Structural studies on human Angiotensin-I converting enzyme (ACE) and the design of novel structure-based inhibitors

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Angiotensin-I converting enzyme (ACE) inhibitors are widely used to treat cardiovascular diseases, including high blood pressure, heart failure, coronary artery disease and kidney failure. However, current-generation ACE inhibitors, which were developed in the 1970?s and 1980?s, are hampered by common side effects. This underscores the importance of the determination of the 3D structure of ACE and the design of 2nd generation ACE-inhibitor complex/s that are safer and more effective. Our success in the determination of the crystal structure of human testis ACE (Natesh et al., 2003) and recently the N-domain of somatic ACE (Corradi et al., 2006) using X-ray crystallography have provided the platform for true structure-based design of ACE inhibitors. This is a significant breakthrough in terms of the structural biology of the protease and, more importantly, the mechanism of ACE inhibition. This paves the way for a more rigourous approach exploiting the differences between the domains through a structure based drug design approach of novel domain-selective inhibitors. Our proposed experiments are directed at structural study of the full-length somatic ACE and crystal structures of complexes of ACE with domain selective inhibitors will be determined through a collaborative effort with Dr. Sturrock (UCT, South Africa) and Cresset Ltd (UK).