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Inhibitors secretase inhibition

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. [Pg.265]

Although several reviews on secretase inhibition have been published [10-12], the rapid progress in the field demands continuous survey. And despite this significant progress potent non-peptidic inhibitors of /i-secretase are still unknown. Several peptide-based inhibitors were patented or reported immediately after J. Tang s disclosure of the BACE-inhibitor complex X-ray structure in 2000. Figures 3.5.1 and 3.5.2 show fragments of the homodimeric structures, which were reviewed recently [13]. Non-peptidic inhibitors of presenilin are known from patents... [Pg.265]

Proteasome inhibition by lactacystin and Bz-LLL-COCHO (benzol-Leu-Leu-Leu-glyoxal) causes a significant increase of ABP and cell death by altering APP processing at the y-secretase site (406). Resveratrol does not inhibit ABP production because it has no effect on 3-, or y-secretases, but promotes instead intracellular degradation of ABP via a mechanism that involves the proteasome. The resveratrol-induced decrease of ABP can be effectively prevented by several selective proteasome inhibitors and by small interfering RNA-directed silencing on the proteasome subunit P5 (407). [Pg.269]

Wong, G.T., Manfra, D., Poulet, F.M., et al. (2004) Chronic treatment with the y-secretase inhibitor LY-411,575 inhibits P-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem., 279, 12876-12882. [Pg.341]

Another mechanism of synaptic dysfunction in AD may involve amyloid ft peptide (Aft a 40 to 42 amino acid peptide). A marked increase in Aft levels occurs in brain tissue from AD patients. A ft inhibits glutamatergic neurotransmission and reduces synaptic plasticity (Snyder et al., 2005). Treatment of cortical neuronal cultures with Aft facilitates endocytosis of NMDA receptor. Aft-mediated endo-cytosis of NMDA receptor requires the a-1 nicotinic receptor, protein phosphatase 2B, and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyrl472 correlates with receptor endocytosis. The addition of a y-secretase inhibitor not only reduces Aft but also restores surface expression of NMDA receptors, suggesting that A plays an important role in the regulation of NMDA and AMPA receptor trafficking (Snyder et al., 2005 Morishita et al., 2005). [Pg.170]

Several peptidic aldehydes have been reported to be inhibitors for either y-secretase or yS-secretase or both. Common to both series are lipophilic di- and tripeptides with bulky N-terminal protection, e.g. Z-LLL-CHO (MG132), Z-YIL-CHO, and Boc-GW-CHO. The general lack of specificity of these aldehydes and their simultaneous inhibition of serine and cysteine proteases makes interpretation of data rather cumbersome. Indirect mechanisms through general protease inhibition result in complex concentration activity observations. Z-LLL-CHO (MG132), in fact, blocks maturation of the amyloid precursor protein. Some of these drawbacks were avoided by difluoro ketones as pioneered by Merryl Dow (Scheme 3.5.6), which... [Pg.270]

Pharmaceuticals currently in use to combat Alzheimer s disease are mainly acetylcholine esterase (ACE) inhibitors designed to slow down the removal of acetylcholine so that neurons keep active, however, they do not reverse plaque formation. The only other approach is to inhibit the activities of the secretases, in particular, to favour the formation of AP40 over AP42. [Pg.220]

Paris D, Quadros A, Patel N, DeUeDonne A, Humphrey J, MuUan M (2005) Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. Eur J Pharmacol 514 1-15... [Pg.820]

Designed peptides based on the transmembrane domain of APP and constrained in a helical conformation potently can inhibit y-secretase, apparently by interacting with this docking site (51). Conversion of these helical peptide inhibitors into affinity labeling reagents (Fig. 4) led to the localization of... [Pg.790]


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See also in sourсe #XX -- [ Pg.265 ]




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INHIBITION INHIBITOR

Secretases

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