Artificial proteases toward catalytic drugs for amyloid diseases

Abstract

We have proposed catalytic drugs based on artificial proteases as a new paradigm in drug design. Catalytic cleavage of the backbone of a protein related to a disease may effect a cure. Catalytic drugs can be designed even for proteins lacking active sites. Soluble oligomers of amyloid β-42 peptide (Aβ42) are implicated as the primary toxic species in amyloid diseases such as Alzheimer's disease (AD). Cleavage of Aβ42 included in an oligomer may provide a novel method for reduction of Aβ42 oligomers, offering a new therapeutic option. The Co(III) complex of cyclen was used as the catalytic center for peptide hydrolysis. Binding sites of the catalysts that recognize the target were searched by using various chemical libraries. Four compounds were selected as cleavage agents for the oligomers of Aβ42. After reaction with the cleavage agents for 36 h at 37 °C and pH 7.50, up to 30 mol % of Aβ42 (4.0 μM) was cleaved, although the target oligomers existed as transient species. Considerable activity was manifested at the concentrations of the agents as low as 100 nM.