The in vivo characterisation of a C-domain specific ACE inhibitor

The ACE protein is a zinc-dependent dipeptidyl carboxypeptidase comprised of two homologous domains termed the C- and N-domain. The C-domain is primarily responsible for the catalytic production of Ang II, while the tetrapeptide acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is predominantly cleaved by the N-domain, and both domains play a role in the metabolism of vasodilatory peptide bradykinin. In the event of myocardial infarction (MI), cardiac output and blood pressure decreases, resulting in activation of the RAS and an increase in both Ang II production and bradykinin metabolism. While initially compensatory, prolonged RAS activation has been shown to have long-term detrimental effects, and pharmaceutical intervention in the form of ACE inhibition is the first line treatment following an MI event. The ACE inhibitors currently in clinical use target both domains equally, and it has been suggested that the major side-effects of this drug class are largely attributable to the inhibition of bradykinin breakdown. A novel C-domain selective ACE inhibitor lisinopril-Trp (lisW-S) incorporates a tryptophan moiety into the P2' position of the clinically available ACE inhibitor lisinopril.

Grantor dc:publisher.institution

Department of Surgery

Year dc:date.issued

2013

Author dc:creator

• Sharp, Sarah-Kate

Advisor dc:contributor.advisor

• Davies, Neil

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/11555

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/11555