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

Lead Research Organisation: University of Bath
Department Name: Biology and Biochemistry

Abstract

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).

Technical Summary

Angiotensin I-converting enzyme (ACE) plays a critical role in blood pressure regulation. The clinical success of the 1st generation ACE inhibitors in the treatment of hypertension, congestive heart failure, renal insufficiency and atherosclerosis is well established. However, current-generation ACE inhibitors are frequently not tolerated and do not discriminate between the two active sites of somatic ACE, located in the N- and C-terminal domains, respectively. The N-and C-domain active sites are significantly different. Hence, the development of novel domain selective inhibitors by structure-based drug design will produce inhibitors with the potential for greater efficacy, fewer side effects, and treatment of new indications (e.g., polycythemia). Toward this goal, we have been successful in determining the 3D structure of testis ACE [identical to the C-domain of somatic ACE (Natesh et al., 2003)] and recently the N-domain of somatic ACE (Corradi et al., 2006) in collaboration with Dr. E. D. Sturrock (UCT, South Africa). The long term objective of this proposal is to develop novel ACE inhibitors for the treatment of hypertension based on the 3D structures of testis and somatic protein. This research would also help in better understanding the relationship between the structure and function of both testis and somatic ACE.
 
Description Project grant, G1001685
Amount £447,324 (GBP)
Funding ID G1001685 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2014
 
Title Deposition of Structural data with Protein Data Bank 
Description X-ray diffraction data and Atomic coordinates of reported structures 
Type Of Material Biological samples 
Provided To Others? No  
Impact The structural data are made available in the public domain. This will be useful for structure-based-drug-design research on Angiotensin-1 converting enzyme aimed at cardivascular diseases. 
 
Description Academic collaboration 
Organisation College of France
Department Centre for Interdisciplinary Research in Biology
Country France 
Sector Academic/University 
PI Contribution Professor Ravi Acharya's group (Bath) - Structural Biology
Collaborator Contribution Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry
Impact Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration
 
Description Academic collaboration 
Organisation Saclay Nuclear Research Centre
Department Service d’Ingénierie Moléculaire des Protéines (SIMOPRO)
Country France 
Sector Academic/University 
PI Contribution Professor Ravi Acharya's group (Bath) - Structural Biology
Collaborator Contribution Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry
Impact Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration
 
Description Academic collaboration 
Organisation University of Cape Town
Department Institute of Infectious Disease and Molecular Medicine (IIDMM)
Country South Africa 
Sector Academic/University 
PI Contribution Professor Ravi Acharya's group (Bath) - Structural Biology
Collaborator Contribution Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry
Impact Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration
 
Description Academic collaboration 
Organisation University of Leeds
Department School of Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Ravi Acharya's group (Bath) - Structural Biology
Collaborator Contribution Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry
Impact Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration