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| Small molecules (green and red) binding to amyloid fibrils--Courtesy of Lin Jiang, David Eisenberg/UCLA, Howard Hughes Medical Institute |
Scientists have used a structure-based drug design approach to generate therapeutic agents for a number of infectious and metabolic diseases in the past. Now, a team of scientists at the University of California, Los Angeles, is for the first time using the technique to find new compounds designed to treat neurodegenerative disorders like Alzheimer's, Parkinson's and Lou Gehrig's diseases.
Structure-based drug design focuses on the physical structure of a targeted protein to help identify compounds that will interact with it.
The investigators set out to identify both natural and synthetic compounds that prevent the characteristic clumping and toxicity of amyloid fibrils--harmful, elongated, ropelike protein molecules--found in the brains of patients with neurodegenerative diseases. The team screened 18,000 compounds for those most likely to bind tightly and effectively to the amyloid-beta protein.
The most promising compounds were tested for their effectiveness at blocking the buildup of amyloid beta and their ability to protect mammalian cells grown in culture from the protein's toxic effects, which has been challenging in the past. The researchers identified 8 compounds and three compound derivatives that were able to reduce the toxicity of amyloid beta while at the same time increasing the stability of amyloid fibrils.
The findings, published in the new open-access journal eLife, support growing evidence that oligomers--smaller assemblies of amyloid beta--and not the fibrils themselves, are the toxic agents responsible for Alzheimer's symptoms.
- here's the press release
- and the research article