Glutaminyl Cyclase and Its Inhibitors

Year 2022, Volume: 6 Issue: 1, 59 - 75, 15.07.2022

Kaan Küçükoğlu Yasemin Gülbahar Açıl

Abstract

Human glutaminyl cyclase (hQC), which has two isoforms, is an important enzyme that catalyzes pyroglutamate modification. N-Terminal pyroglutamate (pE) modification is an important post-translational event in mammals. The pE modification catalyzed by QC is a necessary modification for the maturation and function of many proteins and peptides. However, studies have shown that the increase in the amount of QC is associated with some diseases. With the abnormal increase in the secretion of QC, Alzheimer's (AD), Huntington's disease (HD), melanomas, thyroidcarcinomas, rapid formation of atherosclerosis, septic arthritis occur. With this abnormal increase, the increase in pE-amyloid beta (Aβ) and pE-chemokine ligand (CCL2) formation resulting from pE modification catalyzed by QC may cause various pathologies. Considering the consequences of abnormal secretion of QC and predisposing to the formation of diseases, it was aimed to reduce the formation of pE-modified mediators by inhibiting QC. The discovery of new drugs to inhibit QC is considered an important approach for the prevention and treatment of many physiological problems and diseases, including AD, inflammation, cancer. Therefore, it was thought that these pathological conditions could be prevented by QC inhibition, and various QC inhibitors were developed to combat it. In this review, various QC inhibitors, and their molecular structures, activities and also possible treatment options were examined. Extensive research has been done on varoglutamstat, which is in phase 2 of clinical trials, and QC inhibitors in general are summarized.

Keywords

Alzheimer, Amyloid Beta, Glutaminyl cyclase enzyme, Pyroglutamate modification, Varoglutamstat

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