammalian metalloproteinases such as those described above. For example, pharmaceutical companies are working on making inhibitors of anthrax lethal factor as a bio-defense tool. Anthrax lethal factor is a metalloproteinase that causes lethality in organisms infected with Bacillus Anthracis. Other programs focus on making LPXC inhibitors as antibacterial agents as LPXC is an enzyme important for gram-negative bacterial membrane synthesis.Now that the human genome has been sequenced, we realize, that the number of metalloproteinases is small, and that with proper selectivity, drugs can be made from targeting a select few. This issue focuses on different metalloproteinases that possess properties that render them as useful targets for drug discovery.

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/content/journals/cpb/10.2174/138920108783497640
2008-02-01
2025-07-13
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  • Article Type:
    Research Article
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