Fighting Alzheimer's by cutting off amyloid at its source

3D brain against purple background
A drug that binds to a precursor protein instead of gamma secretase itself is designed to prevent brain plaques without toxic side effects in Alzheimer's disease. (alex-mit/iStock/Getty Images Plus)

The abnormal clumping of the protein amyloid beta in the brain is a hallmark of Alzheimer’s disease, but efforts to prevent the phenomenon with drugs have so far proven disappointing. Researchers at Rensselaer Polytechnic Institute believe they’ve hit upon a better way to prevent brain plaques, and they’re doing it by blocking the enzyme gamma secretase from making amyloids.

The idea of blocking gamma secretase isn’t new—several pharma companies tried and failed to develop drugs to inhibit the enzyme several years ago. But instead of targeting gamma secretase itself, the Rensselaer Polytechnic team found a drug that can block a site on a precursor protein that the enzyme needs to bind to in order to become amyloid. They described the compound in the journal Chemical Communications.

"Historically, drug trials for gamma secretase inhibitors failed because traditional enzyme inhibitors have severe side effects. They stopped all of the normal functions of gamma secretase," said Chunyu Wang, M.D., Ph.D., a professor at Rensselaer Polytechnic Institute, in a statement. "Our compound binds to the cleavage site of the precursor protein instead of the enzyme itself, which may avoid many problems associated with traditional enzyme inhibitors."

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Wang used computer modeling to search for a drug that could inhibit the activity of gamma secretase in amyloid production without affecting other vital functions the enzyme performs. He screened tens of millions of compounds starting in 2018 until he hit upon a “covalent inhibitor,” or a drug that forms a permanent chemical bond with its target.

The drug candidate, which he dubbed C1, blocks amyloid production in test tubes and cell culture, the Rensselaer Polytechnic researchers reported.

RELATED: Drug 'chaperone' fends off Alzheimer's in mice by preventing toxic protein clumping

Despite the past failures of gamma secretase inhibitors, amyloid remains a target of interest in Alzheimer’s drug development. Biogen investors are eagerly awaiting the FDA filing of Biogen’s aducanumab, an amyloid-targeted drug that the company resurrected after initially questioning its efficacy in a phase 3 trial. Analysts are now expecting Biogen to file for approval within weeks.

Several startups and academic groups are pursuing a variety of tactics for targeting brain plaques, including T3D Therapeutics, which raised $15 million in a series B funding last year to develop Alzheimer’s drugs that work by correcting faulty glucose and fat metabolism. Temple University researchers said last month that they developed a drug that boosts levels of a molecule called VPS35, which works in brain cells to stabilize or remove harmful proteins like amyloid before they can form plaques.

Wang, a member of Rensselaer Polytechnic’s Center for Biotechnology and Interdisciplinary Studies, worked with several institutions to discover C1, including the Icahn School of Medicine at Mount Sinai at New York University. He’s currently seeking a patent on the research, according to the statement.

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