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Structure-Based Design of Domain-Selective Angiotensin-Converting Enzyme Inhibitors

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Drug Discovery in Africa

Abstract

Cardiovascular disease (CVD) affects a significant proportion of the African adult population and requires new and improved strategies for the effective control of this disease. Angiotensin-converting enzyme (ACE) is a two-domain zinc metallopeptidase that plays a central role in the renin-angiotensin-aldosterone system and has thus been identified as a promising therapeutic target in the treatment of CVD and its major risk factor, hypertension. Numerous ACE inhibitors have been developed that are used clinically but tend to result in adverse drug events, such as persistent cough and life-threatening angioedema. Research over the previous two decades has allowed for an improved understanding of the function of the two ACE domains and thus provides a basis for the design of second-generation, domain-selective ACE inhibitors. This chapter reviews our current understanding of ACE biochemistry, first-generation ACE inhibitors and the utilised technologies and progress towards the development of such inhibitors that could be useful in the treatment of hypertension and lung fibrosis.

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Abbreviations

ACE:

Angiotensin-converting enzyme

AcSDKP:

N-acetyl-serylaspartyllysylproline

ADE:

Adverse drug event

AngI:

Angiotensin I

AngII:

Angiotensin II

Ang1-7:

Angiotensin 1-7

AT1R:

Angiotensin type 1 receptor

AT2R:

Angiotensin type 2 receptor

BK:

Bradykinin

BPF:

Bradykinin-potentiating factor

CPA:

Carboxypeptidase A

CVD:

Cardiovascular disease

kAF:

keto-ACE Phe inhibitor

kAW:

keto-ACE Trp

LisW:

Lisinopril Trp

PDB:

Protein Data Bank (http://www.rcsb.org/pdb)

RAAS:

Renin-angiotensin-aldosterone system

tACE:

Testis angiotensin-converting enzyme

WHO:

World Health Organisation

ZMRG:

Zinc Metalloprotease Research Group

References

  1. Kearney PM, Whelton M, Reynolds K et al (2005) Global burden of hypertension: analysis of worldwide data. Lancet 365:217–223

    Google Scholar 

  2. Steyn K, Gaziano TA, Bradshaw D et al (2001) Hypertension in South African adults: results from the Demographic and Health Survey, 1998. J Hypertens 19:1717–1725

    Article  CAS  Google Scholar 

  3. World Health Organisation Online Data Bank Repository (2008) Accessible through http://www.who.int

  4. Acharya KR, Sturrock ED, Riordan JF et al (2003) ACE revisited: a new target for structure-based drug design. Nat Rev Drug Discov 2:891–902

    Article  CAS  Google Scholar 

  5. Elliott WJ (1996) Higher incidence of discontinuation of angiotensin converting enzyme inhibitors due to cough in black subjects. Clin Pharmacol Ther 60:582–588

    Article  CAS  Google Scholar 

  6. Gibbs CR, Lip GY, Beevers DG (1999) Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol 48:861–865

    Article  CAS  Google Scholar 

  7. Ehlers MR (2006) Safety issues associated with the use of angiotensin-converting enzyme inhibitors. Expert Opin Drug Saf 5:739–740

    Article  CAS  Google Scholar 

  8. Fyhrquist F, Saijonmaa O (2008) Renin-angiotensin system revisited. J Intern Med 264:224–236

    Article  CAS  Google Scholar 

  9. Page IH, Helmer OM (1940) A crystalline pressor substance (angiotonin) resulting from the interaction between renin and renin activator. J Exp Med 71:29–42

    Article  CAS  Google Scholar 

  10. Skeggs LT, Marsh WH, Kahn JR et al (1954) The purification of hypertensin I. J Exp Med 100:363–370

    Article  CAS  Google Scholar 

  11. Skeggs LT, Kahn JR, Shumway NP (1956) The preparation and function of the hypertensin-converting enzyme. J Exp Med 103:295–299

    Article  CAS  Google Scholar 

  12. Timmermans PB, Wong PC, Chiu AT et al (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45:205–251

    CAS  Google Scholar 

  13. Lemarie CA, Schiffrin EL (2010) The angiotensin II type 2 receptor in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 11:19–31

    Article  CAS  Google Scholar 

  14. Rice GI, Thomas DA, Grant PJ et al (2004) Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 383:45–51

    Article  CAS  Google Scholar 

  15. Santos RA, Simoes e Silva AC, Maric C et al (2003) Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 100:8258–8263

