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Discovery of Neuroregenerative Peptoid from Amphibian Neuropeptide That Inhibits Amyloid‑β Toxicity and Crosses Blood–Brain Barrier

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journal contribution
posted on 08.11.2018, 00:00 by Krishnangsu Pradhan, Gaurav Das, Varsha Gupta, Prasenjit Mondal, Surajit Barman, Juhee Khan, Surajit Ghosh
Development of potential therapeutics for Alzheimer’s disease (AD) requires a multifaceted strategy considering the high levels of complexity of the human brain and its mode of function. Here, we adopted an advanced strategy targeting two key pathological hallmarks of AD: senile plaques and neurofibrillary tangles. We derived a lead short tetrapeptide, Ser-Leu-Lys-Pro (SLKP), from a dodeca-neuropeptide of amphibian (frog) brain. Results suggested that the SLKP peptide had a superior effect compared to the dodecapeptide in neuroprotection. This result encouraged us to adopt peptidomimetic approach to synthesize an SLKP peptoid. Remarkably, we found that the SLKP peptoid is more potent than its peptide analogue, which significantly inhibits Aβ fibrillization, moderately binds with tubulin, and promotes tubulin polymerization as well as stabilization of microtubule networks. Further, we found that SLKP peptoid is stable in serum, shows significant neuroprotection against Aβ mediated toxicity, promotes significant neurite outgrowth, maintains healthy morphology of rat primary cortical neurons and crosses the blood–brain barrier (BBB). To the best of our knowledge, our SLKP peptoid is the first and shortest peptoid to show significant neuroprotection and neuroregeneration against Aβ toxicity, as well as to cross the BBB offering a potential lead for AD therapeutics.