ACE Angiotensin I Converting Enzyme 10 ACE inhibitors available in US benazepril captopril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril and trandolapril ACE inhibitors were the 4th most prescribed drug class in the U S 159 8 million Rx in 2008 Lisinopril was the 2nd most prescribed drug in the US 75 5 million Rx in 2008 1 Endogenously generated peptides are involved in the physiology and pathology of all major organ systems and play important roles in many processes These include neurotransmission immune function cell proliferation pain analgesia fluid balance in the kidney endocrine functions reproduction contraction relaxation of all types of smooth muscle regulation of the cardiovascular system satiety obesity etc 2 1 TO MIMIC THE ACTION OF A PEPTIDE A Administer the Peptide See next page for advantages disadvantages Non peptide agonists can be effective drugs however rational design of these drugs is generally not possible Requires random large scale screening approach B Block the Degradation by Peptidase s This is a good strategy because the level of the peptide can be specifically increased at its normal site s of action and peptidase inhibitors can be synthesized with good stability and bioavailability Disadvantages include 1 Blocking one peptidase may interfere with the metabolism of more than one peptide 2 Inhibition of more than one peptidase may be needed to block the degradation of a peptide 3 Enhancing general levels of a peptide with multiple actions may produce side effects 2 TO BLOCK THE ACTION OF A PEPTIDE A Use a Receptor Antagonist This is an excellent approach because the specific actions of a peptide mediated by a single receptor type can be blocked leading to the potential for few unwanted side effects However many peptide receptor antagonists are themselves peptides and suffer from the disadvantages listed above Development of non peptide antagonists may with good bioavailability and stability is possible but is still not a straightforward process B Block the Synthesis Processing of the Peptide This is also an excellent approach and one exemplified by the development of Angiotensin Converting Enzyme ACE inhibitors In this approach all the actions of the peptide can be blocked and enzyme inhibitors can be synthesized with high affinity specificity and bioavailability However disadvantages include the following 1 Cannot block a specific action of a peptide if it acts on more than one receptor 2 Intermediate forms of a peptide that build up when processing is blocked may have their own biological activity 3 Processing enzymes may process other peptide hormones ACE inhibitors do not suffer this disadvantage as the Renin Angiotensin system specifically processes and generates only angiotensin and not other peptides 3 4 5 Top Left Schematic diagram of the structure of human ACE The majority of the ACE molecule projects into the extracellular space and is boud to the plasma membrane via a C terminal transmembrane spanning helix followed by a short 30 residue cytoplasmic tail The two homologous active site domains are denoted by the HEMGH sequence which contains two zinc binding histidine residues and the catalytic glutamic acid The distribution of carbohydrate is shown for all 17 potential Asn linked glycosylation sites The extent of actual glycosylation varies from tissue to tissue and may not involve all potential sites Top Middle Superposition of the crystal structures of the N domain blue and Cdomain pink showing the similarity of their primarily alpha helical structures Active site zinc ion is shown in green Top Right Space filling model of the C domain of ACE showing the deep central groove containing the active site and bound inhibitor lisinopril yellow Bottom Model of two possible orientations of the N and C domain in the ACE holoenzyme 6 A common misconception is that peptidases are peptide specific perpetuated by the names given to some of the enzymes e g Angiotensin I Converting Enzyme Enkephalinase etc Peptidases recognize amino acids around the peptide bond being hydrolyzed and therefore can potentially cleave many different peptides 7 Clinically used ACE inhibitors In 1974 Cushman and Ondetti at Bristol Meyers Squibb used a model based on the structure of carboxypeptidase A and a snake venom peptide that inhibited ACE to synthesize captopril which contained a free SH group to bind the active site zinc This was the first clinically used ACE inhibitor When the X ray crystal structure of ACE was finally determined in 2003 it turned out to have no homology to carboxypeptidase A Because the SH group can cause rash and taste disturbances at higher doses second generation ACE inhibitor enalaprilat used a COOH group instead of SH to bind zinc Most ACE inhibitors use a free COOH group to bind zinc except fosinopril which uses phosphinic acid However the free COOH or phosphinic acid group causes poor absorption so they are synthesized the prodrug esters which is absorbed well and converted by esterases to the active drug Only Lisinopril and Captopril are active compounds that do not require conversion 8 Angiotensin Converting Enzyme ACE plays a central role in the control of peptide hormones that regulate blood pressure Thus ACE inhibitors are effective antihypertensive agents Inhibitors of other steps in the pathway are also effective antihypertensives These include Renin inhibitors Aliskiren brand name Tekturna and angiotensin receptor antagonists the sartans e g Losartan 9 An additional mechanism by which ACE inhibitors can work involves the angiotensin metabolite Angiotensin 1 7 1 residue shorter than angiotensin II This metabolite can be generated directly from angiotensin I by endopeptidases such as neutral endopeptidase prolylendopeptidase and thimet oligopeptidase Angiotensin 1 7 acting through its receptor also called the Mas receptor has effects opposite to those of angiotensin II and thereby is a negative regulator of the renin angiotensin system ACE inhibitors promote angiotensin 1 7 generation via 2 mechanisms 1 increasing angiotensin 1 levels by inhibiting conversion to angiotensin II increases substrate concentration and thus conversion by endopeptidases 2 by blocking ACE metabolism of angiotensin 1 7 into the inactive metabolite angiotensin 1 5 10 From Hypertension Primer 4th Edition edited by JL Izzo Jr DA Sica HR Black Publisher Lippincott Williams Wilkins November 1 2007 11 From Hypertension Primer 4th Edition
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