The polyphenol EGCG directly targets intracellular amyloid-ß aggregates and promotes their lysosomal degradation.

The accumulation of amyloidogenic protein aggregates in neurons is a pathogenic hallmark of a large number of neurodegenerative diseases including Alzheimer's disease (AD). Small molecules targeting such structures and promoting their degradation may have therapeutic potential for the treatment of AD. Here, we searched for natural chemical compounds that decrease the abundance of stable, proteotoxic ß-sheet-rich amyloid-ß (Aß) aggregates in cells. We found that the polyphenol (-)-epigallocatechin gallate (EGCG) functions as a potent chemical aggregate degrader in SH-EP cells. We further demonstrate that a novel, fluorescently labeled EGCG derivative (EGC-dihydroxybenzoate (DHB)-Rhodamine) also shows cellular activity. It directly targets intracellular Aß42 aggregates and competes with EGCG for Aß42 aggregate binding in vitro. Mechanistic investigations indicated a lysosomal accumulation of Aß42 aggregates in SH-EP cells and showed that lysosomal cathepsin activity is critical for efficient EGCG-mediated aggregate clearance. In fact, EGCG treatment leads to an increased abundance of active cathepsin B isoforms and increased enzymatic activity in our SH-EP cell model. Our findings suggest that intracellular Aß42 aggregates are cleared through the endo-lysosomal system. We show that EGCG directly targets intracellular Aß42 aggregates and facilitates their lysosomal degradation. Small molecules, which bind to protein aggregates and increase their lysosomal degradation could have therapeutic potential for the treatment of amyloid diseases.

Exploring Cyclic Sulfamidate Building Blocks for the Synthesis of Sequence-Defined Macromolecules.

The preparation of sequence-defined macromolecules using cyclic sulfamidates on solid-phase is outlined. The challenges surrounding an AB+CD approach are described with focus on understanding the formation of ring-opened side products when using amide coupling reagents. To avoid undesired side product formation, a strategy of iterative ring-openings of cyclic sulfamidates on solid-phase is explored. Ring-opening on primary and secondary amines is successfully reported, generating both linear and branched chain growth. However, attempts to selectively cleave N-sulfate bearing sp3 -hybridized groups cannot be demonstrated, limiting the overall building block scope for this methodology. Consequently, the active ring-opening of cyclic sulfamidates on amine-functionalized oligo(amidoamine) backbones is successfully applied to produce sequence-defined, N-sulfated macromolecules.