Synthesis
DOI: 10.1055/a-1509-5904
special topic
Special Issue dedicated to Prof. Sarah Reisman, recipient of the 2019 Dr. Margaret Faul Women in Chemistry Award

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

Anton El Khoury
,
Paul M. Seidler
,
David S. Eisenberg
,
Funding provided by the Donald J. and Jane M. Cram Endowment (to P.H.), the NIH (R56 AG070895 to D.E.), and the HHMI (D.E.).


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.

Supporting Information



Publication History

Received: 16 April 2021

Accepted after revision: 17 May 2021

Publication Date:
17 May 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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