Small molecule amyloid disrupters demonstrate therapeutic efficacy for transthyretin amyloidosis

Abstract

The escalating global trend of an aging population has brought attention to the rising prevalence of late-onset amyloid disorders. Among them, transthyretin amyloidosis (ATTR) presents a growing medical challenge, particularly in the elderly. Herein we report the first therapeutic efficacy of a small molecule catalyst that selectively disrupts and neutralizes the intrinsic toxicity of aggregated transthyretin via photooxygenation. The established conditions demonstrated improved motility defect severity within the ATTR model C. elegans, the singularly acknowledged experimental modality recapitulating the clinical manifestation of ATTR. The approach was applicable to photooxygenation of cardiac amyloid fibrils extracted from an ATTR patient. In silico analysis provided a molecular rationale for the reactivity performance of the optimized catalyst, key to bridging the gap between in vivo applicability and therapeutic efficacy.