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.

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

“…This reduced probability agrees with the reduced experimental 1 H- 15 N HSQC chemical shift perturbation of central region residues when certain small compounds are titrated into Aβ monomer sample. (435,436) …”

Palladium-catalyzed C–H bond carboxylation of acetanilides: an efficient usage of N,N-dimethyloxamic acid as the carboxylate source

“…19 We also carried out the reaction with diacetanilides, only the para-diacetanilides gave the desired product with 56% yield (17). Apart from the acetamido group, other directing amido moieties were tested in this ortho-carboxylation reaction, isopropyl groups gave the best results while the tert-butyl and phenyl moiety gave lower yields of the desired products (18)(19)(20).…”

The Role of NLRP3 Inflammasome in Alzheimer’s Disease and Potential Therapeutic Targets

“…On the contrary, some researchers have put forward different views. Connors et al found that Tranilast is likely to promote fibrillation by shifting Aβ monomer conformations to those capable of seed formation and fibril elongation, which indicates that elderly patients treated with Tranilast may increase the risk of AD ( Connors et al, 2013 ). The role of Tranilast in AD still needs further research, and whether Tranilast plays a role in AD by inhibiting the activation of NLRP3 inflammasome is also unknown.…”