Aloxistatin

Aloxistatin (E64d) is a cell-permeable and irreversible broad-spectrum cysteine protease inhibitor. Aloxistatin (E64d) exhibits entry-blocking effect for MERS-CoV. IC50 & Target: Cysteine protease^[1] In Vitro: Inhibition of protease-resistant prion protein (PrP-res) accumulation in ScNB cells by cysteine protease inhibitor Aloxistatin (E64d) with IC₅₀ of 0.5±0.11 μM. For the cell surface PrP-sen detection, PrP-sen is immunoprecipitated from media treated with phosphatidylinositol-specific phospholipase C (PIPLC) to release pulse-³⁵S-labeled PrP-sen from the cell surface. Aloxistatin is maintained at 15 μM, respectively, in the labeling media of all but the control cells ^[1]. Aloxistatin (E64d) (which specifically blocks cysteine proteases, but not serine proteases such as granzymes) is able to completely block turnover of the CatL substrate Z-Phe-Arg-aminomethylcoumarin, when pre-incubated with NK-92 or YT 5 cells^[2]. Aloxistatin (E64d) is a broad-spectrum cell-permeable inhibitor of cysteine proteases^[3]. In Vivo: Oral administration of Aloxistatin (E64d) to guinea pigs results in a dose-dependent reduction in brain, CSF and plasma Aβ(40) and Aβ(42). Aloxistatin also causes a biphasic dose-dependent reduction in brain CTFβ. Aloxistatin causes a dose-dependent increase in brain sAβPPα. The mean sAβPPα levels are significantly higher than the no dose group for Aloxistatin doses of 5 mg/kg/day or greater with the highest Aloxistatin dose resulting in the maximum increase in sAβPPα of about 54% more than the control group. Similar to the Aβ effect, oral Aloxistatin administration produces a biphasic dose-dependent reduction in brain cathepsin B activity. The minimum effective dose is about 1 mg/kg/day with the highest Aloxistatin dose causing the maximum reduction in brain cathepsin B activity of about 91% lower than that of the control group. Thus, Aloxistatin reduces guinea pig brain cathepsin B activity in a manner which is consistent with the compound inhibiting cathepsin B β-secretase activity^[4]. Aloxistatin (E64d) inhibits the increases in the expression of AT_1AR and ACE genes in rats. Administration of RNH-6270 or Aloxistatin reduces the increase in the superoxide production of the intramyocardial coronary arteries in HF rats^[5].