Metalloproteases matrix

One intensively investigated feature of the inflammatory process in COPD is the release of proteases from neutrophils and monocytic cells that destroy elastin and other components of the interstitial matrix (Table 1). The best studied protease is neutrophil elastase. Independent of its elastolytic activity, neutrophil elastase is a potent secretagogue. More recently matrix metalloproteases (MMP) have received increasing attention, in particular MMP 12 (macrophages elastase). To which extent and how exactly these proteases become activated is not clear at present. 

ROS, reactive oxygen species AHR, airway hyperresponsiveness MMP, matrix metalloprotease. Correlates with cough and chronic bronchitis. bNumber increases with disease severity. 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

Kanbe K, Takagishi K, Chen Q. Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4. Arthritis Rheum 2002 46(1) 130-137. 

The matrix metalloprotease (MMP) family of zinc hydrolases are thought to play important roles in extracellular tissue remodeling in angiogenesis and other normal physiological processes, in some inflammatory processes and in metastatic processes in cancer. Like the zinc carboxypeptidases, the MMPs also utilize a zinc-coordinated water molecule to initiate attack on the scissile amide bond of protein substrates. These enzymes are synthesized by the ribosome in a latent form composed of a catalytic domain and an N-terminal extension, referred to as the prodomain the latent, or inactive form of the enzyme is referred to as a zymogen or... 

T cell activation in the lamina propria is associated with epithelial cell shedding, leading to loss of villi. It has been postulated that this is mediated by increased production of matrix metalloproteases (MMP), which, by degrading the lamina propria matrix, represent a major pathway by which T cells cause injury in the gut (Pender et al., 1997). Production of MMPs also facilitates movement of cells out of the vasculature into sites of inflammation and contributes substantially to the degradation of connective tissue during inflammatory disease (Stetler-Stevenson, 1996). Furthermore, MMPs are required for the release of soluble TNF-a from its membrane... 

M. F. Browner, Matrix Metalloproteases Structure-Based Drug Discovery Targets , Perspect. Drug Discov. Design 1995, 2, 343-351. 

The hbraries of enzyme substrates were obtained by spht-pool synthesis to yield one-bead-one-compound hbraries. The substrate assay was performed with a range of proteolytic enzymes such as subtilisin Carlsberg [26], cruzipain [27], protein disulfide isomerase [28-29], matrix metalloprotease MM P-9 [30], papain [31],... 

Heath EI, Grochow LB. Qinical potential of matrix metalloprotease inhibitors in cancer therapy. Drugs 2000 59 1043-55. 

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

Yang Z, Ma M, Xu B (2009) Using matrix metalloprotease-9 (MMP-9) to trigger supramolecular hydrogelation. Soft Matter 5 2546-2548... 

Lynas, J. F., Martin, S. L., Walker, B., Baxter, A. D., Bird, J., Bhogal, R., Montana, J. G., Owen, D. A. (2000) Solid-phase synthesis and biological screening of N-a-mercaptoamide template-based matrix metalloprotease inhibitors. Comb Chem High Throughput Screening 3, 37—41. 

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