4 '-iodo-4 '-deoxydoxorubicin disrupts the fibrillar structure of transthyretin amyloid

Transthyretin (TTR) is a tetrameric protein synthesized mainly by the liver and the choroid plexus, from where it is secreted into the plasma and the cerebrospinal fluid, respectively, Some forms of polyneuropathy, vitreopath y, and cardiomyopathy are caused by the deposition of normal and/or mutant TTR molecules in the form of amyloid fibrils. Familial amyloidotic polyneur opathy is the most common form of TTR amyloidosis related to the V30M varia nt. It is still unclear the process by which soluble proteins deposit as am yloid. The treatment of amyloid-related disorders might attempt the stabili zation of the soluble protein precursor to retard or inhibit its deposition as amyloid; or aim at the resorption of the deposited amyloid. The anthrac ycline 4'-iodo-4'-deoxydoxorubicin (I-DOX) has been shown to reduce the amy loid load in immunoglobulin light-chain amyloidosis, We investigated 1) whe ther I-DOX has affinity for TTR amyloid in tissues, 2) determined the I-DOX binding constants to TTR synthetic fibrils, and 3) determined the nature o f the effect of I-DOX on TTR fibrils. We report that 1) I-DOX co-localizes with amyloid deposits in tissue sections of patients with familial amyloido tic polyneuropathy; 2) I-DOX strongly interacts with TTR amyloid fibrils an d presents two binding sites with k(d) of 1.5 x 10(-11) mol/L and 5.6 x 10( -10) mol/L, respectively; and 3) I-DOX disrupts the fibrillar structure of TTR amyloid into amorphous material, as assessed by electron microscopy but does not solubilize the fibrils as confirmed by filter assays. These data support the hypothesis that I-DOX and less toxic derivatives can prove effi cient in, the treatment of TTR-related amyloidosis.