An overview of glutaminyl cyclase inhibitors for Alzheimer's disease

Abstract

A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer's disease brains, including the pyroglutamate-Aβ (AβpE₃). AβpE₃ species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE₃, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn²⁺ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer's disease-modifying strategy.

Keywords: Alzheimer's disease • drug discovery; glutaminyl cyclase inhibitors; pyroglutamate-amyloid-β (AβpE3); small molecules.