MLN-4760 is a selective inhibitor of human angiotensin-converting enzyme 2 (ACE2; IC₅₀=0.44nM). MLN-4760 binds with high affinity to the zinc ion in the active site of ACE2, mimicking the transition state during peptide hydrolysis, thereby blocking the conversion of angiotensin II to angiotensin(1-7)[1-2]. MLN-4760 is primarily used in studies related to kidney diseases, cardiovascular diseases, and inflammatory bowel disease[3-4].
In vitro, treatment of high glucose (HG)-cultured human umbilical vein endothelial cells (HUVECs) with MLN-4760 (100nM) for 24 hours, MLN-4760 significantly inhibited the expression of ACE2 and Ang-(1-7) in HUVECs. MLN-4760 also downregulated the activity of the insulin signaling pathway (IRS-1/PI3K/Akt/eNOS) and exacerbated oxidative stress and inflammatory responses[5]. Pretreatment of high glucose (30mM)-cultured human renal tubular epithelial cells (HK2) with MLN-4760 (5μM) for 24 hours, followed by intervention with Dapagliflozin (10μM) for 24 hours, MLN-4760 significantly reversed the Dapagliflozin-induced upregulation of ACE2 expression and inhibition of epithelial-mesenchymal transition (EMT), while restoring the expression level of the pro-fibrotic factor TGF-β1[6].
In vivo, administration of MLN-4760 (1mg/kg/day) via subcutaneous implantation of a mini-osmotic pump for 14 days in spontaneously hypertensive rats, MLN-4760 significantly increased the body weight gain rate and the visceral fat-to-body weight ratio, while elevating the concentration of hydrogen sulfide (H₂S) in both plasma and cardiac tissues[7]. MLN-4760 (1mg/kg/day) administered via subcutaneous implantation of a mini-osmotic pump for 14 days in spontaneously hypertensive rats, MLN-4760 significantly reduced the osmotic resistance of red blood cells and induced morphological abnormalities in erythrocytes[8].
References:
[1] Kluknavsky M, Micurova A, Cebova M, et al. MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of Nfe2l2 Gene, Nitric Oxide and Hydrogen Sulfide. Antioxidants (Basel). 2022 Dec 1;11(12):2385.
[2] Joshi S, Balasubramanian N, Vasam G, et al. Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells. Eur J Pharmacol. 2016 Mar 5;774:25-33.
[3] Jasenovec T, Radosinska D, Kollarova M, et al. Effects of Taxifolin in Spontaneously Hypertensive Rats with a Focus on Erythrocyte Quality. Life (Basel). 2022 Dec 7;12(12):2045.
[4] Berenyiova A, Bernatova I, Zemancikova A, et al. Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760-Benefit or Detriment in Essential Hypertension? Biomedicines. 2021 Dec 24;10(1):38.
[5] Wang Y, Fu W, Xue Y, et al. Ginsenoside Rc Ameliorates Endothelial Insulin Resistance via Upregulation of Angiotensin-Converting Enzyme 2. Front Pharmacol. 2021 Feb 23;12:620524.
[6] Wang S, Zhang X, Chong N, et al. Dapagliflozin ameliorates high glucose-induced epithelial-mesenchymal transition via up-regulating ACE2 mediated by EZH2 in diabetic nephropathy. J Endocrinol Invest. 2025 Oct;48(10):2499-2509.
[7] Cacanyiova S, Cebova M, Simko F, et al. The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760. Biol Res. 2023 Oct 25;56(1):55.
[8] Jasenovec T, Radosinska D, Kollarova M, et al. Angiotensin System Modulations in Spontaneously Hypertensive Rats and Consequences on Erythrocyte Properties; Action of MLN-4760 and Zofenopril. Biomedicines. 2021 Dec 14;9(12):1902.
MLN-4760是一种选择性的人血管紧张素转换酶2（ACE2；IC50=0.44nM）抑制剂，MLN-4760可高亲和力地结合ACE2的活性位点锌离子，模拟肽水解过程中的过渡态，从而阻断血管紧张素II向血管紧张素(1-7)的转化[1-2]。MLN-4760主要被用于肾脏疾病、心血管疾病以及炎症性肠病的相关研究中[3-4]。
在体外，MLN-4760（100nM）处理高葡萄糖（HG）培养的人脐静脉内皮细胞（HUVECs）24小时，随后以胰岛素（100nM）刺激30分钟，MLN-4760显著抑制HUVECs细胞中ACE2和Ang-(1-7)的表达，同时下调胰岛素信号通路（IRS-1/PI3K/Akt/eNOS）的活性，并加剧氧化应激和炎症反应[5]。MLN-4760（5μM）预处理高葡萄糖（30mM）培养的人肾小管上皮细胞（HK2）24小时，随后以Dapagliflozin（10μM）干预24小时，MLN-4760显著逆转Dapagliflozin诱导的ACE2表达上调和上皮-间质转化（EMT）抑制，同时恢复促纤维化因子TGF-β1的表达水平[6]。
在体内，MLN-4760（1mg/kg/day）通过皮下植入微型渗透泵连续给药自发性高血压大鼠14天，MLN-4760显著增加大鼠的体重增长率和内脏脂肪/体重比值，同时升高血浆及心脏组织中硫化氢（H₂S）浓度 [7]。MLN-4760（1mg/kg/day）通过皮下植入微型渗透泵连续给药自发性高血压大鼠14天，MLN-4760显著降低大鼠红细胞的渗透抵抗性，并诱导红细胞形态异常[8]。