Cyclen-Containing Inhibitors of Carboxypeptidase A Synthesized in Search of Target-Selective Artificial Proteases

Previously, we reported the first substrate-selective artificial protease by using myoglobin as the substrate. Target-selective peptide-cleaving catalysts can be used as drugs if the target is a protein or an oligopeptide related to a disease. For example, a peptide-cleaving catalyst specifically recognizing HIV protease and rapidly cleaving it into two pieces can be used as a new drug for AIDS. Since only a catalytic amount of the drug is needed, the drug dosage and the side effects can be reduced by using the peptide-cleaving catalysts. The myoglobin-cleaving catalysts reported previously were designed by attaching a catalytic group to a binding site that recognizes the surface of myoglobin. The Cu(II) or Co(III) complex of cyclen (Cyc) was used as the catalytic group in view of their catalytic activity in peptide hydrolysis. Thus, connection of a catalytic group to a binding site can be considered as a general method for creation of targetselective peptide-cleaving catalysts. The binding site may recognize either a certain portion on the surface of the target protein as in the case of the myoglobin-cleaving catalyst mentioned above or the active site of the target protein. In view of a vast amount of ligand molecules reported to have high affinity toward many disease-related proteins, the known ligand molecules may be utilized as the binding site of the peptide-cleaving catalysts. In this regard, we undertook synthesis of peptide-cleaving catalysts selective for carboxypeptidase A (CPA) by using CPA inhibitors as the binding site of the catalysts. The idea of designing a CPA-selective peptide-cleaving catalyst based on a known CPA inhibitor is illustrated in Scheme 1.