Cleavage agents for soluble oligomers of human islet amyloid polypeptide

Abstract

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.

Metal assisted peptide bond hydrolysis: Chemistry, biotechnology and toxicological implications

“…It seems that the future applications of metal assisted peptide bond hydrolysis in biotechnology belong to the latter two approaches, if their weak points will be overcome. There is also some promise in the cyclen complexes, especially in their most recent applications for amyloid digestion [134][135][136][137].…”

“…In another development of the work on cyclen complexes by Suh and coworkers several libraries of Co(III) complexes were designed, synthesized, and derivatized on the cyclen frame [134][135][136]. Several complexes were active against soluble oligomers of human amyloidogenic peptides: the Alzheimer's Disease A␤(1-42) peptide, human islet amyloid polypeptide (h-IAPP) related to type 2 diabetes and ␣-synuclein, related to Parkinson's Disease.…”

Artificial Metalloprotease Based on Co(III)oxacyclen-Aldehyde Conjugate

“…13 The Co(III) complexes of A and B were prepared according to the method reported previously. 7,[9][10][11]15 The substrate proteins were obtained from Sigma. Rate measurements carried out as reported previously.…”

“…[2][3][4][5][6][7][8][9][10][11] Proteolytic activity of the Cu(II) complex (Cu(II)cyclen) of cyclen was greatly enhanced on attachment to polystyrene backbone apparently due to the hydrophobic microenvironment.…”

Cleavage Agents for α-Synuclein

“…4 As a new therapeutic option for amyloidoses, we have proposed reduction of the level of the pathogenic oligomers of AmPs through peptide cleavage. 1,2,7 As shown in Figure 1 where the cleavage agent is indicated as (R)-(LCo III ), cleavage of an AmP included in a target oligomer reduces the concentration of the target oligomer, leading to decreases in the concentrations of other oligomers which readily transform into the target oligomer.…”