In a new study, researchers found that a drug used to treat and prevent HIV/AIDS is showing promise as a potential therapy for Alzheimer’s disease.
The research was conducted by a team at Vanderbilt University and elsewhere.
Cholesterol is thought to contribute to the formation of clusters or plaques of amyloid-beta protein that are the hallmark of Alzheimer’s disease.
In the late 1990s, the enzyme P450 46A1 (CYP46A1) was found to be important in breaking down and eliminating cholesterol from the brain.
Previous research has shown that structural modifications of the anti-AIDS drug efavirenz (EFV) can increase its ability to activate enzymes that remove cholesterol from the brain.
Scientists reported that CYP46A1 could be activated in mice by low doses of EFV.
The therapeutic window for CYP46A1 activation by EFV in mice appears to be quite narrow, however.
But at higher doses, however, EFV is thought to bind both the allosteric and active sites. This inhibits the enzyme because it can no longer latch onto cholesterol.
The goal of the current research is to generate a more potent compound that enhances the beneficial effects while avoiding potential side effects.
The team found that EFV metabolites, compounds that result from the breakdown of the drug in the body, may increase CYP46A1 activation without inhibiting the enzyme at higher concentrations.
The team now is trying to make this approach to improving memory and cognitive function even better.
The lead author of the study is Vanderbilt University biochemist F. Peter Guengerich, Ph.D.
The study is published in the Journal of Medicinal Chemistry.
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