Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis

Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis
Y SekijimaJeffery W Kelly

Abstract

Rate-limiting transthyretin (TTR) tetramer dissociation and monomer misfolding enable misassembly into numerous aggregate morphologies including amyloid, a process genetically linked to and thought to cause amyloid pathology. T119M TTR trans-suppressor subunit inclusion into tetramers otherwise composed of disease-associated subunits ameliorates human amyloidosis by increasing the tetramer dissociation barrier. Diflunisal binding to the 99% unoccupied L-thyroxine binding sites in TTR also increases the tetramer dissociation barrier; hence, we investigated the feasibility of using diflunisal for the treatment of human TTR amyloidosis using healthy volunteers. Diflunisal (125, 250 or 500 mg bid) was orally administered to groups of 10 subjects for 7 days to evaluate serum diflunisal concentration, diflunisal binding stoichiometry to TTR, and the extent of diflunisal imposed TTR kinetic stabilization against urea- and acid-mediated TTR denaturation in human serum. The rates of urea-mediated tetramer dissociation and acid-mediated aggregation as a function of diflunisal concentration were also evaluated in vitro, utilizing physiologically relevant concentrations identified by the above experiments. In the 250 mg bid group, 12 h aft...Continue Reading

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