MG-101 (Calpain Inhibitor I, ALLN) also known as Calpain Inhibitor I, selectively inhibits various cysteine proteases, including calpain I, calpain II, cathepsin B, and cathepsin L. The corresponding Ki values for these enzymes are 90pM, 220pM, 150pM, and 500pM[1]. Calpains are a family of calcium-dependent cysteine proteases[2] that play important roles in many cellular processes. MG-101 has been shown to protect against neuronal damage in ischemic stroke models by inhibiting calpain activity [3]. Additionally, MG-101 can inhibit the activity of the SARS-CoV-2 virus[4].
In vitro, pre-treatment of iBREC (immortalized bovine retinal endothelial cells) with MG-101 (20nM) for 4 hours, followed by stimulation with VEGF (250µg/ml) for 4 hours, significantly increased the accumulation of aflibercept within the cells, inhibited its degradation, and suppressed lysosomal protease activity[5]. In primary rat retinal neurons treated with MG-101 (2.5–7.5µM) for 6–24 hours, MG-101 significantly reduced cell viability, induced cell death, and caused retinal neuronal death through necrosis and apoptosis[6].
In vivo, pre-treatment of mice with MG-101 (10mg/kg) via intraperitoneal injection, followed by ischemic preconditioning (IPC), significantly inhibited the degradation of cardiac myosin-binding protein C (cMyBP-C) induced by myocardial ischemia/reperfusion (I/R) injury and promoted its phosphorylation[7]. In rats, MG-101 (20mg/kg) administered via intraperitoneal injection significantly improved biochemical marker levels in serum and brain tissue and reduced the number of apoptotic cells, showing protective effects against neuroapoptotic cell damage caused by CuO-NP and I/R[8].
References:
[1] Li SZ, Zhang HH, Zhang JN, et al. ALLN hinders HCT116 tumor growth through Bax-dependent apoptosis. Biochem Biophys Res Commun. 2013 Jul 26;437(2):325-30.
[2] Hamidi R, Ataei F, Hosseinkhani S. Inhibition of noncaspase proteases, calpain and proteasome, via ALLN and Bortezomib contributes to cell death through low degradation of pro-/anti-apoptotic proteins and apoptosis induction. Med Oncol. 2022 Jun 18;39(9):125.
[3] Matsui Y, Kanou T, Matsui T, et al. Protective Effect of Calpain Inhibition During Cold Ischemia on Ischemia-reperfusion Injury After Lung Transplantation. Transplantation. 2023 Sep 1;107(9):1945-1954.
[4] Narayanan A, Narwal M, Majowicz SA, et al. Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay. Commun Biol. 2022 Feb 25;5(1):169.
[5] Deissler HL, Lang GK, Lang GE. Fate of the Fc fusion protein aflibercept in retinal endothelial cells: competition of recycling and degradation. Graefes Arch Clin Exp Ophthalmol. 2019 Jan;257(1):83-94.
[6] Li N, Shang L, Wang SC, et al. The Toxic Effect of ALLN on Primary Rat Retinal Neurons. Neurotox Res. 2016 Oct;30(3):392-406.
[7] Liang C, Aisa Z, Sun L, et al. Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis. Exp Cell Res. 2023 Dec 15;433(2):113859.
[8] Karimkhani H, Shojaolsadati P, Yiğitbaşı T, et al. The effect of calpain inhibitor-I on copper oxide nanoparticle-induced damage and cerebral ischemia-reperfusion in a rat model. Biomed Pharmacother. 2024 May;174:116539.
MG-101 (Calpain Inhibitor I, ALLN)是半胱氨酸蛋白酶 的抑制剂，抑制钙蛋白酶I，钙蛋白酶II，组织蛋白酶B和组织蛋白酶L，其Ki值分别为90，220，150和500pM[1]。钙蛋白酶是一类依赖钙离子的半胱氨酸蛋白酶家族[2]，在许多细胞过程中发挥重要作用MG-101抑制钙蛋白酶活性已被证明在缺血性中风模型中对神经元损伤具有保护作用[3]。MG-101还能抑制SARS-CoV-2病毒活性[4]。
在体外，MG-101（20nM）预处理iBREC（牛视网膜内皮细胞）4小时后，再以VEGF（250µg/ml）刺激4小时，可显著增加细胞内aflibercept的积累，同时抑制其降解，并抑制溶酶体蛋白酶活性[5]。MG-101（2.5–7.5µM）处理原代大鼠视网膜神经元6–24小时，MG-101显著降低细胞活力，诱导细胞死亡，而且MG-101可通过坏死和凋亡诱导视网膜神经元死亡[6]。
在体内，MG-101（10mg/kg）通过腹腔注射预处理小鼠后，再进行缺血预处理（IPC），显著抑制了心肌缺血/再灌注（I/R）损伤诱导的心脏肌球蛋白结合蛋白C（cMyBP-C）的降解，并促进了其磷酸化水平的提高[7]。MG-101（20mg/kg）通过腹腔注射给予大鼠，用于处理CuO-NP诱导的损伤和脑缺血/再灌注损伤。MG-101显著改善了血清和脑组织中的生化标志物水平，减少了凋亡细胞数量，对CuO-NP和I/R诱导的神经细胞损伤具有保护作用[8]。