Chemistry-based design of inhibitors for carboxypeptidase A

Carboxypeptidase A (CPA) is one of the most extensively studied zinc proteases and serves as a prototypical enzyme for a large family of metalloproteases that play important roles in biological systems. CPA has been used as a model enzyme for developing design strategies of inhibitors that restrain the catalytic activity of zinc proteases. Recently, there has been made a remarkable progress in designing small molecule inactivators that inhibit the enzymic activity of CPA irreversibly by chemically modifying a functional group at the active site of the enzyme. Of these irreversible inhibitors mechanism-based inactivators are of special interest due to their high selectivity for target enzyme and long duration of enzyme inhibition. These inactivators have been designed rationally on the basis of established topology of the active site and catalytic mechanism of the enzyme. Chemistry inherent to the zinc ion at the active site of the enzyme has been exploited in the design. The present review covers the progress in the CPA inactivator design strategy. The design strategy developed with CPA may be transferred to other zinc proteases of medicinal interest, leading to discovery of a novel type of therapeutically useful enzyme inhibitors.