Glycosidic scaffold bearing multiple galloyl moieties from pomegranate disrupts transthyretin amyloids

TL;DR

A compound from pomegranate can break down harmful protein clumps linked to a type of amyloidosis, potentially offering a new treatment.

Contribution

PGG, a pomegranate-derived compound, disrupts TTR amyloid fibrils and shows therapeutic potential for TTR amyloidosis.

Findings

PGG disrupts both V30M and wild-type TTR amyloid fibrils.

PGG extends lifespan and reduces aggregation in a C. elegans TTR model.

PGG selectively targets TTR amyloids without affecting amyloid-β fibrils.

Abstract

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-O-galloyl-β-D-glucose (PGG), derived from pomegranate (Punica granatum 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 Caenorhabditis elegans-expressing human TTR81-127, 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.

•1,2,3,4,6-penta-O-galloyl-β-glucose (PGG) disrupts TTR but not Aβ amyloid fibrils•Galloyl groups are essential for PGG’s amyloid-disrupting activity•PGG reduces TTR aggregates and extends lifespan in a C. elegans TTR model•PGG disaggregates amyloid fibrils derived from ATTRv patient tissues

1,2,3,4,6-penta-O-galloyl-β-glucose (PGG) disrupts TTR but not Aβ amyloid fibrils

Galloyl groups are essential for PGG’s amyloid-disrupting activity

PGG reduces TTR aggregates and extends lifespan in a C. elegans TTR model

PGG disaggregates amyloid fibrils derived from ATTRv patient tissues

Health sciences; Natural product chemistry; Biological sciences; Natural product biochemistry

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