Abstract and Commentary
Synopsis: This strategy yields potent inhibitors of A-beta aggregation and could lead to therapeutics for Alzheimer’s disease and other forms of neurodegeneration.
Source: Gestwicki J, et al. Harnessing Chaperones to Generate Small-Molecule Inhibitors of Amyloid Aggregation. Science. 2004;306:865-871.
Aggregation of the a peptide generated by the proteolytic cleavage of the amyloid precursor protein (APP) is thought to play a key role in the pathogenesis of Alzheimer’s disease. Genetic studies have shown that mutations in APP, as well as genes involved in APP processing are implicated in disease development. It is possible that drugs which inhibit A aggregation may therefore be useful in its treatment. In the present study, Gestwicki and colleagues developed a novel approach. They envisioned a Trojan Horse strategy in which a small bifunctional molecule would gain access to the relevant biologic compartment and bind tightly to a chaperone, and thereby, gain steric bulk needed to disrupt a protein-protein interaction. To test this hypothesis Gestwicki et al synthesized small molecules that increased their steric bulk by binding to chaperones, but also had a moiety available for interaction with A. The entity which they utilized to bind A was Congo Red, and the compound which they used to bind to a chaperone was an enzyme inhibitor, FK506, which binds to the FKBP chaperone family. They developed a large number of compounds, these compounds showed a markedly increased potency in their ability to block beta-amyloid aggregation. They were effective at 50 nM, as opposed to other compounds which require a 10 nM range. They then showed that these compounds were effective in blocking toxicity to cell lines in vitro.
This finding raises the possibility that it may be possible to develop new small molecule inhibitors of A aggregation. This might be a novel therapeutic approach for the treatment of Alzheimer’s disease. The one caveat is they have not yet shown that these compounds are going to be effective in animal studies. — M. Flint Beal
Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.