Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A,ACS Chemical Neuroscience

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Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-04-19 00:00:00 , DOI: 10.1021/acschemneuro.8b00060
Daniëlle Copmans ₁ , Mostafa Rateb _{2,

3} , Jioji N. Tabudravu ₂ , Mercedes Pérez-Bonilla ₄ , Nina Dirkx ₁ , Riccardo Vallorani ₁ , Caridad Diaz ₄ , José Pérez del Palacio ₄ , Alan J. Smith ₂ , Rainer Ebel ₂ , Fernando Reyes ₄ , Marcel Jaspars ₂ , Peter A. M. de Witte ₁

Affiliation

In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A₂, pseurotin F1, 11-O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A₂ and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A₂ and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A₂ and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A₂ and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular.

中文翻译：

基于斑马鱼的红海抗癫痫化合物的发现：Pseurotin A ₂和Azaspirofuran A

为了寻找新型抗癫痫药，由欧洲FP7资助的PharmaSea项目使用斑马鱼胚胎和幼虫作为药物发现平台，筛选海洋天然产物，以鉴定有希望的体内抗癫痫发作，以进行进一步开发。在该项目的框架内，从生物活性海洋真菌中分离出了七个已知的杂螺环γ-内酰胺，即伪神经素A，伪神经素A ₂，伪神经素F1、11- O-甲基伪藻蛋白A，伪神经素D，氮杂螺旋呋喃A和氮杂螺旋呋喃B。烟曲霉及其抗癫痫活性在幼虫斑马鱼戊四氮（PTZ）癫痫模型中进行了评估。伪神经素A ₂和azaspirofuran A被确定为抗癫痫发作药物，而其紧密的化学类似物没有活性。此外，对斑马鱼中脑的电生理分析表明，假神经素A ₂和氮杂螺呋喃A也可改善PTZ诱导的癫痫样放电。接下来，为了确定这些发现是否转化为哺乳动物，在小鼠6 Hz（44 mA）精神运动性癫痫发作模型中分析了这两种化合物。他们剂量依赖性地降低了癫痫发作的持续时间，从而证实了它们的抗癫痫发作特性并暗示了对耐药性癫痫发作的活性。最后，在全面的ADMET评估中，发现伪神经素A ₂和氮杂螺呋喃A呈药物样。基于这两种物种均具有突出的抗癫痫活性和药物相似性，我们提出了伪神经素A₂和azaspirofuran A作为先导化合物，在癫痫发作的治疗中值得进一步研究。这项研究不仅提供了伪神经素和氮杂螺呋喃类抗癫痫活性的第一个证据，而且还证明了斑马鱼模型在（海洋）天然产物药物发现中的价值，特别是在ASD发现中的价值。

更新日期：2018-04-19

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