Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease

The absence of effective therapeutics against Alzheimer’s disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chem...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 7; no. 1; p. 13115
Main Authors: Beck, Michael W., Derrick, Jeffrey S., Kerr, Richard A., Oh, Shin Bi, Cho, Woo Jong, Lee, Shin Jung C., Ji, Yonghwan, Han, Jiyeon, Tehrani, Zahra Aliakbar, Suh, Nayoung, Kim, Sujeong, Larsen, Scott D., Kim, Kwang S., Lee, Joo-Yong, Ruotolo, Brandon T., Lim, Mi Hee
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 13.10.2016
Nature Publishing Group
Nature Portfolio
Subjects:
119/118
13/106
140/131
639/638/11/296
639/638/92/613
639/638/92/96
82/29
Alzheimer Disease - drug therapy
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid - antagonists & inhibitors
Amyloid - metabolism
Amyloid beta-Peptides - antagonists & inhibitors
Amyloid beta-Peptides - metabolism
Animals
Chemistry
Design
Drug Design
Free Radicals - antagonists & inhibitors
Free Radicals - metabolism
Humanities and Social Sciences
Humans
Ionization
Life sciences
Metals
Metals - antagonists & inhibitors
Metals - metabolism
Mice, Inbred C57BL
Mice, Transgenic
Molecular Structure
multidisciplinary
Pathogenesis
Pathology
Permeability
Protein Aggregates - drug effects
Proteins
Reactive Oxygen Species - antagonists & inhibitors
Reactive Oxygen Species - metabolism
Science
Science (multidisciplinary)
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
South Korea
Ann Arbor Michigan
United States > US
Michigan
ISSN:2041-1723, 2041-1723
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The absence of effective therapeutics against Alzheimer’s disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal–Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets’ reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs. To advance our understanding of pathological features associated with Alzheimer’s disease (AD), chemical tools with distinct specificity towards AD targets would be valuable. Here the authors used a structure-mechanism-based design strategy to obtain small molecules as chemical regulators for distinct pathological factors linked to AD pathology.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
These authors contributed equally to this work
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms13115