Structure Based Inhibitor Design Studies on Angiotensin Converting Enzyme Homologues

Abstract

Angiotensin converting enzyme, ACE (EC number 3. 4. 15. 1), is a zinc dependent dipeptidyl carboxypeptidase that has an essential role in mammalian blood pressure regulation as part of the renin-angiotensin aldosterone system. ACE acts to increase blood pressure through its actions on two peptides: angiotensin I and bradykinin. In light of this role ACE is a key target in the treatment of hypertension and ACE inhibitors have been widely used since the 1980s. Although these are effective drugs, a number of side effects are commonly associated with their use. These occur as a result of the inhibition of the roles of ACE in other physiological processes. Somatic ACE consists of two homologous domains, each with a functional peptidase active site. Only one of these domains, the C-domain, is required for blood pressure homeostasis. There is a great deal of interest in developing a new generation of ACE inhibitors to selectively target the C-domain, whilst leaving the N-domain active and able to fulfil the other biological functions of ACE. In the work presented here, AnCE, an ACE homologue from Drosophila melanogaster, has been used as a model to study the structural basis of ACE inhibition by a number of different inhibitory peptides. This has highlighted how interactions with active site residues could be exploited in the development of new, domain selective, inhibitors. ACE homologues in insects are thought to have a conserved role in reproduction. The ACE-like enzymes from Anopheles gambiae are of particular interest due to the role of this organism in the transmission of malaria. In the work presented here the recombinant expression of an ACE homologue from Anopheles gambiae is reported for the first time. This is an important step towards the structural and biochemical characterisation of these enzymes.

Date of Award	11 Feb 2016
Original language	English
Awarding Institution	University of Bath
Supervisor	Ravi Acharya (Supervisor)