Georgiadis Dimitris, Ziotopoulou Angeliki, Kaloumenou Eleni, Lelis Angelos, Papasava Antonia
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece.
Front Pharmacol. 2020 Sep 23;11:585838. doi: 10.3389/fphar.2020.585838. eCollection 2020.
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.
胰岛素调节氨肽酶（IRAP，EC 3.4.11.3）是锌氨肽酶M1家族中的一个多功能成员。在其多种生物学功能中，IRAP是妊娠后期催产素水平的调节剂，它通过4型葡萄糖转运蛋白的转运影响细胞对葡萄糖的摄取，并且它介导树突状细胞的抗原交叉呈递。越来越多的证据表明，对IRAP的药理学抑制可能有望成为治疗几种病理状态（如记忆障碍、神经退行性疾病等）的有效方法。为了研究IRAP的生理作用及其调节的治疗潜力，人们致力于发现小分子抑制剂。此外，IRAP最近的晶体结构和详细的计算研究极大地促进了可靠的构效关系的建立。本综述旨在总结药物化学家在设计和开发IRAP抑制剂方面的努力，特别强调影响抑制剂选择性的因素。
