Substrate-related peptidyl-aldehyde inhibitors of the proteolytic activity of the multicatalytic proteinase complex

摘要

The present invention provides novel peptidylaldehyde inhibitors of proteolysis mediated by the multicatalytic proteinase complex (MPC) or proteasome. The inhibitors have the general formulaZ-P4-P3-P2-P1-CHO(I)wherein P1 is selected from among branched chain amino acids occurring naturally in proteins and norleucine; P2 is selected from among non-polar L-amino acids; P3 is proline or hydroxyproline; P4 is selected from among non-polar L-amino acids; CHO is an aldehyde replacement for the COOH group on the P1 amino acid; and Z is an amino blocking group attached to the NH2 group on the P4 amino acid. The amino blocking group Z may be chosen from among benzyloxycarbonyl, benzoylglycine, tertiary butoxycarbonyl, acetylbenzyloxycarbonyl, benzoylglycine, tertiary butoxycarbonyl, acetyl or other NH2 blocking groups known in protein and peptide chemistry. The inhibitors inhibit intracellular protein degradation in cells, as well as inhibit mitosis and proliferation of dividing cell populations. As such, the inhibitors have use in inhibiting undesired intracellular proteolysis and mitosis in excessively proliferating cells.