Understanding IRAP inhibition using diverse substrates, inhibitors and mutagenesis — ASN Events
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  3. Understanding IRAP inhibition using diverse substrates, inhibitors and mutagenesis

Understanding IRAP inhibition using diverse substrates, inhibitors and mutagenesis (#318)

Rie Nakao 1 , Nicholas Barlow 1 , Anika Vear 2 , Siew Yeen Chai 2 , Adam Kennedy 3 , Andrea Robinson 3 , Philip Thompson 1
  1. Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria, Australia
  2. Department of Physiology, Monash Biomedicine Discovery Institute, Monash University , Clayton, Victoria, Australia
  3. School of Chemistry, Monash University , Clayton, Victoria, Australia

Insulin-regulated aminopeptidase, IRAP is known to control key physiological functions of the body by processing a range of substrates, notably oxytocin and vasopressin. The hexapeptide Ang IV and its analogues have been found to inhibit IRAP’s catalytic activity and also to markedly enhanced memory retention and retrieval in rats. Therefore, IRAP may be a target for the development of a new class of therapeutic agents for the treatment of memory loss. My research aims to study the biochemistry of IRAP and its inhibitors utilising a combination of techniques. Firstly, using novel fluorescently labelled substrates we showed that different inhibitor classes have substrate dependence. Secondly, we have also proposed a distinction in the binding mode of Ang IV analogues that act as inhibitors or as substrates. Third, we showed that altering the oxytocin disulfide by isosteres alters the susceptibility to IRAP hydrolysis. We have employed mutagenesis of the IRAP catalytic site together with molecular modelling to generate complementary data with respect to IRAP’s engagement with substrates and inhibitors. The generated data will give us insights into the design of drug-like IRAP inhibitors.

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