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November 11, 2020 Wednesday 12:51:46 PM IST

Researchers show how to target a 'shape-shifting' protein in Alzheimer’s disease

Technology Inceptions

A team of researchers, led by the University of Cambridge, have identified a new mechanism of targeting amyloid-beta, a protein fragment that clumps together and kills healthy brain cells in people with Alzheimer’s disease. Working with colleagues from Imperial College London, Institut Pasteur, and the University of Florence, the researchers found that it is possible for a drug-like molecule to target amyloid-beta in its disordered state, reducing its ability to form the toxic clusters which are the hallmark of Alzheimer’s disease. The results, reported in the journal Science Advances, could form the basis of a new avenue for the development of potential treatments for the disease.

The approach developed by the researchers is based on the so-called disordered binding mechanism that they discovered, where small molecules form a disordered complex with the protein target, so that it is like the protein and the drug are ‘dancing’ with one another. The team also used high-performance computing methods to study the binding interaction at the atomic level. These intensive calculations allowed the researchers to ‘see’ how the binding was occurring at the atomic level, which is otherwise almost impossible to observe experimentally. Further tests were then carried out in nematode worms, which are often used as a model organism to study Alzheimer’s disease.

While this research is still preliminary in terms of clinical translation, it demonstrates that targeting the formation of these plaques by preventing the aggregation of amyloid-beta is a major therapeutic strategy. To date the mainstream approach has been to develop antibodies to bind to the aggregates, promoting their removal and interfering with their self-assembly.

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