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Crafting of Neuroprotective Octapeptide from Taxol-Binding Pocket of β-Tubulin
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acschemneuro.7b00457
Prasenjit Mondal 1, 2 , Gaurav Das 1, 2 , Juhee Khan 1, 2 , Krishnangsu Pradhan 1 , Surajit Ghosh 1, 2
Affiliation  

Microtubules play a crucial role in maintaining the shape and function of neurons. During progression of Alzheimer’s disease (AD), severe destabilization of microtubules occurs, which leads to the permanent disruption of signal transduction processes and memory loss. Thus, microtubule stabilization is one of the key requirements for the treatment of AD. Taxol, a microtubule stabilizing anticancer drug, has been considered as a potential anti-AD drug but was never tested in AD patients, likely because of its’ toxic nature and poor brain exposure. However, other microtubule-targeting agents such as epothilone D (BMS-241027) and TPI-287 (abeotaxane) and NAP peptide (davunetide) have entered in AD clinical programs. Therefore, the taxol binding pocket of tubulin could be a potential site for designing of mild and noncytotoxic microtubule stabilizing molecules. Here, we adopted an innovative strategy for the development of a peptide based microtubule stabilizer, considering the taxol binding pocket of β-tubulin, by using alanine scanning mutagenesis technique. This approach lead us to a potential octapeptide, which strongly binds to the taxol pocket of β-tubulin, serves as an excellent microtubule stabilizer, increases the expression of acetylated tubulin, and acts as an Aβ aggregation inhibitor and neuroprotective agent. Further, results revealed that this peptide is nontoxic against both PC12 derived neurons and primary cortical neurons. We believe that our strategy and discovery of peptide-based microtubule stabilizer will open the door for the development of potential anti-AD therapeutics in near future.

中文翻译:

从β-管蛋白的紫杉醇结合口袋中制备神经保护性八肽

微管在维持神经元的形状和功能中起着至关重要的作用。在阿尔茨海默氏病(AD)的进展过程中,会发生微管的严重失稳,这会导致信号转导过程的永久破坏和记忆丧失。因此,微管稳定化是治疗AD的关键要求之一。紫杉醇是一种稳定微管的抗癌药物,被认为是潜在的抗AD药物,但从未在AD患者中进行过测试,这可能是由于其毒性性质和不良的大脑暴露。但是,其他微管靶向剂,如埃坡霉素D(BMS-241027)和TPI-287(阿波他烷)和NAP肽(达富尼特)也已进入AD临床计划。所以,微管蛋白的紫杉醇结合口袋可能是设计轻度和无细胞毒性的微管稳定分子的潜在位点。在这里,我们考虑到β-微管蛋白的紫杉醇结合口袋,采用丙氨酸扫描诱变技术,采用了一种创新的策略开发基于肽的微管稳定剂。这种方法使我们产生了一种潜在的八肽,该八肽与β-微管蛋白的紫杉醇口袋牢固结合,可作为出色的微管稳定剂,增加乙酰化微管蛋白的表达,并充当Aβ聚集抑制剂和神经保护剂。此外,结果表明该肽对源自PC12的神经元和原代皮层神经元均无毒。
更新日期:2017-11-20
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