Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers.

Two structurally distinct peptides, angiotensin IV and LVV-haemorphin 7, both competitive high-affinity inhibitors of insulin-regulated aminopeptidase (IRAP), were found to enhance aversion-associated and spatial memory in normal rats and to improve performance in a number of memory tasks in rat deficits models. These findings provide compelling support for the development of specific, high-affinity inhibitors of the enzyme as new cognitive enhancing agents. Different classes of IRAP inhibitors have been developed including peptidomimetics and small molecular weight compounds identified through in silico screening with a homology model of the catalytic domain of IRAP. The proof of principal that inhibition of IRAP activity results in facilitation of memory has been obtained by the demonstration that the small-molecule IRAP inhibitors also exhibit memory-enhancing properties.