Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase

Abstract

The peptides angiotensin IV and LVV-hemorphin 7 were found to enhance memory in a number of memory tasks and reverse the performance deficits in animals with experimentally induced memory loss. These peptides bound specifically to the enzyme insulin-regulated aminopeptidase (IRAP), which is proposed to be the site in the brain that mediates the memory effects of these peptides. However, the mechanism of action is still unknown but may involve inhibition of the aminopeptidase activity of IRAP, since both angiotensin IV and LVV-hemorphin 7 are competitive inhibitors of the enzyme. IRAP also has another functional domain that is thought to regulate the trafficking of the insulin-responsive glucose transporter GLUT4, thereby influencing glucose uptake into cells. Although the exact mechanism by which the peptides enhance memory is yet to be elucidated, IRAP still represents a promising target for the development of a new class of cognitive enhancing agents.

Figure 1

Predicted domain structure of insulin-regulated aminopeptidase with key features highlighted.

Figure 2

Chemical structures of angiotensin IV and reported peptidomimetic analogues.

Figure 3

Ribbon representation of a homology model of the complete extracellular region of insulin-regulated aminopeptidase. The amino-terminal catalytic domain is highlighted in red with the catalytic zinc ion shown as a grey sphere.