10.1042/BJ20100383
The research focuses on the development and characterization of a new series of non-covalent proteasome inhibitors with high potency and selectivity for the 20S β5-subunit. These inhibitors are derived from a capped tri-peptide and were identified through high-throughput screening of a large compound library. The compounds are selective for the β5 (chymotrypsin-like) site over the β1 (caspase-like) and β2 (trypsin-like) sites of the 20S core particle of the proteasome. The study involves the synthesis of these compounds, their optimization guided by X-ray crystallography, and their evaluation in various biochemical and cellular assays. Key chemicals involved in this research include the di-peptide and tri-peptide inhibitors themselves, bortezomib (a known proteasome inhibitor used for comparison), and various substrates such as Ac-WLA-AMC, Ac-ANW-AMC, and Suc-LLVY-AMC used to measure proteasome activity. The research also utilizes reagents like HBTU for peptide coupling and employs techniques such as X-ray crystallography to determine the binding mode of the inhibitors. These non-covalent inhibitors show significant potential for inhibiting cancer cell proliferation and modulating proteasome-dependent cellular processes, with some compounds achieving low nanomolar IC50 values in vitro and in cells.
