Angewandte Chemie International Edition
Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For full article and contact information, see Angew. Chem. Int. Ed. 2003, 42 (24), 2758 - 2761
New Hope for Avoiding Protein Deposits?
Researchers develop a new potential agent against
amyloidoses caused by the misfolding of transthyretin
From Alzheimer's to mad cow disease, many pathologies stem from the aggregation of proteins in the brain or other tissues. The process of amyloidosis ultimately resulting in the formation of fibrous deposits results when misfolded proteins clump together into increasingly larger structures. One protein that tends to aggregate in this manner is transthyretin (TTR). American researchers have now developed a new agent that could be the basis for a new drug against TTR-induced amyloidoses.
TTR is made up of four identical subunits, and one of its functions is to transport the thyroid hormone thyroxine through the bloodstream. In its tetrameric form, TTR cannot form clumps. It is only when the tetramer dissociates into four individual monomers that it becomes aggregation prone. If the monomers change shape, they can aggregate into various larger structures including the dreaded amyloid fibers. . The non-fibrillar precusors and the fibrils are deposited in the peripheral nerves and in heart tissue apparently causing polyneuropathy and cardiomyopathy, as well as age-induced systemic amyloidosis.
Previous research studies carried out by Jeffrey W. Kelly and his group at the Scripps Research Institiute in California have shown that is possible to inhibit the formation of TTR amyloids by small molecule stabilization of the normal tetrameric Structure, thus preventing dissociation. The sought-after agent must fit exactly into the binding cavity of the tetramer, which normally takes up thyroxine. The class of compounds known as benzoxazoles has now become the focus of attention for the researchers. These compounds consist of an aromatic ring system composed of one six-membered carbon ring and one five-membered ring, which contains one nitrogen and one oxygen atom. The researchers attached an additional six-membered ring, which has two halogen atoms attached to it, to the tip of the five-membered ring. Screening of these types of benzoxazoles found a candidate that very selectively binds to TTR and prevents the formation of aggregates including fibrils, even under extreme conditions. The extraordinary success of this highly promising drug candidate stems, according to a structural analysis, from the alignment of two chlorine atoms. These dock precisely in two binding sites within the binding cavity of the tetramer that are normally occupied by two iodine atoms of the thyroid hormone thyroxine.