NH125 is a multitarget active substance and an inhibitor of several members of the histidine protein kinase family[1]. NH125 can inhibit the activity of eukaryotic elongation factor-2 kinase (eEF-2K) with an IC50 of 60nM [2]. NH125 can also target and inhibit the two-component signal transduction system in bacteria, exerting antibacterial effects[3]. NH125 can reduce the expression of the RNA-binding protein CPEB3 to increase the level of synaptic GluA2[4].
In vitro, pre-treatment of Staphylococcus aureus strain Newman with NH125 (41–298μM) for 1 hour, followed by cultivation for 24 hours in the presence of sub-lethal doses of cell wall-targeting antibiotics (Oxacillin at 0.5MIC or Vancomycin at 0.5MIC), significantly enhanced the inhibitory effects of the antibiotics on bacterial growth and reduced the expression levels of antibiotic resistance-related genes (vraSR, pbpB, and blaZ)[5]. Co-treatment of tumor cells with NH125 (0.25μM) and endoplasmic reticulum (ER) stress inducers (Curcumin at 5-50μM or Velcade at 25-800nM) for 48 hours significantly enhanced the cytotoxicity of the ER stress inducers against tumor cells and promoted apoptosis compared to treatment with the ER stress inducers alone[6].
In vivo, NH125 (1mg/kg) was administered intraperitoneally once daily to mice with LPS-induced depression. NH125 reduced the levels of pro-inflammatory cytokines and increased the immobility time of the mice[7]. NH125 (1mg/kg) was also administered intraperitoneally once daily to SARM1 knockout (SARM1KO) mice for 3 consecutive days. NH125 significantly improved depressive-like behaviors in SARM1KO mice, reducing immobility time, increasing sucrose preference, and restoring synaptic protein levels while increasing dendritic spine density[8].
References:
[1] Devkota AK, Tavares CD, Warthaka M, et al. Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact. Biochemistry. 2012 Mar 13;51(10):2100-12.
[2] Arora S, Yang JM, Kinzy TG, et al. Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. Cancer Res. 2003 Oct 15;63(20):6894-9.
[3] Yamamoto K, Kitayama T, Ishida N, et al. Identification and characterization of a potent antibacterial agent, NH125 against drug-resistant bacteria. Biosci Biotechnol Biochem. 2000 Apr;64(4):919-23.
[4] Bender CL, Yang Q, Sun L, et al. NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression. Neuropharmacology. 2016 Feb;101:531-7.
[5] Bhattarai S, Marsh L, Knight K, et al. NH125 Sensitizes Staphylococcus aureus to Cell Wall-Targeting Antibiotics through the Inhibition of the VraS Sensor Histidine Kinase. Microbiol Spectr. 2023 Jun 15;11(3):e0486122.
[6] Cheng Y, Ren X, Zhang Y, et al. Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells. Autophagy. 2013 Feb 1;9(2):208-19.
[7] Li W, Ali T, Zheng C, et al. Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression. J Neuroinflammation. 2021 Feb 1;18(1):38.
[8] Li W, Zhu W, Chen J, et al. SARM1 deficiency induced depressive-like behavior via AMPKα/p-eEF2 axis to synapse dysfunction. Neuropharmacology. 2025 Jan 1;262:110206.
NH125是一种多靶标的活性物质，是多种组氨酸蛋白激酶家族成员的抑制剂[1]，其中NH125可抑制真核延长因子2激酶（eEF-2K）活性，IC50=60nM[2]。NH125还可靶向抑制细菌的双组分信号转导系统活性，发挥抑菌作用[3]。NH125可降低RNA结合蛋白CPEB3的表达，以提高突触GluA2的水平[4]。
在体外，NH125（41–298μM）预处理金黄色葡萄球菌Newman菌株1h，随后在亚致死剂量的细胞壁靶向抗生素（如苯唑西林0.5MIC或万古霉素0.5MIC）存在下培养24h，NH125显著增强抗生素对细菌生长的抑制作用，并降低与抗生素耐药性相关的基因（vraSR、pbpB和blaZ）的表达水平[5]。NH125（0.25μM）与内质网应激诱导剂（Curcumin；5-50μM或Velcade；25-800nM）同时处理48h，相对于单独内质网应激诱导剂处理组，NH125显著增强内质网应激诱导剂对肿瘤细胞的细胞毒性，促进细胞凋亡[6]。
在体内，NH125（1mg/kg）每天一次腹腔注射，用于处理LPS诱导的抑郁小鼠模型。NH125降低了小鼠的促炎细胞因子的水平，并增加了小鼠的运动时间[7]。NH125（1mg/kg）每天一次腹腔注射于SARM1基因敲除（SARM1KO）小鼠，连续处理3天。NH125显著改善了SARM1KO小鼠的抑郁样行为，减少了小鼠的不动时间，增加了蔗糖偏好，并且恢复了突触蛋白水平，增加了树突棘密度[8]。