Peptide-Based Acetylcholinesterase Inhibitor Crosses the Blood-Brain Barrier and Promotes Neuroprotection.,ACS Chemical Neuroscience

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Peptide-Based Acetylcholinesterase Inhibitor Crosses the Blood-Brain Barrier and Promotes Neuroprotection.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-08-01 , DOI: 10.1021/acschemneuro.8b00253
Prasenjit Mondal _{1,

2} , Varsha Gupta ₁ , Gaurav Das _{1,

2} , Krishnangsu Pradhan ₁ , Juhee Khan ₁ , Prabir Kumar Gharai ₁ , Surajit Ghosh _{1,

2}

Affiliation

Design and development of acetylcholinesterase (AChE) inhibitor has tremendous implications in the treatment of Alzheimer's disease (AD). Here, we have adopted a computational approach for the design of a peptide based AChE inhibitor from its active site. We identified an octapeptide, which interacts with the catalytic anionic site (CAS) of AChE enzyme and inhibits its activity. Interestingly, this peptide also inhibits amyloid aggregation through its interaction at the 17-21 region of amyloid-beta (Aβ) and stabilizes microtubules by interacting with tubulin as well. Eventually, in the PC12 derived neurons, it shows noncytotoxicity, promotes neurite out-growth, stabilizes intracellular microtubules, and confers significant neuroprotection even upon withdrawal of nerve growth factor (NGF). Further, results reveal that this peptide possesses good serum stability, crosses the blood-brain barrier (BBB), and maintains the healthy architecture of the primary cortical neurons. This work shows discovery of an excellent peptide-based AChE inhibitor with additional potential as a microtubule stabilizer, which will pave the way for the development of potential anti-AD therapeutics in the near future.

中文翻译：

基于肽的乙酰胆碱酯酶抑制剂穿过血脑屏障并促进神经保护。

乙酰胆碱酯酶（AChE）抑制剂的设计和开发对阿尔茨海默氏病（AD）的治疗具有巨大的意义。在这里，我们采用了一种从其活性位点设计基于肽的AChE抑制剂的计算方法。我们确定了八肽，它与AChE酶的催化阴离子位点（CAS）相互作用并抑制其活性。有趣的是，该肽还通过在淀粉样蛋白β（Aβ）的17-21区相互作用来抑制淀粉样蛋白聚集，并通过与微管蛋白相互作用来稳定微管。最终，在PC12衍生的神经元中，它表现出非细胞毒性，促进神经突向外生长，稳定细胞内微管，甚至在撤消神经生长因子（NGF）时也具有显着的神经保护作用。进一步，结果表明，该肽具有良好的血清稳定性，可穿过血脑屏障（BBB），并维持初级皮层神经元的健康结构。这项工作表明发现了一种优秀的基于肽的AChE抑制剂，它具有作为微管稳定剂的额外潜力，这将为不久的将来开发潜在的抗AD治疗药物铺平道路。

更新日期：2018-07-17

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