2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors.

Henri T. