Researchers Show How to Target a Shape-Shifting Protein in Alzheimer's Disease

A study in Science Advances suggests it is possible to design drugs that can target the shape-shifting amyloid-beta protein involved in Alzheimer's disease, reports Medical Xpress . "By revealing a new drug-binding mechanism, we have extended traditional drug discovery approaches based on the optimization of the binding affinity to include disordered proteins," said Professor Michele Vendruscolo at the University of Cambridge. The approach is based on the disordered binding mechanism, in which small molecules cohere into a disordered complex with the protein target. Experimentation led to a mathematical model of how the drug inhibited the aggregation of amyloid-beta at the microscopic level, and later the atomic level. "In contrast to the traditional lock-and-key binding mechanism, in which a drug tightly interacts with its target in a specific conformation, we found that both the small molecule and the disordered protein remained extremely dynamic, and that the small molecule interacted with many parts of the protein," said Schmidt Science Fellow Gabriella Heller. She also observed that "disordered proteins are also involved in a wide range of diseases including cancer and cardiovascular disease. We hope that we can extend this understanding to also target disordered proteins involved in other diseases."