PROTACs - A novel strategy for the treatment of Alzheimer disease

The presence of β-amyloid plaques and neurofibrillary tangles of tau are two main pathological hallmarks of Alzheimer disease (AD).

Lowered efficiency of degradation pathways, such as the Ubiquitin Proteasome System, further exacerbates the aberrant protein accumulation.

Proteolysis-Targeting Chimeras (PROTACs) are hetero-bifunctional molecules that can bring the E3 ligase into the vicinity of the protein of interest, leading to protein ubiquitination, followed by proteasomal degradation.

We aim to perform intensive research to promote the development of small-molecule PROTACs for AD treatment, especially for tau degradation.Published small-molecule tau-targeting PROTACs are using ligands binding to two common E3 ligases: von Hippel-Lindau protein and cereblon. But they are distributed in all tissues and target many proteins, not only tau.

To develop more specific and potent PROTACs, we will first explore tau-targeting E3 ligases in human AD brains, choose E3 candidates, and develop novel ligands binding to tau/E3 ligases. Then we will use different linkers to combine ligands and design new PROTACs.

Protein-binding affinities and tau-reducing effects in vitro will be evaluated with follow-up structure-based optimization.

The most potent PROTACs with the least off-target effects will move on to in vivo study.This project will increase our understanding of tau-targeting E3 ligases in AD brains and bring breakthrough medicines for AD and other neurodegenerative diseases.