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Soluble oligomers of human islet amyloid polypeptide (h-IAPP) are implicated in the initiation of beta-cell apoptosis leading to type 2 diabetes mellitus (T2DM). Cleavage of the h-IAPP included in an oligomer may provide a novel method for reducing the level of h-IAPP oligomers, offering a new therapeutic option for T2DM. From the combinatorial library of triazine derivatives prepared by exploiting the Co(III) complex of cyclen as the cleavage center for peptide bonds, eight compounds were selected as cleavage agents for oligomers of h-IAPP. After reaction with cleavage agents for 36 h at 37 degrees C and pH 7.50, up to 20 mol% of h-IAPP (initial concentration: 4.0 microM) was cleaved, although the target oligomers existed as transient species. Considerable activity was manifested at agent concentrations as low as 100 nM.

This tutorial review describes the evolution of peptide-hydrolyzing metal catalysts towards artificial metalloproteases cleaving target proteins selectively. The catalytic cleavage of the backbone of a protein related to a disease may effect a cure. In particular, a new therapeutic option for amyloid diseases such as Alzheimer's disease, diabetes and Parkinson's disease has been presented. The new paradigm of drug design based on artificial metalloproteases should be of interest to researchers in the areas of biomimetic chemistry, as well as medicinal chemistry.