Helfende Kombination: Peptidspaltende Agentien für Amyloid‐β‐42(Aβ42)‐Oligomere (siehe Schema) – den neurotoxischen Zwischenstufen bei der Alzheimer‐Krankheit – wurden aus einer kombinatorischen Bibliothek erhalten, die mit dem CoIII‐Komplex von 1,4,7,10‐Tetraazacyclododecan als Reaktionszentrum aufgebaut wurde. Die Aβ42‐Oligomere werden bereits bei submikromolaren Konzentrationen der Agentien effektiv gespalten.
To provide a firm basis for the new paradigm of drug discovery based on peptide-cleaving catalysts, oligopeptide-cleaving catalysts were searched for by using human angiotensin I (Ang-I) and angiotensin II (Ang-II) as the substrates. Catalyst candidates containing the Co(III) complex of cyclen as the catalytic center were prepared by multicomponent condensation reactions. From two types of chemical libraries containing about 3,600 catalyst candidates, two compounds [SS-Co(III)X and S-Co(III)Y] were selected as the most active catalysts. On incubation with SS-Co(III)X and S-Co(III)Y, both Ang-I and Ang-II were cleaved by oxidative decarboxylation instead of peptide hydrolysis: the N-terminal Asp residues of Ang-I and Ang-II were converted to pyruvate residues. Catalysts for oxidative decarboxylation of the N-terminal Asp residue contained in an oligopeptide are unprecedented in both biological and chemical systems. Detailed kinetics analysis suggested that Ang-I and Ang-II can be cleaved with half-lives much less than 1 h if the structures of the chelating ligands of the catalysts are further improved. The results indicated that the concept of the peptide-cleaving catalysts can be expanded to include oligopeptides as the targets and nonhydrolytic reactions as the means for cleavage.
To provide a firm basis for the new paradigm of drug discovery based on catalysts for oxidative cleavage of N-terminal aspartate (Asp) residues of oligopeptides, oligopeptide-cleaving catalysts were searched by using melanin-concentrating hormone (MCH) as the substrate. MCH is a target for designing drugs to reduce obesity. Catalyst candidates containing the Co(III) complex of cyclen as the catalytic center were prepared by multicomponent condensation reactions. From three kinds of chemical libraries containing about 19,000 catalyst candidates, one compound was identified as the MCH-cleaving catalyst. On incubation with the catalyst, the N-terminal Asp residue of MCH was converted to the pyruvate residue by oxidative decarboxylation. Detailed kinetics analysis revealed the catalytic nature of the action of the catalyst. In addition, the kinetics data indicated that MCH can be cleaved with half-lives of 3 h or less with submicromolar catalyst concentrations if the structure of the catalyst is further improved.
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