Molecular Tweezers Targeting Transthyretin Amyloidosis

摘要: Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation molecular mechanisms underlying misfolding pathogenic self-assembly, there is still no effective therapy for treatment these fatal disorders. Recently, “molecular tweezers”, CLR01, has been reported to inhibit self-assembly toxicity different amyloidogenic proteins vitro, including TTR, interfering with hydrophobic electrostatic interactions known play an important role aggregation process. In addition, CLR01 showed therapeutic effects animal models Alzheimer’s disease Parkinson’s disease. Here, we assessed ability modulate cell culture model. assays found that inhibited oligomerization conditioned medium alleviated TTR-induced neurotoxicity redirecting into formation innocuous assemblies. To determine whether was vivo, tested compound mice expressing V30M, model familial amyloidotic polyneuropathy, which recapitulates main pathological features human Immunohistochemical Western blot analyses significant decrease burden gastrointestinal tract peripheral nervous system treated concomitant reduction aggregate-induced endoplasmic reticulum stress response, protein oxidation, apoptosis. Taken together, our preclinical data suggest promising lead development innovative, disease-modifying amyloidosis.