Structure-Activity-Relationship and binding site elucidation for N-acyl-fluspirilene 20s proteasome activation and its potential therapeutic potential for neurodegenerative diseases 3 views

Neurodegenerative diseases (NDs) arise from the breakdown of the well-controlled cycle of protein synthesis and degradation, also known as proteostasis. The proteasome system is critical for degrading proteins in both ubiquitin-dependent and ubiquitin-independent manners. The latter, predominantly by the 20S proteasome, is essential in degrading proteins that lack a stable three-dimensional structure, including intrinsically disordered proteins (IDPs). When protein synthesis outpaces degradation, IDPs aggregate and form toxic oligomers that may inhibit the 20S proteasome, further exacerbating ND progression. Our lab hypothesizes that enhancing proteasome-mediated protein degradation may reduce pathogenic accumulation of IDPs, providing a novel therapeutic strategy for neurodegenerative diseases. The dissertation herein aims to understand the necessary components for N-acyl-fluspirilene’s ability to enhance 20S proteasome activity and overcome oligomer-induced 20S-inhibition. The second portion of this project focuses on developing an in vitro, high-throughput assay to identify molecules that degrade ⍺-synuclein, an IDP responsible for Parkinson’s Disease. Finally, the binding site for 20S enhancement was elucidated by using a covalent binder of the N-acyl-fluspirilene family.

PHD (Doctor of Philosophy)

Neurodegeneration; Medicinal Chemistry; 20S Proteasome; Assay Development

English

2026-04-30