Glycosidic scaffold bearing multiple galloyl moieties from pomegranate disrupts transthyretin amyloids

Transthyretin (TTR) amyloidosis involves TTR misfolding and aggregation, causing systemic organ dysfunction. Current therapies stabilize TTR tetramers or reduce TTR production but are less effective against existing amyloid deposits. Here, we identified 1,2,3,4,6-penta-<i>O</i>-galloyl-β-D-glucose (PGG), derived from pomegranate (<i>Punica granatum</i> L.) leaf-and-branch extracts (PGL), as a disruptor of preformed TTR amyloid fibrils. PGG disaggregated fibrils formed by V30M and wild-type (WT) TTR, which are linked to hereditary Transthyretin Amyloidosis (ATTR) (ATTRv) and ATTRwt, respectively. Structure-activity relationship studies showed galloyl moieties are essential. In <i>Caenorhabditis elegans</i>-expressing human TTR_81-127, PGG reduced TTR aggregation and extended both lifespan and healthspan. PGG selectively targeted TTR amyloids without affecting amyloid-β fibrils, indicating specificity. PGG disrupted TTR amyloid fibrils isolated from patient cardiac tissue. These findings suggest that PGG shows therapeutic potential for TTR amyloidosis by directly targeting and disrupting pathogenic amyloid aggregates.