Peptide-cleaving catalyst selective for melanin-concentrating hormone: Oxidative decarboxylation of N-terminal aspartate catalyzed by Co(III)cyclen.
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.
Kim
Min Gyum
MG
Department of Chemistry, Seoul National University, Seoul, 151-747, Korea.
Kim
Myoung-soon
MS
Lee
Seong Du
SD
Suh
Junghun
J
D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D003653:Decarboxylation; D007028:Hypothalamic Hormones / Q000737:chemistry* / Q000378:metabolism; D008543:Melanins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010907:Pituitary Hormones / Q000737:chemistry* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity
D007028:Hypothalamic Hormones; D008543:Melanins; D009942:Organometallic Compounds; D019151:Peptide Library; D010455:Peptides; D010907:Pituitary Hormones; C442399:cyclencobalt(III); D001224:Aspartic Acid; C019463:melanin-concentrating hormone