    Article  CAS  Google Scholar 

  16. Roks AJ, van Geel PP, Pinto YM et al (1999) Angiotensin-(1-7) is a modulator of the human renin-angiotensin system. Hypertension 34:296–301

    Article  CAS  Google Scholar 

  17. Kim HS, Krege JH, Kluckman KD et al (1995) Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 92:2735–2739

    Article  CAS  Google Scholar 

  18. Yanai K, Saito T, Kakinuma Y et al (2000) Renin-dependent cardiovascular functions and renin-independent blood-brain barrier functions revealed by renin-deficient mice. J Biol Chem 275:5–8

    Article  CAS  Google Scholar 

  19. Ito M, Oliverio MI, Mannon PJ et al (1995) Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA 92:3521–3525

    Article  CAS  Google Scholar 

  20. Krege JH, John SW, Langenbach LL et al (1995) Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 375:146–148

    Article  CAS  Google Scholar 

  21. Esther CR, Howard TE, Marino EM et al (1996) Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 74:953–965

    CAS  Google Scholar 

  22. Rawlings ND, Barrett AJ, Bateman A (2010) MEROPS: the peptidase database. Nucleic Acids Res 38:D227–D233

    Article  CAS  Google Scholar 

  23. Skidgel RA, Engelbrecht S, Johnson AR et al (1984) Hydrolysis of substance p and neurotensin by converting enzyme and neutral endopeptidase. Peptides 5:769–776

    Article  CAS  Google Scholar 

  24. Skidgel RA, Erdos EG (1985) Novel activity of human angiotensin I converting enzyme: release of the NH2- and COOH-terminal tripeptides from the luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA 82:1025–1029

    Article  CAS  Google Scholar 

  25. Hu J, Igarashi A, Kamata M et al (2001) Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 276:47863–47868

    CAS  Google Scholar 

  26. Sun X, Becker M, Pankow K et al (2008) Catabolic attacks of membrane-bound angiotensin-converting enzyme on the N-terminal part of species-specific amyloid-beta peptides. Eur J Pharmacol 588:18–25

    Article  CAS  Google Scholar 

  27. O’Neill HG, Redelinghuys P, Schwager SL et al (2008) The role of glycosylation and domain interactions in the thermal stability of human angiotensin-converting enzyme. Biol Chem 389:1153–1161

    Google Scholar 

  28. Anthony CS, Corradi HR, Schwager SL et al (2010) The N domain of human angiotensin-I-converting enzyme: the role of N-glycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407. J Biol Chem 285:35685–35693

    Article  CAS  Google Scholar 

  29. Kost OA, Bovin NV, Chemodanova EE et al (2000) New feature of angiotensin-converting enzyme: carbohydrate-recognizing domain. J Mol Recognit 13:360–369

    Article  CAS  Google Scholar 

  30. Kohlstedt K, Gershome C, Friedrich M et al (2006) Angiotensin-converting enzyme (ACE) dimerization is the initial step in the ACE inhibitor-induced ACE signaling cascade in endothelial cells. Mol Pharmacol 69:1725–1732

    Article  CAS  Google Scholar 

  31. Soubrier F, Alhenc-Gelas F, Hubert C et al (1988) Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci USA 85:9386–9390

    Article  CAS  Google Scholar 

  32. Wei L, Alhenc-Gelas F, Corvol P et al (1991) The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. J Biol Chem 266:9002–9008

    CAS  Google Scholar 

  33. Turner AJ, Hooper NM (2002) The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23:177–183

    Article  CAS  Google Scholar 

  34. Jaspard E, Wei L, Alhenc-Gelas F (1993) Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. J Biol Chem 268:9496–9503

    CAS  Google Scholar 

  35. Kakoki M, Smithies O (2009) The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int 75:1019–1030

    Article  CAS  Google Scholar 

  36. Georgiadis D, Beau F, Czarny B et al (2003) Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors. Circ Res 93:148–154

    Article  CAS  Google Scholar 

  37. Fuchs S, Xiao HD, Hubert C et al (2008) Angiotensin-converting enzyme C-terminal catalytic domain is the main site of angiotensin I cleavage in vivo. Hypertension 51:267–274

    Article  CAS  Google Scholar 

  38. Kehoe PG (2009) Angiotensins and Alzheimer’s disease: a bench to bedside overview. Alzheimers Res Ther 1:3–10

    Article  CAS  Google Scholar 

  39. Rieger KJ, Saez-Servent N, Papet MP et al (1993) Involvement of human plasma angiotensin I-converting enzyme in the degradation of the haemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline. Biochem J 296(Pt 2):373–378

    CAS  Google Scholar 

  40. Peng H, Carretero OA, Raij L et al (2001) Antifibrotic effects of N-acetyl-seryl-aspartyl-Lysyl-proline on the heart and kidney in aldosterone-salt hypertensive rats. Hypertension 37:794–800

    Article  CAS  Google Scholar 

  41. Peng H, Carretero OA, Brigstock DR et al (2003) Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension. Hypertension 42:1164–1170

    Article  CAS  Google Scholar 

  42. Peng H, Carretero OA, Vuljaj N et al (2005) Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation 112:2436–2445

    Article  CAS  Google Scholar 

  43. Peng H, Carretero OA, Liao TD et al (2007) Role of N-acetyl-seryl-aspartyl-lysyl-proline in the antifibrotic and anti-inflammatory effects of the angiotensin-converting enzyme inhibitor captopril in hypertension. Hypertension 49:695–703

    Article  CAS  Google Scholar 

  44. Rasoul S, Carretero OA, Peng H et al (2004) Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension. J Hypertens 22:593–603

    Article  CAS  Google Scholar 

  45. Lin CX, Rhaleb NE, Yang XP et al (2008) Prevention of aortic fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 295:H1253–H1261

    Article  CAS  Google Scholar 

  46. Liao TD, Yang XP, D’Ambrosio M et al (2010) N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal injury and dysfunction in hypertensive rats with reduced renal mass: council for high blood pressure research. Hypertension 55:459–467

    Article  CAS  Google Scholar 

  47. Wang M, Liu R, Jia X et al (2010) N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal inflammation and tubulointerstitial fibrosis in rats. Int J Mol Med 26:795–801

    Google Scholar 

  48. Rousseau A, Michaud A, Chauvet MT et al (1995) The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensin-converting enzyme. J Biol Chem 270:3656–3661

    Article  CAS  Google Scholar 

  49. Fuchs S, Xiao HD, Cole JM et al (2004) Role of the N-terminal catalytic domain of angiotensin-converting enzyme investigated by targeted inactivation in mice. J Biol Chem 279:15946–15953

    Article  CAS  Google Scholar 

  50. Junot C, Gonzales MF, Ezan E et al (2001) RXP 407, a selective inhibitor of the N-domain of angiotensin I-converting enzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis. J Pharmacol Exp Ther 297:606–611

    CAS  Google Scholar 

  51. Li P, Xiao HD, Xu J et al (2010) Angiotensin-converting enzyme N-terminal inactivation alleviates bleomycin-induced lung injury. Am J Pathol 177:1113–1121

    Article  CAS  Google Scholar 

  52. Ondetti MA, Cushman DW (1982) Enzymes of the renin-angiotensin system and their inhibitors. Annu Rev Biochem 51:283–308

    Article  CAS  Google Scholar 

  53. Patchett AA, Cordes EH (1985) The design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme. Adv Enzymol Relat Areas Mol Biol 57:1–84

    CAS  Google Scholar 

  54. Cushman DW, Ondetti MA (1999) Design of angiotensin converting enzyme inhibitors. Nat Med 5:1110–1113

    Article  CAS  Google Scholar 

  55. Menard J, Patchett AA (2001) Angiotensin-converting enzyme inhibitors. Adv Protein Chem 56:13–75

    Article  CAS  Google Scholar 

  56. Patchett AA (2002) 2002 Alfred Burger Award Address in Medicinal Chemistry. Natural products and design: interrelated approaches in drug discovery. J Med Chem 45:5609–5616

    Article  CAS  Google Scholar 

  57. Smith CG, Vane JR (2003) The discovery of captopril. FASEB J 17:788–789

    Article  CAS  Google Scholar 

  58. Ng KK, Vane JR (1968) Fate of angiotensin I in the circulation. Nature 218:144–150

    Article  CAS  Google Scholar 

  59. Ferreira SH, Bartelt DC, Greene LJ (1970) Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom. Biochemistry 9:2583–2593

    Article  CAS  Google Scholar 

  60. Gavras H, Brunner HR, Laragh JH et al (1974) An angiotensin converting-enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients. N Engl J Med 291:817–821

    Article  CAS  Google Scholar 

  61. Byers LD, Wolfenden R (1973) Binding of the by-product analog benzylsuccinic acid by carboxypeptidase A. Biochemistry 12:2070–2078

