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, methods to site-specifically modify the EGCG D-ring with aminoPEGylated linkers are reported. The resultant molecules inhibit tau fibril seeding by 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.

Key words

(–)-epigallocatechin gallate - Alzheimer’s disease - tau disaggregation - nanoparticle conjugation - click reaction - TBTA

Publication History

Received: 16 April 2021

Accepted after revision: 17 May 2021

Accepted Manuscript online:
17 May 2021

Article published online:
08 June 2021

• References

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