Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants.

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Miller SR, Sekijima Y, Kelly JW

Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants.

Lab Invest. 2004 May;84(5):545-52.

PubMed ID

14968122 [ View in PubMed

]

Abstract

Transthyretin (TTR) tetramer dissociation and misfolding affords a monomeric amyloidogenic intermediate that misassembles into aggregates including amyloid fibrils. Amyloidogenesis of wild-type (WT) TTR causes senile systemic amyloidosis (SSA), whereas fibril formation from one of the more than 80 TTR variants leads to familial amyloidosis, typically with earlier onset than SSA. Several nonsteroidal anti-inflammatory drugs (NSAIDs) stabilize the native tetramer, strongly inhibiting TTR amyloid fibril formation in vitro. Structure-based designed NSAID analogs are even more potent amyloid inhibitors. The effectiveness of several NSAIDs, including diclofenac, diflunisal, and flufenamic acid, as well as the diclofenac analog, 2-[(3,5-dichlorophenyl) amino] benzoic acid (inhibitor 1), has been demonstrated against WT TTR amyloidogenesis. Herein, the efficacy of these compounds at preventing acid-induced fibril formation and urea-induced tetramer dissociation of the most common disease-associated TTR variants (V30M, V122I, T60A, L58H, and I84S) was evaluated. Homotetramers of these variants were employed for the studies within, realizing that the tetramers in compound heterozygote patients are normally composed of a mixture of WT and variant subunits. The most common familial TTR variants were stabilized substantially by flufenamic acid and inhibitor 1, and to a lesser extent by diflunisal, against acid-mediated fibril formation and chaotrope denaturation, suggesting that this chemotherapeutic option is viable for patients with familial transthyretin amyloidosis.

DrugBank Data that Cites this Article

Drug Carriers

Drug	Carrier	Kind	Organism	Pharmacological Action	Actions
Diclofenac	Transthyretin	Protein	Humans	Unknown	Not Available	Details
Diflunisal	Transthyretin	Protein	Humans	Unknown	Not Available	Details
Flufenamic acid	Transthyretin	Protein	Humans	Unknown	Not Available	Details