A new screening system can identify compounds that might inhibit huntingtin protein aggregation in Huntington's disease (HD). Initial testing points to the benzothiazole family of compounds as potential therapies for the disease, according to a report in the current early online edition of Proceedings of the National Academy of Sciences.
Erich Wanker, Volker Heiser, and colleagues at the Max Planck Institute for Molecular Genetics in Berlin, and Merck in Darmstadt, Germany, report that they have developed a filter retardation assay based on the fact that polyQ-containing protein aggregates (of which huntingtin is one) are resistant to denaturing by sodium dodecyl sulphate (SDS). The aggregates will be retained on a cellulose acetate filter, whereas SDS-soluble proteins are not. Taking advantage of these properties, the researchers created a medium-throughput screening system that could evaluate the poly-Q aggregate-inhibiting properties of hundreds of chemical agents at once.
Among the almost 200,000 compounds screened, the researchers identified about 300 that inhibit poly-Q huntingtin aggregation. Cluster analysis showed that 25 were benzothiazole derivatives. Other benzothiazole derivatives (notably riluzole) have had some beneficial effects in cerebrovascular and neurodegenerative disorders such as HD and amyotrophic lateral sclerosis (Lou Gehrig's disease).
In cell-cultures studies the most potent inhibitors proved toxic to cells. One of the less potent compounds, with a structure similar to riluzole, significantly inhibited huntingtin aggregation in the cultures without toxicity. It remains to be determined how these benzothiazole derivatives inhibit aggregate formation, though the authors suggest that they probably interact directly with mutant huntingtin, rather indirectly via some other pathway.
Wanker et al. are optimistic about the utility of their method because, they write, the system allows for screening very large compound libraries at once at low cost.—Hakon Heimer
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- Heiser V, Engemann S, Bröcker W, Dunkel I, Boeddrich A, Waelter S, Nordhoff E, Lurz R, Schugardt N, Rautenberg S, Herhaus C, Barnickel G, Böttcher H, Lehrach H, Wanker EE. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16400-6. PubMed.