Toward protein-cleaving catalytic drugs: artificial protease selective for myoglobin.
A protein-cleaving catalyst highly selective for a disease-related protein can be used as a catalytic drug. As the first protein-cleaving catalyst selective for a protein substrate, a catalyst for myoglobin (Mb) was designed by attaching the Cu(II) or Co(III) complex of cyclen to a binding site searched by a combinatorial method using peptide nucleic acid monomers as building units. Various linkers were inserted between the catalytic Co(III) center and the binding site of the Mb-cleaving catalyst. Kinetic data revealed catalytic turnover of the Mb cleavage by the Cu(II) or Co(III) complex. MALDI-TOF MS revealed cleavage of the polypeptide backbone of Mb at selected positions. N-Terminal sequencing of the cleavage products identified the cleavage site and provided evidence for the hydrolytic nature of the Mb cleavage. Various chelating ligands were tested as the ligand for the Co(III) center of the Mb-cleaving catalyst. Among the nine chelating ligands examined, only cyclen and its triaza-monooxo analogue manifested catalytic activity.
Jeon
Joong Won
JW
School of Chemistry, Seoul National University, Seoul 151-747, South Korea.
Son
Sang Jun
SJ
Yoo
Chang Eun
CE
Hong
In Seok
IS
Suh
Junghun
J
D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D003035:Cobalt / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D010450:Endopeptidases / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D018716:Molecular Mimicry; D009211:Myoglobin / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000187:drug effects* / Q000378:metabolism; D013379:Substrate Specificity
D009211:Myoglobin; D011506:Proteins; D003035:Cobalt; D010450:Endopeptidases