title: Tranilast binds to aβ monomers and promotes aβ fibrillation.
abstract: 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 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 Aβ-tranilast interaction. These data suggest that AD may be a potential complication for tranilast usage in elderly patients.
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, NY 12180, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Connors
authors.forename: David J
authors.initials: DJ
authors.lastname: Rosenman
authors.forename: Dahabada H J
authors.initials: DH
authors.lastname: Lopes
authors.forename: Shivina
authors.initials: S
authors.lastname: Mittal
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.forename: Mirco
authors.initials: M
authors.lastname: Sorci
authors.forename: Georges
authors.initials: G
authors.lastname: Belfort
authors.forename: Angel
authors.initials: A
authors.lastname: Garcia
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D018926:Anti-Allergic Agents / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry; D052160:Benzothiazoles; D001665:Binding Sites; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D018625:Microscopy, Atomic Force; D062105:Molecular Docking Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013844:Thiazoles / Q000737:chemistry; D062367:ortho-Aminobenzoates / Q000737:chemistry*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D018926:Anti-Allergic Agents; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D062367:ortho-Aminobenzoates; C009462:thioflavin T; C012293:tranilast