20S Proteasome Inhibition: Designing Noncovalent Linear Peptide Mimics of the Natural Product TMC‐95A

Abstract

Stop the shredder: The 20S proteasome maintains homeostasis and regulates important intracellular processes by subjecting most intracellular proteins to endoproteolytic cleavage. This complex hydrolysis machinery has received considerable attention for the treatment of many diseases, including cancer. We report a new set of noncovalent peptide mimics based on TMC-95A and our rational approach to inhibitor optimization using both crystallographic and kinetic studies.