Metalloproteinases, inhibition

GOTO T, MAEDA H and TANAKA T (2002) A Selective inhibitor of matrix metalloproteinases inhibits the migration of isolated osteoclasts by increasing the life span of podosomes. J Bone Miner Metab. 20 (2) 98-105. 

Gasche, Y., Copin, J. C., Sugawara, T., Fujimura, M. and Chan, P. H. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. /. Cereb. Blood Plow Metab. 21 1393-1400,2001. 

I I De Smet BJG, De Kleijn D, Hanemaaijer R, et al. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty a study in the atherosclerotic yucatan micropig. Circulation 2000 101 2962-2967. 

Sierevogel MJ, Pasterkamp G, Velema E, et al. Oral matrix metalloproteinase inhibition and arterial remodeling after balloon dilation—an intravascular ultrasound study in the pig. Circulation 2001 103 302-307. 

Creemers EE, Cleutjens JP Smrts JE Daernen MJ. Matrix metalloproteinase inhibition after myocardial infarction a new approach to prevent heart failure Circ Res 2001 89(3) 201-210. 

Copin JC, Merlani P, Sugawara T, Chan PH, Gasche Y (2008) Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after emboUc stroke in tats. Exp Neurol 213 196-201... 

Lapchak PA, Chapman DF, Zivin JA (2000) Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 31 3034-3040... 

Pfefferkom T, Rosenberg GA (2003) Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 34 2025-2030... 

Woesner J F 1999 Matrix metalloproteinase inhibition. From the Jurassic to the third millennium. Annals of the New York Academy of Sciences 878 388-403... 

Demeule, M., Brossard, M., Page, M., Gingras, D., and Beliveau, R., Matrix metalloproteinase inhibition by green tea c techms, Biochimica Biophysica Acta, 1478, 51-60, 2000. 

Bedi, A., Kovacevic, D., Hettrich, C., Gulotta, L. V., Ehteshami, J. R., Warren, R. R, and Rodeo, S. A. 2010. The effect of matrix metalloproteinase inhibition on tendon-to-bone healing in a rotator cuff repair model./. Shoulder. Elbow. Surg. 19 384-391. 

Marimastat Metalloproteinase inhibitor, inhibits endothelial cell invasion... 

The enzymatic activity of these potentially harmful enzymes is tightly controlled. Once transcribed into protein, MMPs are expressed as inactive zymogens and require distinct activation processes to convert them into active enzymes. After secretion, MMP-activity is regulated by the noncovalent binding of tissue inhibitors of metalloproteinases ( TIMPs) as shown in Fig. 2 for MMP-2 and TIMP-2. Four TIMPs have been identified so far TIMP-1, TIMP-2, TIMP-3, and TIMP-4. All known MMPs can be inhibited by at least one of the four known TIMPs. Nevertheless, individual differences with regard to bond strength and thus the magnitude of inhibition of a particular MMP do exist. 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

Corbel M, Caulet-Maugendre S, Germain N, Molet S, Lagente V, Boichot E. Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat. J Pathol 2001 193(4) 538—545. 

Chapman KT, Kopka IE, Durette PI, Esser CK, Lanza TJ, Izquierdo-Martin M, Niedzwiecki L, Chang B, Harrison RK, Kuo DW, Lin T-Y, Stein RL, Hagmann WK. Inhibition of matrix metalloproteinases by N-Carboxyalkyl peptides. J Med Chem 1993 36 4293-4301. 

Huang, C.S., Fan, Y.E., Lin, C.Y., and Hu, M.L. 2007. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein. J Nutr Biochem 18 449 156. 

Pender, S.L., Fell,J.M., Chamow, S.M., Ashkenazi, A. and MacDonald, T.T. (1998) A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production. Journal of Immunology 160, 4098-4103. 

Extended biological investigations concerning structure-function studies were further initiated to evaluate the abilities of these clusters to inhibit Con A-induced membrane type-1-matrix metalloproteinase (MTl-MMP)-mediated pro-MMP-2 activation, cell death, and antiproliferative property in mesenchymal stromal cells (MSC).83... 

The protective antiprotease -antitrypsin (AAT) inhibits several protease enzymes, including neutrophil elastase. In the presence of unopposed AAT activity, elastase attacks elastin, which is a major component of alveolar walls. A hereditary deficiency of AAT results in an increased risk for premature development of emphysema. In the inherited disease, there is an absolute deficiency of AAT. In emphysema resulting from cigarettesmoking, the imbalance is associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several other proteases, including cathepsins and metalloproteinases. In addition, oxidative stress reduces antiprotease (or protective) activity. 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

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. 

A1. Alvarez, O. A., Carmichael, D. F., and DeClerck, Y. A., Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J. Natl. Cancer Inst. 82, 589-595 (1990). 

Dl. DeClerck, Y. A., Yean, T. D., Chan, D., Shimada, H., and Lansley, K. E., Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor. Cancer Res. 51, 2151-2157 (1991). 

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