ABSTRACT
Fibril formation and accumulation in peripheral organs is a common feature of both senile systemic amyloidosis and familial amyloid polyneuropathy. The causative agent of such fibrils appears to be the protein transthyretin (TTR). Under physiological conditions, TTR is a stable tetramer, therefore, unit dissociation and subsequent conformational changes of the monomers are necessary events in producing TTR fibrils. Standard chemical procedures for altering salicylic functions, and solution and solid phase peptide synthesis protocols for the conjugation with amino acids were used. Time savings and automation of kinetic monitoring of fibril formation are the key features of the method. Both series of iodinated and non-iodinated compounds were screened as TTR amyloid inhibitors at different concentrations to gain time course curves from which initial rates of fibril formation were calculated. The data provided clearly shows that the introduction of a iodine atom in the adjacent position of the phenol group in any of the diflunisal analogues investigated greatly enhaces the inhibitory activity.
