Alzheimer's Disease Treatment Compounds Inhibit Interaction of Amyloid Beta Peptide and Amyloid ABAD

Track Code: 
12KU071L
Summary: 

A novel class of small molecule Alpha, Beta-ABAD interaction inhibitors for the treatment of Alzheimer's Disease.

Overview: 
The accumulation of amyloid beta peptide (Alpha, Beta) in Alzheimer's disease (AD) plays a central role in the various pathologies of the disease. In particular, studies have highlighted the significance of mitochondrial Alpha, Beta accumulation in impairing mitochondrial structure and function including membrane potential, membrane permeability transition pore, respiration, energy metabolism, oxidative stress, mitochondrial dynamics, and calcium homeostasis. Therefore, inhibiting Alpha, Beta-induced mitochondrial toxicity is a promising and novel approach to improving cognitive function and preventing and/or slowing the progression of AD. Amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme, is one such promising therapeutic target to achieve Alpha, Beta inhibition. ABAD interacts with Alpha, Beta to facilitate cognitive dysfunction in AD. Studies show that antagonizing Alpha, Beta - ABAD interaction significantly reduces Aβ accumulation, protects against aberrant mitochondrial and neuronal function, and improves learning memory in AD transgenic mice. Dr. Yan's discovery is a family of novel small molecule Alpha, Beta-ABAD interaction inhibitors.

To learn more about the technology a published white paper (pdf) is available for download.

download white paper

How it works: 

Quantitative structure - activity relationship (QSAR) analysis helped design these novel and reactive Alpha, Beta-ABAD inhibitors by predicting physicochemical properties to increase selectivity and affinity. Dr. Yan applied 3D QSAR methods to evaluate the molecular property fields between five known Alpha, Beta-ABAD inhibitors and 20 candidate novel compounds. The compounds with satisfactory properties were tested via molecular docking against ABAD to find out whether they are able to bind to the protein and inhibit Alpha, Beta-ABAD interaction. Benzothiazoleurea and frentizole analogues demonstrated remarkably superior permeation across biological membranes and oral bioavailability, in addition to a 30x increase in potency and reduced drug-drug interaction. In the end, 14 of the 20 compounds demonstrated high potency with attractive drug-like properties.

Benefits: 

In quantitative structure-activity relationship and pharmacokinetic tests, Dr. Yan's compounds inhibited Alpha, Beta-ABAD interaction with high specificity and demonstrated attractive drug-like properties - including absorption, toxicity, blood brain barrier penetration, and potency - superior to those of known Alpha, Beta-ABAD interaction inhibitors.

Moreover, a molecular docking study of these novel compounds showed better interaction with the binding site - suggesting that they are safer and more effective drugs for treating AD.

Why it is better: 

Known inhibitors of Alpha, Beta-ABAD interaction have several disadvantages including low solubility, inability to cross the blood brain barrier (BBB), high toxicity, and/or low cell permeability. Efforts to design better Alpha, Beta-ABAD inhibitors have been unsuccessful due to poor ADME (absorption, distribution, metabolism and excretion) properties.

Licensing Associate: 
Aswini Betha, PhD · abetha@ku.edu · 913-588-5713
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Inventor(s): 
Shirley Yan
KoteswaraRao Valasani
Status: 
Patent-Pending