Researchers at Canadian Light Source have discovered a molecular glue that can bind two proteins together and inactivate one, a discovery that could help scientists develop new ways to treat diseases caused by overactive proteins.
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Up to 85% of disease-causing proteins remain beyond conventional drugs because they have hard-to-target structures.
Targeting difficult proteins
Proteins regulate many of the body’s cellular functions, from immune responses to cell division. When proteins become overactive or fail to function properly, they can contribute disease.
Scientists from University of British Columbia discovered a new method for designing drugs that bind more strongly to these proteins and block their disease-causing activity. Their research focused on treating a cancer protein that fuels the growth of most prostate cancers and showed that proteins previously thought to be untreatable, such as the prostate cancer protein, could be targeted by drugs.
Using molecular glue to target proteins
University of Toronto researcher Dr. Chetan Chana, says many disease-causing proteins are difficult to target because they lack obvious drug-binding pockets or acquire mutations.
A molecular glue binds two proteins together and signals one for destruction.
“Molecular adhesives are difficult to design rationally and have been frankly discovered to date,” Chana said. “So it has been difficult to rationally design a molecule that can be used to destroy proteins, let alone modulate the activity of a protein, and that makes them resistant to current therapies.”
Chana’s research team discovered a molecular glue, CLEO4-88, that can inactivate proteins instead of destroying them. This discovery could expand the way scientists develop future treatments for diseases.
“CLEO4-88 works differently by binding to only one protein and causing a conformational change that allows it to bind to a second protein,” added Chana.
Using high-powered X-rays at Canadian light sourcethe researchers noticed that the molecular glue reduced the activity of ACAA1, a protein involved in how cells process fats.
“Many proteins perform multiple functions within cells, meaning that their complete destruction could interfere with healthy biological processes and create unwanted side effects,” Chana said. “Selectively slowing or attenuating harmful protein activity may provide a more balanced therapeutic approach to certain diseases.”
Potential future applications could help target proteins that conventional drugs still struggle to reach, including proteins linked to cancers and metabolic disorders.
Research was conducted at the Canadian Light Source, a national research facility at the University of Saskatchewan, on Treaty Territory 6 and Métis Homeland. The findings were published in the journal Nature Chemical Biology.
