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C-Glycosylflavones Against Alzheimer's Disease: From Discovery to Mechanism of Action.

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Title:C-Glycosylflavones Against Alzheimer's Disease: From Discovery to Mechanism of Action.
Authors:Liang, Zhibin
Contributors:Molecular Biosciences & Bioeng (department)
Keywords:C-Glycosylflavone
Drug Discovery
Molecular Mechanism
Pharmacology
Neuroscience
show 1 moreAlzheimer’s Disease
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Date Issued:May 2018
Publisher:University of Hawaiʻi at Mānoa
Abstract:Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and is the sixth leading cause of death in the U.S. Current AD medications only temporarily relieve symptoms, and none can prevent, cure, or even slow AD. There is an urgent demand for effective drugs for AD prevention and treatment. C-Glycosylflavones, a class of phytochemicals, display diverse benefits to human health and recently noted for their neuroprotective effects. They are a novel and valuable source of anti-AD agents. Identification and validation of therapeutic targets of C-glycosylflavones for neuroprotection against AD are crucial to convey the mechanistic understanding of these agents in pharmaceutical applications. The principal objectives of the dissertation research aim to unravel the mechanistic basis of natural and synthetic C-glycosylflavones for potential AD therapies. Different research strategies such as target/phenotype-based screening and chemical proteomics approaches were adopted and integrated into an innovative drug discovery paradigm for target identification and validation of C-glycosylflavones.
Our efforts to search for natural anti-AD agents led to the discovery that a C-glycosylflavone called isoorientin from corn silks is neuroprotective. Isoorientin selectively inhibits glycogen synthase kinase-3β (GSK-3β), an enzyme most relevant to AD tauopathy. Molecular docking and enzyme kinetics indicated that isoorientin selectively inhibits GSK-3β via a substrate competition rather than the common ATP competition. Cellular studies demonstrated that isoorientin effectively attenuates tau hyperphosphorylation and amyloid neurotoxicity in human SH-SY5Y cells. By applying computer-aided drug design approach, novel analogues of C-glycosylflavones as GSK-3β inhibitors were synthesized. The new analogues show significant improvements of potency and passive membrane permeability compared to isoorientin. In addition, they have distinct kinase
selectivity to GSK-3β and effectively block GSK-3β–mediated tau and amyloid neurotoxicities. Finally, by harnessing the chemical proteomics and bioinformatics technologies, we revealed that C-glycosylflavones are novel multitarget ligands for potential AD prevention.
Collectively, the present dissertation elaborates a hypothesis-driven research on AD drug discovery. The new findings and knowledge gained through this study will broaden the understanding of mechanism of actions of C-glycosylflavones for potential AD therapies.
Description:Ph.D. Thesis. University of Hawaiʻi at Mānoa 2018.
URI:http://hdl.handle.net/10125/62563
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Molecular Biosciences and Bioengineering


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