Nor NOHA monoacetate

Nor NOHA monoacetate, a synthetic chemical derivative of L-arginine, is a selective and reversible inhibitor of Arginase-1 ^[1]. Nor NOHA monoacetate, by reacting with riboflavin, spontaneously releases NO-like molecules in the cell culture medium and can spontaneously react with H₂O₂, thereby reducing H₂O₂ and producing NO-like molecules^[2]. Nor NOHA monoacetate has been widely used to alter immune responses in experimental mouse models of pulmonary tuberculosis, including in the setting of HIV co-infection^[3].

In vitro, Nor NOHA monoacetate treatment for 24h significantly inhibited arginase activity in intact bovine coronary venular endothelial cells (BCVECs) with an IC₅₀ value of 10µM^[4]. Treatment of K562 cells with 1mM Nor NOHA monoacetate for 72h significantly induced apoptosis under hypoxic conditions (1.5% O₂)^[5]. Treatment with 1mM Nor NOHA monoacetate for 24 hours decreased arginase activity and resulted in decreased synthesis of αS1-casein, αS2-casein, β-casein, and κ-casein in bovine mammary epithelial cells (BMECs), accompanied by the decreased mRNA expression of CSN1S1, CSN1S2, CSN2, and CSN3^[6].

In vivo, a single dose of 100mg/kg Nor NOHA monoacetate administered intravenously 15min before the onset of ischemia reduced cardiac infarct size in rats, resulting in an increase in the plasma citrulline/arginine ratio and plasma nitrite levels^[7]. Topical transdermal administration of 5mM Nor NOHA monoacetate (30µl) twice daily for 21 days significantly reduced tumor volume and weight in the PDVC57 cell-xenograft tumor mouse model^[8].

References:
[1] Grobben Y, Willemsen-Seegers N, Uitdehaag J C M, et al. High-throughput fluorescence-based activity assay for arginase-1[J]. SLAS DISCOVERY: Advancing the Science of Drug Discovery, 2020, 25(9): 1018-1025.
[2] Momma T Y, Ottaviani J I. Arginase inhibitor, Nω-hydroxy-L-norarginine, spontaneously releases biologically active NO-like molecule: Limitations for research applications[J]. Free Radical Biology and Medicine, 2020, 152: 74-82.
[3] Chauhan S, Nusbaum R J, Huante M B, et al. Therapeutic modulation of Arginase with nor-NOHA alters immune responses in experimental mouse models of pulmonary tuberculosis including in the setting of human immunodeficiency virus (HIV) co-infection[J]. Tropical Medicine and Infectious Disease, 2024, 9(6): 129.
[4] Li H, Meininger C J, Bazer F W, et al. Intracellular sources of ornithine for polyamine synthesis in endothelial cells[J]. Amino Acids, 2016, 48(10): 2401-2410.
[5] Ng K P, Manjeri A, Lee L M, et al. The arginase inhibitor Nω− hydroxy− nor− arginine (nor− NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target[J]. PLoS One, 2018, 13(10): e0205254.
[6] Wang M Z, Ding L Y, Wang C, et al. Arginase inhibition reduces the synthesis of casein in bovine mammary epithelial cells[J]. Journal of Dairy Science, 2017, 100(5): 4128-4133.
[7] Jung C, Gonon A T, Sjöquist P O, et al. Arginase inhibition mediates cardioprotection during ischaemia–reperfusion[J]. Cardiovascular research, 2010, 85(1): 147-154.
[8] Mittal A, Wang M, Vidyarthi A, et al. Topical arginase inhibition decreases growth of cutaneous squamous cell carcinoma[J]. Scientific reports, 2021, 11(1): 10731.

Nor NOHA monoacetate是L-精氨酸的合成化学衍生物，是Arginase-1的一种选择性、可逆性抑制剂^[1]。Nor NOHA monoacetate通过与核黄素反应，可在细胞培养基中自发释放类NO分子，并能自发与H₂O₂反应，从而减少H₂O₂并产生类NO分子^[2]。Nor NOHA monoacetate已广泛用于改变肺结核实验小鼠模型的免疫反应，包括在HIV共感染的情况下^[3]。

在体外，Nor NOHA monoacetate处理24小时以IC₅₀值为10µM显著抑制了完整牛冠状小静脉内皮细胞(BCVECs)的精氨酸酶活性^[4]。用1mM的Nor NOHA monoacetate在低氧条件下（1.5% O₂）处理K562细胞72小时显著诱导了细胞凋亡^[5]。用1mM的Nor NOHA monoacetate处理24小时降低了精氨酸酶活性，导致牛乳腺上皮细胞(BMECs)中αS1-酪蛋白、αS2-酪蛋白、β-酪蛋白和κ-酪蛋白的合成减少，同时伴随CSN1S1、CSN1S2、CSN2和CSN3的mRNA表达降低^[6]。

在体内，缺血开始前15分钟静脉注射单剂量100mg/kg的Nor NOHA monoacetate减少了大鼠的心脏梗死面积，导致血浆瓜氨酸/精氨酸比值和血浆亚硝酸盐水平升高^[7]。在PDVC57细胞异种移植瘤小鼠模型中，每日两次局部经皮给药5mM的Nor NOHA monoacetate（30µl）连续21天显著降低了肿瘤体积和重量^[8]。