Abstract
Insulin-Regulated Aminopeptidase (IRAP, EC 3.4.11.3) is a multi-tasking member of the M1 family of zinc aminopeptidases. Among its diverse biological functions, IRAP is a regulator of oxytocin levels during late stages of pregnancy, it affects cellular glucose uptake by trafficking of the glucose transporter type 4 and it mediates antigen cross-presentation by dendritic cells. Accumulating evidence show that pharmacological inhibition of IRAP may hold promise as a valid approach for the treatment of several pathological states such as memory disorders, neurodegenerative diseases, etc. Aiming to the investigation of physiological roles of IRAP and therapeutic potential of its regulation, intense research efforts have been dedicated to the discovery of small-molecule inhibitors. Moreover, reliable structure-activity relationships have been largely facilitated by recent crystal structures of IRAP and detailed computational studies. This review aims to summarize efforts of medicinal chemists toward the design and development of IRAP inhibitors, with special emphasis to factors affecting inhibitor selectivity.
Highlights
Insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3) is a type II transmembrane Znprotease that belongs to the M1 family of aminopeptidases (Rogi et al, 1996; Laustsen et al, 1997; Nomura et al, 2013)
In this mini-review, we present the different classes of IRAP inhibitors, we briefly discuss key interactions that govern inhibitor binding and we provide selectivity profile data and possible interpretation of observed selectivity
After two decades of intense efforts toward the discovery of IRAP inhibitors, it would not be an exaggeration to say that the field is still in its infancy
Summary
Insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3) is a type II transmembrane Znprotease that belongs to the M1 family of aminopeptidases (Rogi et al, 1996; Laustsen et al, 1997; Nomura et al, 2013). The development of IRAP inhibitors was initially aiming to the development of cognitive enhancers, applications in the regulation of immune responses or as antifibrotic agents are emerging fields of pharmacological interest. In this mini-review, we present the different classes of IRAP inhibitors, we briefly discuss key interactions that govern inhibitor binding and we provide selectivity profile data and possible interpretation of observed selectivity. Regardless of the methodology, general conclusions on the comparison of inhibition profiles are not significantly affected by this discrepancy
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