Here we discuss the structural features of current inhibitors and outline how next-generation ACE inhibitors could be designed by using the three-dimensional molecular structure of human testis ACE. ![]() Therefore, the design of specific domain-selective ACE inhibitors is expected to produce next-generation drugs that might be safer and more effective. Moreover, we now know that ACE actually consists of two parts (called the N- and C-domains) that have different functions. However, the use of these ACE inhibitors, which were developed in the late 1970s and early 1980s, is hampered by common side effects. It preferentially hydrolyses at least three other physiologically important peptides, so targeted inhibition of the N-domain might have novel therapeutic applications.Ĭurrent-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. In contrast to the C-domain, the N-domain seems to have relatively low affinity for the peptides that control blood pressure. Data indicate that C-domain-selective inhibitors will have less severe side effects than current-generation inhibitors, which generally target both the N- and C-domains. The C-domain seems to be primarily responsible for the regulation of blood pressure. The design of domain-selective inhibitors might produce new drugs with improved safety and efficacy - this endeavour will be facilitated by the recent determination of the three-dimensional structure of ACE. Side effects of treatment with ACE inhibitors include cough and angioedema.ĪCE comprises an N- and a C-domain, each containing an active site with distinct substrates and activation properties. It is therefore a major target for cardiovascular therapies.ĪCE inhibitors (for example, captopril, enalaprilat and lisinopril) have been on the market for more than 20 years. ACE is central to the renin–angiotensin system that regulates blood pressure, fluid homeostasis, and renal and vascular function. ![]() ![]() Angiotensin-converting enzyme (ACE) is a chloride-dependent metalloenzyme that catalyses the hydrolytic cleavage of dipeptides from the carboxyl terminus of many regulatory oligopeptides.
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