    Article  CAS  Google Scholar 

  62. Ondetti MA, Rubin B, Cushman DW (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196:441–444

    Article  CAS  Google Scholar 

  63. Cushman DW, Cheung HS, Sabo EF et al (1977) Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry 16:5484–5491

    Article  CAS  Google Scholar 

  64. Natesh R, Schwager SL, Evans HR et al (2004) Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry 43:8718–8724

    Article  CAS  Google Scholar 

  65. Patchett AA, Harris E, Tristram EW et al (1980) A new class of angiotensin-converting enzyme inhibitors. Nature 288:280–283

    Article  CAS  Google Scholar 

  66. Biollaz J, Burnier M, Turini GA et al (1981) Three new long-acting converting-enzyme inhibitors: relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther 29:665–670

    Article  CAS  Google Scholar 

  67. Natesh R, Schwager SL, Sturrock ED et al (2003) Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 421:551–554

    Article  CAS  Google Scholar 

  68. Wei L, Clauser E, Alhenc-Gelas F et al (1992) The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors. J Biol Chem 267:13398–13405

    CAS  Google Scholar 

  69. Wyvratt MJ, Patchett AA (1985) Recent developments in the design of angiotensin-converting enzyme inhibitors. Med Res Rev 5:483–531

    Article  CAS  Google Scholar 

  70. Nussberger J, Cugno M, Amstutz C et al (1998) Plasma bradykinin in angio-oedema. Lancet 351:1693–1697

    Article  CAS  Google Scholar 

  71. Emanueli C, Grady EF, Madeddu P et al (1998) Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P. Hypertension 31:1299–1304

    Article  CAS  Google Scholar 

  72. Adam A, Cugno M, Molinaro G et al (2002) Aminopeptidase P in individuals with a history of angiooedema on ACE inhibitors. Lancet 359:2088–2089

    Article  CAS  Google Scholar 

  73. Ainslie GM, Benatar SR (1985) Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extra-thoracic involvement, radiographic type and therapy. Q J Med 55:253–270

    CAS  Google Scholar 

  74. Westall GP (2003) Interstitial lung disease. BC Decker, London

    Google Scholar 

  75. Ehlers MR, Maeder DL, Kirsch RE (1986) Rapid affinity chromatographic purification of human lung and kidney angiotensin-converting enzyme with the novel N-carboxyalkyl dipeptide inhibitor N-[1(S)-carboxy-5-aminopentyl]glycylglycine. Biochim Biophys Acta 883:361–372

    Article  CAS  Google Scholar 

  76. Pantoliano MW, Holmquist B, Riordan JF (1984) Affinity chromatographic purification of angiotensin converting enzyme. Biochemistry 23:1037–1042

    Article  CAS  Google Scholar 

  77. Ehlers MR, Kirsch RE, Giles RGF, Yorke SC (1986) Synthesis of (1 S)-N-(1-carboxy-5-aminopentyl)-glycylglycine: A prospective competitive inhibitor for angiotensin-converting enzyme. S Afr J Chem 39:134–136

    CAS  Google Scholar 

  78. El Dorry HA, Bull HG, Iwata K et al (1982) Molecular and catalytic properties of rabbit testicular dipeptidyl carboxypeptidase. J Biol Chem 257:14128–14133

    CAS  Google Scholar 

  79. Bull HG, Thornberry NA, Cordes EH (1985) Purification of angiotensin-converting enzyme from rabbit lung and human plasma by affinity chromatography. J Biol Chem 260:2963–2972

    CAS  Google Scholar 

  80. Ehlers MRW, Kirsch RE (1988) Catalysis of angiotensin I hydrolysis by human angiotensin-converting enzyme: effect of chloride and pH. Biochemistry 27:5538–5544

    Article  CAS  Google Scholar 

  81. Ehlers MR, Fox EA, Strydom DJ et al (1989) Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc Natl Acad Sci USA 86:7741–7745

    Article  CAS  Google Scholar 

  82. Yu XC, Sturrock ED, Wu Z et al (1997) Identification of N-linked glycosylation sites in human testis angiotensin-converting enzyme and expression of an active deglycosylated form. J Biol Chem 272:3511–3519

    Article  CAS  Google Scholar 

  83. Gordon K, Redelinghuys P, Schwager SL et al (2003) Deglycosylation, processing and crystallization of human testis angiotensin-converting enzyme. Biochem J 371:437–442

    Article  CAS  Google Scholar 

  84. Watermeyer JM, Sewell BT, Schwager SL et al (2006) Structure of testis ACE glycosylation mutants and evidence for conserved domain movement. Biochemistry 45:12654–12663

    Article  CAS  Google Scholar 

  85. Watermeyer JM, Kroger WL, O’Neill HG et al (2008) Probing the basis of domain-dependent inhibition using novel ketone inhibitors of angiotensin-converting enzyme. Biochemistry 47:5942–5950

