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Researchers Develop Molecular Glue to Reduce Activity of Hard-to-Target Proteins
University of Toronto and University of British Columbia scientists created a molecular glue that binds to one protein and alters its shape to reduce activity of a second protein. The approach was tested on ACAA1, a protein involved in fat processing, using X-ray imaging at the Canadian Light Source.
May 16, 12:53 PM·1m read1 source
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Scientists from the University of British Columbia and University of Toronto developed a molecular glue that reduces the activity of proteins previously considered difficult to target with conventional drugs. The glue, called CLEO4-88, binds to one protein and induces a shape change that allows it to interact with a second protein.
Researchers observed this effect on ACAA1, a protein involved in how cells process fats.
The team used high-powered X-rays at the Canadian Light Source to confirm that the glue lowered ACAA1 activity without destroying the protein. University of Toronto researcher Dr. Chetan Chana said the method differs from earlier molecular glues that mark proteins for destruction.
Chana noted that many disease-driving proteins lack obvious drug-binding sites or acquire mutations that make them resistant to current treatments. The new glue avoids complete protein removal, which researchers said could limit unwanted side effects.
The findings were published in Nature Chemical Biology.
Researchers said the approach may help target proteins linked to cancers and metabolic disorders that remain beyond the reach of existing drugs. The work was conducted at the Canadian Light Source, a national research facility at the University of Saskatchewan on Treaty 6 Territory and the Homeland of the Métis.
