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ACS Chem Neurosci. 2018 Mar 21;9(3):462-468. doi: 10.1021/acschemneuro.7b00350. Epub 2017 Dec 6.

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

Author information

1
Drug Discovery Laboratory, Department of Neurology , UCLA , Los Angeles , California 90095 , United States.
2
Department of Orthopedic Surgery, DGSOM , UCLA , Los Angeles , California 90095 , United States.
3
Department of Orthopedic Surgery , University of Southern California (USC) , Los Angeles , California 90033 , United States.

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.

KEYWORDS:

Humanin; NMDA; excitotoxicity; gp130 receptor; microfluidics; primary neurons

PMID:
29161500
DOI:
10.1021/acschemneuro.7b00350
[Indexed for MEDLINE]

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