A structure-based rational drug design approach has produced new compounds capable of inhibiting the formation of insoluble protein fibrils found in certain genetic diseases. The research focused on transthyretin (TTR), a protein that can form amyloid fibers that damage neural or cardiac tissue. Though TTR-associated amyloid diseases are thought to be relatively rare, the insoluble structures are biophysically similar to the fibrils formed in Alzheimer's disease. In the new work, the researchers used x-ray crystallography to develop detailed three-dimensional structures of TTR bound to compounds that have been shown to inhibit TTR amyloidosis. Using this structural information, the team then synthesized new small molecules that they predicted would act more specifically on TTR, without the side effects of current drug treatments. Subsequent co-crystallization of TTR bound to the newly synthesized compounds verified the theoretical predictions. “We're…trying to use a similar approach for Alzheimer's disease, but that of course requires structural information, and that's what everyone is trying to get right now,” says senior author James Sacchetini. The findings are reported in Nature Structural Biology (7, 312–321, 2000) and the J. Am. Chem. Soc. 122, 2178–2192, 2000)