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A Small Molecule Mimetic of the Humanin Peptide as a Candidate for Modulating NMDA-Induced Neurotoxicity.

Abstract：

:Humanin (HN), a 24-amino acid bioactive peptide, has been shown to increase cell survival of neurons after exposure to Aβ and NMDA-induced toxicity and thus could be beneficial in the treatment of Alzheimer's disease (AD). The neuroprotection by HN is reported to be primarily through its agonist binding properties to the gp130 receptor. However, the peptidic nature of HN presents challenges in its development as a therapeutic for AD. We report here for the first time the elucidation of the binding site of Humanin (HN) peptide to the gp130 receptor extracellular domain through modeling and the synthesis of small molecule mimetics that interact with the HN binding site on the gp130 receptor and provide protection against NMDA-induced neurotoxicity in primary hippocampal neurons. A brain permeable small molecule mimetic was identified through exploratory medicinal chemistry using microfluidic flow chemistry to facilitate the synthesis of new analogues for screening and SAR optimization.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Alam MP,Bilousova T,Spilman P,Vadivel K,Bai D,Elias CJ,Evseenko D,John V

doi

10.1021/acschemneuro.7b00350

subject

Has Abstract

pub_date

2018-03-21 00:00:00

pages

462-468

issue

3

issn

1948-7193

journal_volume

9

pub_type

杂志文章

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