J Med Chem: HIV drug feveron may be expected to treat Alzheimer's disease

January 7, 2020 / BIOON / -- recently, an International Journal of medical chemistry In the previous research report, scientists from Vanderbilt University and other institutions found that a drug used to treat and prevent HIV / AIDS may help treat Alzheimer's disease, and relevant research may help develop new therapies to improve the brain memory and cognitive function of Alzheimer's patients Photo source: Journal of Medical Chemistry (2019) Doi: 10.1021/acs.jmedchem.9b01383 The researchers said that the structural modification of EFV (efavirenz), an anti AIDS drug, could increase its ability to activate specific enzymes, which can help remove cholesterol from the brain; cholesterol is believed to induce the aggregation of β - amyloid plaques, which is the main marker of Alzheimer's disease In the late 1990s, enzymes p45046a1 (CYP46A1) has been found to be important for breaking down and eliminating cholesterol in the brain Recently, researchers and their colleagues found that CYP46A1 can be activated by low dose EFV in mice, and then they conducted clinical trials of the drug in patients with mild cognitive impairment caused by Alzheimer's disease However, the therapeutic window of CYP46A1 activated by EFV seems very narrow in mice, and EFV can inhibit the activity of CYP46A1 in high dose In the current study, researchers aim to develop a potential compound to enhance the therapeutic efficacy of EFV while avoiding potential side effects in patients In the past 35 years, researchers have studied and understood the mechanism of P450 enzyme on metabolism of drugs, carcinogens and other biological molecules including cholesterol Five years ago, researcher Guengerich and colleagues found that EFV could activate CYP46A1 enzyme by binding to its allosteric site, which is different from cholesterol binding site However, at high doses, EFV can bind to allosteric sites and active sites, which can inhibit the function of the enzymes, because it can't tightly grasp cholesterol; in this study, researchers found that the metabolites of EFV can increase the activation level of CYP46A1, but can't inhibit the function of the enzymes at high concentrations; metabolism of EFV The products come from the compounds produced by the metabolism of drugs in the body In the future, researchers will continue to further study and reveal the molecular mechanism of the effective treatment of Alzheimer's disease by this HIV drug Original source: Natalia mast, Peter verwilst, Clayton J Wilkey, et al In vitro activation of cyclochrome P450 46a1 (CYP46A1) by efavirenz related compounds, Journal of Medical Chemistry (2019) Doi: 10.1021/acs.jmedchem.9b01383