Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors

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Abstract

Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration.

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Acknowledgements

We are grateful for the support of the NIH (DK 46335), the Skaggs Institute for Chemical Biology and the Lita Annenberg Hazen Foundation (JWK), as well as startup funding from the Indiana University School of Medicine, Department of Biochemistry and Molecular Biology (SMJ). David Mortenson is supported by a postdoctoral fellowship from the Hewitt Foundation. While tafamidis was discovered at The Scripps Research Institute, it was developed at FoldRx Pharmaceuticals by the substantial expertise

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