ACE2 Inhibitor, MLN-4760

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一般描述

MLN-4760 is a highly potent and selective cell-permeable inhibitor of angiotensin converting enzyme 2, which is its primary target. (ACE2; IC₅₀= 440 pM against soluble human ACE2).

生化/生理作用

MLN-4760 is bioavailable and exhibits far greater selectivity for carboxypeptidase (IC50 = 0.44 nM against 50 pM human ACE2; [ZnCl₂] = 10 μM, [MCA-APK(DNP)] = 50 μM) over bovine carboxypeptidase A or ACE peptidyldipeptidase activity (IC50 = 27 μM and >100 μM against 0.5 nM bovine CPDA and 1 nM porcine ACE, respectively; [Substrate] = 50 μM) and porcine ACE (IC50 = 27 and >100 μM, respectively). This reversible ACE2 inhibitor binds to the active site zinc with high-affinity and emulates the transition state during peptide hydrolysis. It reduces serum and kidney ACE 2 activity and abolishes angiotensin II-induced hypertension in mice. MLN-4760 selectively blocks angiotensin (ANG-(1-7)) formation in ACE2 wild type (WT) mice subjected to low ANG II concentrations (<0.1 μM), but at higher ANG II concentrations it does not affect ANG -(1-7) levels in mice. This ACE2 inhibitor enhances tumor necrosis factor (TNF) (10 pg/mL) stimulated expression of proinflammatory cytokines in murine endothelial cells, (1 μM using SVEC-40 line and primary aorta endothelial cultures)in vitro. MLN-4760 is widely employed for studying ACE2 involvement in kidney, cardiovascular and inflammatory bowel diseases via drinking water (10 mg/kg/d), i.v. (0.1 mg/kg), and s.c. (30 mg/kg/d to 300 mg/kg/12 h) injection in rats and mice,in vivo. The inhibitor leucine moiety is shown to simultaneously target ACE2 substrate S1 pocket with its isobutyl group and active site zinc via its carboxylate, while the compound′s 3,5-dichlorobenzyl group effectively occupy S1′ subsite.
MLN-4760 also enables to study the effect of reduced ACE2 activity on the lung′s susceptibility for Coronavirus disease (COVID) related acute respiratory distress syndrome (ARDS).

包装

Packaged under inert gas

警告

Toxicity: Standard Handling (A)

重悬

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

法律信息

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

基本信息

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