All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients. (Agencies)
The new structure-based approach to drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.
The University of California, Los Angeles researchers report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer's and other degenerative diseases.
A number of non-structure-based screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils.
Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils.
In addition, several dyes have been found to reduce amyloid's toxic effects, although significant side effects prevent them from being used as drugs.
Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, researchers conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.
Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein's toxic effects, which in the past has proved very difficult.
Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect. While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein's toxicity and to increase the stability of amyloid fibrils.
The finding lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer's symptoms.
The researchers’ hypothesis that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.
All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.