Inhibition of yeast 20S proteasome by biaryl- and biaryl ether-cross-bridged tripeptide derivatives as TMC-95A analogs

摘要

The proteasome is the primary component of the intracellular protein degradation pathway, which acts as an effective machinery for regulating vital cell processes. It is a multicatalytic protease complex containing various active sites within its central core, i.e. the 20S proteasome whose barrel-shaped structure consists of four rings of subunits tightly packed in a α_(1-7)β_(1-7)β_(1-7)α_(1-7) geometry. In the eukaryotic 20S proteasome the three subunits β1, β2 and β5 are autolytically processed to generate the enzyme active sites. These exhibit a certain degree of substrate specificity with the β1 subunits responsible for post-glutamyl peptide hydrolyzing caspase-like (PGPH) activity, the β2 subunits for trypsin-like (TL) and the β5 subunits for chymotrypsin-like (CL) activity. Because of the promising therapeutic potential of proteasome inhibition, much attention has been paid to the development of synthetic and to the discovery of natural ligands. Besides the synthetic inhibitors derived from 2-aminobenzylstatine, only the secondary metabolites TMC-95A and the diastereoisomers TMC-95B/C/D from Apiospora montagnei were recognized as potent reversible inhibitors of human 20S proteasome. The TMC-95 compounds are cyclic tripeptide derivatives constrained into a 17-membered ring structure by an endocyclic biaryl system derived from tyrosine and a highly oxidized tryptophan side chain (Fig. 1, compound 1). Its non-covalent binding to the β1, β2 and β5 active sites of yeast 20S proteasome has been characterized by X-ray crystallographic analysis.