Metalloproteinases MMP

Activation of matrix metalloproteinases (MMP) is also involved in vascular and cardiac remodelling. For example, the fibrillar collagen matrix of the heart... 

Fig. 20 Modular resilin-like polypeptide containing domains conferring elastomeric properties, heparin molecule interaction, cell adhesion, and matrix metalloproteinase (MMP) proteolysis. Lysine residues are encoded periodically to permit crosslinking...

Gelman BB, Wolf DA, Rodriguez-Wolf M et al (1997) Mononuclear phagocyte hydrolytic enzyme activity associated with cerebral HIV-1 infection. Am J Pathol 151 1437-1446 Giraudon P, Buart S, Bernard A et al (1997) Cytokines secreted by gUal cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs) possible involvement in neurodegenerative processes. Mol Psychiatry 2(107-10) 84... 

Expression of matrix metalloproteinases (MMPs) and their inhibitors is an important function of the RPE, particularly with respect to the maintenance of appropriate permeability of the Bruch s membrane (Ahir et al., 2002). This function can be tested in vitro (Marin-Castano et al., 2006). For example, it has been shown that the expression of MMP-2, TIPM-2s (tissue inhibitor of MMP-2), and type IV collagen by cultured ARPE-19 cells is affected by repetitive exposures to nonlethal oxidant injury with hydroquinone (Marin-Castano et al., 2006). Oxidative stress decreases MMP-2 activity and increases collagen type IV accumulation. 

Arylmethyl-9-hydroxypyrazino[l,2-f]pyrimidine-l,8-dione derivatives have been claimed as anti-HIV agents <2005W02005/016927, 2005W02005/087766> 6,8-dioxo-pyrazino[l,2-f]pyrimidine-3-carboxamides 164 (Y = NH) <2004W02004/014354> and their saturated analogues <2004USP2004/034009> have been claimed as matrix metalloproteinase MMP-13 enzyme inhibitors, useful in the treatment of rheumatoid arthritis. 

Lombard, C., Saulnier, J. and Wallach, J. (2005). Assays of matrix metalloproteinases (MMPs) activities a review. Biochimie 87, 265-272. 

FlG. 63. Man3GlcNAc2 anchored to PAMAM-based matrix metalloproteinase (MMP) inducer sequence (emmprin 34-58).384... 

Tumor tissues overexpress matrix metalloproteinases (MMPs). A liposomal pDNA carrier (MEND) was developed containing PEG conjugated to lipid via a peptide linker that is a target sequence for MMPs. In this strategy, PEG is removed from the carrier via MMP-triggered cleavage [198]. Intravenous administration in... 

In the normal healthy IVD, the cells not only produce matrix macromolecules and growth factors, they also produce a myriad of proteases [26, 27]. Included in this list of proteases are the matrix metalloproteinases (MMPs) and aggrecanolytic members of the disintegrin and metalloproteinase with thrombospondin motif family (ADAMTS) as well as their respective inhibitors. It is the maintenance of this critical balance that results in a healthy IVD ECM that is subsequently well adapted for its physiologic and biomechanical function. 

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. 

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