UCLA researchers in the Department of Neurology have discovered novel small molecule humanin mimetics for the treatment of Alzheimer's disease and other chronic conditions with dysregulated p-Akt.
BACKGROUND: Alzheimer’s disease (AD) is the most common form of dementia accounting for 60-70% of all cases. Nearly 7 million Americans are living with AD today. AD patient brain tissues are characterized by the presence of plaques largely composed of amyloid- β (Aβ). The current standard of care for AD patients includes drugs targeting glutamate receptors that modestly slow cognitive and memory decline. Amyloid-directed antibodies are a novel therapeutic strategy to specifically target the etiology of the disease. However, biologics-based therapies present challenges as feasible therapeutics due to the limited brain permeability, high costs, and requirement of repeated infusions to patients. Orally available small molecules therapeutics that target the underlying molecular mechanisms of AD are strongly needed.
INNOVATION: Rigorous research has uncovered the mitochondrial protein Humanin (HN) to have protected mitochondria and neurons from Aβ-related toxicity in human brain tissue. Enhancing HN protein has been shown to inhibit amyloid-β (Aβ) aggregation and receptor-mediated uptake, tau phosphorylation, and microglia cytokine release in AD animal models. Based on these findings, UCLA researchers conducted a small molecule screen in order to discover HN mimetics in human cells as a therapeutic approach for AD. After hit validation, HN mimetics were found to increase p-Akt levels in neurons as well as found to be protective against neuronal cell death induced by AD-associated insults. Because of the dysregulation of the p-AKT pathway in other chronic human diseases, HN mimetics can also serve as a therapeutic approach for cardiovascular disease and diabetes.
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ADVANTAGES:
DEVELOPMENT-TO-DATE: Screen hits were validated to increase downstream HN signaling including activation of pAKT pathway. Dose response analyses were conducted on validated hits. Medicinal chemistry in in progress for HN mimetics.