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Tranilast binds to a? monomers and promotes a? fibrillation.

ABSTRACT: The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer's disease (AD), in which amyloid ?-protein (A?) plays a key pathogenic role. We used solution NMR to determine that tranilast binds to A?40 monomers with ?300 ?M affinity. Remarkably, tranilast increases A?40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time. Tranilast likely promotes fibrillation by shifting A? monomer conformations to those capable of seed formation and fibril elongation. Molecular docking results qualitatively agree with NMR chemical shift perturbation, which together indicate that hydrophobic interactions are the major driving force of the A?-tranilast interaction. These data suggest that AD may be a potential complication for tranilast usage in elderly patients.

SUBMITTER: Connors CR

PROVIDER: S-EPMC4082028 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Tranilast binds to aβ monomers and promotes aβ fibrillation.

Connors Christopher R CR Rosenman David J DJ Lopes Dahabada H J DH Mittal Shivina S Bitan Gal G Sorci Mirco M Belfort Georges G Garcia Angel A Wang Chunyu C

Biochemistry 20130531 23

The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer's disease (AD), in which amyloid β-protein (Aβ) plays a key pathogenic role. We used solution NMR to determine that tranilast binds to Aβ40 monomers with ∼300 μM affinity. Remarkably, tranilast increases Aβ40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time. Tranilast likely promotes fibrillation by shifting Aβ monomer confo ...[more]

PMID: 23679559

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