Dyngo-4a is a potent, novel dynamin inhibitor with IC50 values of 0.38μM, 1.1μM, and 2.3μM for DynI (brain), DynI (rec), and DynII (rec), respectively[1]. Dynamin is a large GTPase that hydrolyzes GTP to mediate membrane scission and serves as the key “membrane scissor” in clathrin-mediated endocytosis(CME)[2]. Dyngo-4a blocks the GTPase activity of dynamin, thereby inhibiting CME and is widely used to study mechanisms of neurotransmission, toxin uptake, and viral infection[3][4].
In vitro, treatment of Neuro-2a neuroblastoma cells with Dyngo-4a (10-30μM; 6 days) dose-dependently inhibited cells proliferation and induced their differentiation into Tuj-1-positive neuron-like cells, while markedly up-regulating p-AKT and p-ERK1/2 phosphorylation without affecting p-EGFR[5].
In vivo, Dyngo-4a (i.p.; 30mg/kg at 0h, then 30mg/kg at 4.5–8h (total 60mg/kg)) treatment suppressed BoNT/A-induced muscle paralysis at the rat hemidiaphragm and significantly delayed the onset of botulism in an in vivo murine model[6]. Dyngo-4a (30mg/kg; i.p.; administered on the day of infection) markedly alleviated rotavirus (RV)-induced diarrhea, reducing the diarrhea score from 1.0 to 0.2, while lowering the viral load in the small intestine by approximately 90% and substantially mitigating RV-triggered vacuolar degeneration of small-intestinal villous epithelial cells in 6–8-day-old BALB/c mice[7].
References:
[1] McCluskey A, Daniel JA, Hadzic G, et al. Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis. Traffic. 2013;14(12):1272-1289.
[2] Ferguson SM, De Camilli P. Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol. 2012 Jan 11;13(2):75-88.
[3] Ahmed A, Trezza A, Gentile M, et al. Dynamin-independent CaV1.2 and KCa1.1 channels regulation and vascular tone modulation by the mitochondrial fission inhibitors dynasore and dyngo-4a. Eur J Pharmacol. 2023;951:175786.
[4] Harper CB, Popoff MR, McCluskey A, Robinson PJ, Meunier FA. Targeting membrane trafficking in infection prophylaxis: dynamin inhibitors. Trends Cell Biol. 2013;23(2):90-101.
[5] Huang J, Zhou Y, Zeng S, et al. Dyngo-4a Induces Neuroblastoma Cell Differentiation Through The AKT and ERK1/2 Pathway. CNS Neurol Disord Drug Targets. 2023;22(10):1526-1534.
[6] Harper CB, Martin S, Nguyen TH, et al. Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. J Biol Chem. 2011;286(41):35966-35976.
[7] Zhang Q, Zhang Q, Xu Z, et al. Dyngo-4a protects mice from rotavirus infection by affecting the formation of dynamin 2 oligomers. Sci Bull (Beijing). 2020;65(21):1796-1799.
Dyngo-4a是一种强效的新型dynamin抑制剂，对DynI（脑源）、DynI（重组）和DynII（重组）的IC50分别为 0.38μM、1.1μM和2.3μM [1]。Dynamin是一种大分子GTP酶，通过水解GTP介导膜切割，是网格蛋白介导内吞（CME）过程中的关键“膜剪切酶”[2]。Dyngo-4a通过阻断dynamin的GTP酶活性，抑制CME，被广泛用于研究神经传递、毒素摄取及病毒感染等机制[3][4]。
体外实验中，用10–30μM Dyngo-4a连续处理6天，可剂量依赖性地抑制Neuro-2a神经母细胞瘤细胞增殖，并诱导其分化为Tuj-1阳性神经元样细胞，同时显著上调p-AKT与p-ERK1/2水平，而p-EGFR无明显变化[5]。
体内实验中，Dyngo-4a（腹腔注射；0h给予30mg/kg，4.5–8h 追加30mg/kg，总剂量 60mg/kg）显著抑制大鼠半膈肌的BoNT/A诱导性肌麻痹，并在小鼠体内模型中明显延迟肉毒中毒发作[6]。以 30mg/kg Dyngo-4a（感染当日腹腔注射一次）可明显缓解6–8日龄BALB/c小鼠轮状病毒（RV）所致腹泻，使腹泻评分由1.0 降至0.2，同时将小肠病毒载量降低约90%，并显著减轻RV引起的小肠绒毛上皮细胞空泡变性[7]。