Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design

Abstract

Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.

Enhancement of epidermal growth factor receptor antibody tumor immunotherapy by glutaminyl cyclase inhibition to interfere with CD47/signal regulatory protein alpha interactions

“…Interestingly, inhibition of QC enzymes affects posttranslational pyro‐glutamate formation in many proteins, such as several chemokines, hormones, and other secreted proteins or peptides such as Aβ 46 . The prototypic QC inhibitor SEN177 used in this manuscript is not suitable for in vivo studies due to off‐target toxicity, but more specific and less toxic molecules have been developed 47 . The clinically most advanced QC inhibitor PQ912 is developed for the treatment of Alzheimer’s disease.…”

“… 46 The prototypic QC inhibitor SEN177 used in this manuscript is not suitable for in vivo studies due to off‐target toxicity, but more specific and less toxic molecules have been developed. 47 The clinically most advanced QC inhibitor PQ912 is developed for the treatment of Alzheimer’s disease. Although numerous molecules could be affected by QC inhibition, which could result in potential side‐effects, the application of the QC inhibitor PQ912 in humans shows that it is well tolerated with only mild anemia commonly observed.…”

Estimating the ligand‐binding affinity via λ‐dependent umbrella sampling simulations

“…[ 37,38 ] Furthermore, during free energy simulations, the nature of binding being clarified would be the basis for designing new inhibitors. [ 39–41 ]…”

Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery

“…Rational drug discovery and design has progressed at a precipitous pace with the aid of in silico strategies and innovations in hardware and computational power. While still in its infancy as compared to traditional drug discovery techniques, computer-aided drug discovery (CADD) has helped deliver several success stories [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ] that inspired confidence in its continuous application in the pharmaceutical industry. CADD lends cost- and labor-efficiency in the identification of potential hits for a therapeutic target before delving into extensive experimental assays.…”