Catalytic Synthesis of PEGylated EGCG Conjugates that Disaggregate Alzheimer’s Tau

Abstract

The naturally occurring flavonoid (–)-epigallocatechin gallate (EGCG) is a potent disaggregant of tau fibrils. Guided by the recent cryo-electron microscopy (cryoEM) structure of EGCG bound to fibrils of tau derived from an Alzheimer’s brain donor, we report methods to site-specifically modify the EGCG D-ring with aminoPEGylated linkers. The resultant molecules inhibit tau fibril seeding in Alzheimer’s brain extracts. Formulations of aminoPEGylated EGCG conjugated to the (quasi)-brain-penetrant nanoparticle Ferumoxytol inhibit seeding by AD-tau with linker length affecting activity. The protecting group free catalytic cycloaddition of amino azides to mono propargylated EGCG described here provides a blueprint for access to stable nanoparticulate forms of EGCG potentially useful as therapeutics to eliminate Alzheimer’s-related tau tangles.