Repurposing of Agrochemicals as ATTRv Amyloidosis Inhibitors.

Transthyretin (TTR), a plasma protein, undergoes transformation into amyloid fibers, leading to ATTRv amyloidosis, a disease characterized by organ deposition of TTR amyloid fibrils and subsequent organ failure. Developing compounds that bind and kinetically stabilize TTR is a crucial strategy in the treatment of ATTRv amyloidosis. In this study, we narrowed 651 pesticide-related compounds down to 14 possible TTR binders through in silico screening; subsequent in vitro analysis revealed that 7 of them exhibited amyloid fibril formation inhibition activity. The herbicide components bromoxynil () and ioxynil () showed especially high ligand efficiency and efficiently inhibited amyloid fibril formation of amyloidogenic V30M-TTR. Additionally, aclonifen () exhibited moderate fibril formation inhibition activity, but showed selective binding to TTR comparable to that of tafamidis. While improvement is needed to the selective TTR-binding or fibril formation inhibition activity, the compounds identified herein are promising lead candidates for the development of ATTRv amyloidosis therapeutics.