Needle-in-a-haystack search for new drugs for brain diseases

The scientific equivalent of searching for a needle in a haystack has paid off for researchers seeking leads for potential new medicines for Parkinson’s Disease and other brain disorders. Chronicled in a new episode in the American Chemical Society’s award-winning “Global Challenges/Chemistry Solutions” podcast series, now online, it involved sifting through almost 390,000 chemical compounds. Finally, they located one that blocks formation of cholesterol in the brain.

Aleksey G. Kazantsev, Ph.D., and colleagues at MassGeneral Institute for Neurodegenerative Disease, previously discovered that blocking cholesterol formation in the brain could protect against some of the damage caused by chronic brain disorders like Parkinson’s disease. Several other studies have suggested that too much cholesterol may kill brain cells in similar neurodegenerative diseases. So they launched a search for a so-called “small molecules” — substances ideal for developing into medicines — capable of blocking formation of cholesterol.

He reported the discovery of a small molecule that blocks the activity of a key protein involved in cholesterol production in the journal, ACS Chemical Biology. It successfully lowered cholesterol levels in isolated nerve cells and brain slices from mice. If the molecule proves to be a good target for developing new drugs, Kazabtse says, “it could have a broader application in other neurological conditions, such as Alzheimer’s disease, for which modulation of cholesterol and other associated metabolic pathways might be of therapeutic benefit.”