Chemical tools targeting proteases: design, synthesis, and biological evaluation for therapeutic use

Abstract

This PhD thesis focuses on the design, synthesis, and evaluation of chemical compounds that inhibit proteases and degrade proteins essential for cellular recycling. It is divided into two parts: the first explores protein degradation in lysosomes, while the second examines the Ubiquitin-Proteasome System (UPS). The first part investigates cysteine proteases, their inhibition, and the use of activity-based probes (ABPs). Enzyme inhibitors are developed and converted into probes applied to cellular models related to neuroinflammation. The second part introduces the UPS, its role in protein degradation, and its therapeutic potential. Proteasome inhibitors are designed and synthesized, and PROTACs—molecules that target specific proteins for degradation—are explored. A case study investigates their application in signaling regulation in plants. This research opens new avenues for disease treatment and biotechnology.