Significance: The human immune system fights disease by eradicating sick cells after first recognizing that they are infected or cancerous. This is achieved by specialized cells that detect on the surface of other cells small molecules called antigenic peptides. Pathogens and cancer can evade the immune system by stopping the generation of antigenic peptides. We designed, synthesized and evaluated artificial small molecules that can effectively block a group of enzymes that are key for the production or destruction of antigenic peptides. We show that these compounds can enhance the generation of antigenic peptides in cells and enhance the immune system reaction toward cancer. Inhibitors of this kind may provide a new approach to coax the immune system into recognizing and eliminating cancer cells.

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.