    Article  CAS  Google Scholar 

  86. Watermeyer JM, Kroger WL, O’Neill HG et al (2010) Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. Biochem J 428:67–74

    Article  CAS  Google Scholar 

  87. Corradi HR, Schwager SL, Nchinda AT et al (2006) Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design. J Mol Biol 357:964–974

    Article  CAS  Google Scholar 

  88. Georgiadis D, Cuniasse P, Cotton J et al (2004) Structural determinants of RXPA380, a potent and highly selective inhibitor of the angiotensin-converting enzyme C-domain. Biochemistry 43:8048–8054

    Article  CAS  Google Scholar 

  89. Deddish PA, Marcic B, Jackman HL et al (1998) N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension 31:912–917

    Article  CAS  Google Scholar 

  90. Nchinda AT, Chibale K, Redelinghuys P et al (2006) Synthesis of novel keto-ACE analogues as domain-selective angiotensin I-converting enzyme inhibitors. Bioorg Med Chem Lett 16:4612–4615

    Article  CAS  Google Scholar 

  91. Nchinda AT, Chibale K, Redelinghuys P et al (2006) Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme. Bioorg Med Chem Lett 16:4616–4619

    Article  CAS  Google Scholar 

  92. Corradi HR, Chitapi I, Sewell BT et al (2007) The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380. Biochemistry 46:5473–5478

    Article  CAS  Google Scholar 

  93. Kroger WL, Douglas RG, O’Neill HG et al (2009) Investigating the domain specificity of phosphinic inhibitors RXPA380 and RXP407 in angiotensin-converting enzyme. Biochemistry 48:8405–8412

    Article  CAS  Google Scholar 

  94. du Bois RM (2010) Strategies for treating idiopathic pulmonary fibrosis. Nat Rev Drug Discov 9:129–140

    Article  CAS  Google Scholar 

  95. Dive V, Cotton J, Yiotakis A et al (1999) RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites. Proc Natl Acad Sci USA 96:4330–4335

    Article  CAS  Google Scholar 

  96. Tzakos AG, Gerothanassis IP (2005) Domain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitors. Chembiochem 6:1089–1103

    Article  CAS  Google Scholar 

  97. Jullien ND, Cuniasse P, Georgiadis D et al (2006) Combined use of selective inhibitors and fluorogenic substrates to study the specificity of somatic wild-type angiotensin-converting enzyme. FEBS J 273:1772–1781

    Article  CAS  Google Scholar 

  98. Akif M, Georgiadis D, Mahajan A et al (2010) High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs. J Mol Biol 400:502–517

    Article  CAS  Google Scholar 

  99. Andujar-Sanchez M, Camara-Artigas A, Jara-Perez V (2004) A calorimetric study of the binding of lisinopril, enalaprilat and captopril to angiotensin-converting enzyme. Biophys Chem 111:183–189

    Article  CAS  Google Scholar 

  100. Douglas RG, Ehlers MRW, Sturrock ED (2011) Vasopeptidase inhibition – solving the cardiovascular puzzle? Drug Future 36:33–43

    CAS  Google Scholar 

  101. Kostis JB, Packer M, Black HR et al (2004) Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 17:103–111

    Article  CAS  Google Scholar 

  102. Jullien N, Makritis A, Georgiadis D et al (2010) Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors. J Med Chem 53:208–220

    Article  CAS  Google Scholar 

  103. Cohen GH (1997) ALIGN: a program to superimpose protein coordinates, accounting for insertions and deletions. J Appl Cryst 30:1160–1161

    Article  CAS  Google Scholar 

  104. Schechter I, Berger A (1967) On the size of the active site in proteases. I. Papain. Biochem Biophys Res Comm 27:157–162

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa, 7935

    Ross G. Douglas & Edward D. Sturrock

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  1. Ross G. Douglas
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  2. Edward D. Sturrock
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Correspondence to Edward D. Sturrock .

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Editors and Affiliations

  1. , Dept. of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Kelly Chibale

  2. , Department of Chemistry, Rhodes University, Grahamstown, 6140, South Africa

    Mike Davies-Coleman

  3. and Technology, African Institute of Biomedical Science, Harare, 2294, Zimbabwe

    Collen Masimirembwa

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Douglas, R.G., Sturrock, E.D. (2012). Structure-Based Design of Domain-Selective Angiotensin-Converting Enzyme Inhibitors. In: Chibale, K., Davies-Coleman, M., Masimirembwa, C. (eds) Drug Discovery in Africa. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28175-4_15

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