Azapeptide Carbonyls: A New Class of 20S Proteasome Inhibitors

STEP Category: Undergraduate ResearchThe proteasome is a critical component of the ubiquitin-proteasome pathway (UPP) that is responsible for quality control of newly synthesized proteins in eukaryotic cells. The process of quality control includes regulation of the cell cycle and apoptosis in cells. This is important for various cancer treatments, including multiple myeloma (MM). Current proteasome drugs on the market such as Bortezomib and Carfilzomib have been quite effective. However, Bortezomib causes peripheral neuropathy due to cross-reactivity with HTrA2/Omi, an ATP depend serine protease and Carfilzomib causes adverse cardiovascular effects, but the exact process is unknown. Aza-peptide aldehydes and ketones, a new class of inhibitors, are structured to inhibit with a chemical warhead that consists of an aza-P1 amino acid and an α-carbonyl. In previous in vitro inhibition studies with the 20S proteasome, tripeptidyl aza-peptide aldehydes and ketones have expressed Ki values in the mid 10-50 μM range. With the 20S proteasome, tetrapeptides are known to have increased potency due to the presence of P4 residue. In our research, we mimic the backbone structure of the best substrate for the ß5 active site of the proteasome. The overall aim of this study is to synthesize tetrapeptidyl aza-peptide aldehydes and ketones for improved potency.The Ohio State University Second-year Transformational Experience Program (STEP)Academic Major: BiochemistryAcademic Major: Chemistr