The Discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review

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 crosspresentation 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.

Enhanced recombinant expression and purification of human IRAP for biochemical and crystallography studies

“…As an interesting feature of IRAP function, inhibiting IRAP activity has been shown to be a plausible way of enhancing memory [ 13 , 14 ]. To characterize inhibition of the purified IRAP, we select a short peptide inhibitor (VYPWT).…”

“…IRAP functions in different locations and pathways from ERAP1 and ERAP2 for MHC-I antigen presentation [ 4 , 6 ]. In addition to its immunological importance, IRAP is also a potential memory enhancing target for cognition improvement [ 13 , 14 ]. For most of the IRAP characterization studies reported so far, the recombinant protein was expressed with relatively low yields using mammalian cells such as HEK or COS7 cells, or insect cells sf9 or sf21 [ 8 , 9 , 15 , 16 , 26 , 28 ].…”

“…Even though the mechanism of IRAP inhibition in memory enhancement is not completely understood, it was postulated to effect the preservation of neuropeptides from degradation consequently increasing their half-life. Therefore, screening IRAP inhibitors with memory-enhancing properties has been an active area of research [ 10 , 13 , 14 ]. Despite these biological and pharmacological significances, crystal structures of IRAP were only determined recently, and at a low-intermediate resolution (2.5–3.4 Å) [ 9 , 15 , 16 ].…”

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

“…IRAP has been shown to be important in cross-presentation [ 266 ] and an IRAP inhibitor to be able to enhance cytotoxic responses ex vivo [ 267 ]. Furthermore, the development of inhibitors for these enzymes has reached significant maturity [ 268 , 269 , 270 ]. However, the synergism between inhibition of intracellular antigen processing by aminopeptidases and enhancement of antitumor immunity by ICI has not been explored yet.…”

Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Benzopyran-Based Inhibitors

“…Consequently, it is not surprising that during the last 10–15 years, considerable efforts have been devoted to the discovery of small molecule IRAP inhibitors as potential cognitive enhancers. Comprehensive reviews are now available, and existing IRAP inhibitors reported include drug-like scaffolds like sulfonamides (5) or benzopyrans (6–9, Figure 1 ) ( Hallberg, 2009 ; Barlow and Thompson, 2020 ; Georgiadis et al, 2020 ; Hallberg and Larhed, 2020 ). The later scaffold was identified in 2008 by virtual screening, and subsequently optimized resulting in a series coined as HFI (Howard Florey Institute) ( Albiston et al, 2008 ).…”