TMC-95A, B, C, and D, Novel Proteasome Inhibitors Produced by Apiospora montagnei Sacc. TC 1093

Taxonomy, Production, Isolation, and Biological Activities

Abstract

In our course of screening for novel proteasome inhibitors, TMC-95A and its diastereomers, TMC-95B to D, were isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093. TMC-95A inhibited the chymotrypsin-like (ChT-L), trypsin-like (T-L), and peptidylglutamyl-peptide hydrolyzing (PGPH) activities of 20S proteasome with IC₅₀ values of 5.4 nM, 200 nM, and 60 nM, respectively. TMC-95B inhibited these activities to the same extent as TMC-95A, while the inhibitory activities of TMC-95C and D were 20 to 150 times weaker than that of TMC-95A and B. TMC-95A did not inhibit m-calpain, cathepsin L, and trypsin at 30 μM, suggesting its high selectivity for proteasome. Taxonomy of the producing strain is also described.