Proteolytic activity of Co(III) complex of 1-oxa-4,7,10-triazacyclododecane: a new catalytic center for peptide-cleavage agents.
Catalytic drugs based on target-selective artificial proteases have been proposed as a new paradigm in drug design. Peptide-cleavage agents selective for pathogenic proteins of Alzheimer's disease, type 2 diabetes mellitus or Parkinson's disease have been prepared using the Co(III) aqua complex (Co(III)cyclen) of 1,4,7,10-tetraazacyclododecane as the catalytic center. In the present study, the Co(III) aqua complex (Co(III)oxacyclen) of 1-oxa-4,7,10-triazacyclododecane was examined in search of an improved catalytic center for peptide-cleavage agents. An X-ray crystallographic study of [Co(oxacyclen)(CO(3))](ClO(4)), titration of Co(III)oxacyclen, and kinetic studies on the cleavage of albumin, gamma-globulin, lysozyme, and myoglobin by Co(III)oxacyclen were carried out. Considerably higher proteolytic activity was observed for Co(III)oxacyclen in comparison with Co(III)cyclen, indicating that better target-selective artificial metalloproteases would be obtained using Co(III)oxacyclen as the catalytic center. The improved proteolytic activity was attributed to either steric effects or the increased Lewis acidity of the Co(III) center. The kinetic data also predicted that side effects due to the cleavage of nontarget proteins by a catalytic drug based on Co(III)oxacyclen would be insignificant.
Kim
Hye Mi
HM
Department of Chemistry, Seoul National University, Seoul, 151-747, South Korea.
Jang
Boonjae
B
Cheon
Young Eun
YE
Suh
Myunghyun Paik
MP
Suh
Junghun
J
D002384:Catalysis; D003035:Cobalt / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D013237:Stereoisomerism
C541500:(1-oxa-4,7,10-triazacyclododecane)cobalt(III); D009942:Organometallic Compounds; D010455:Peptides; D003035:Cobalt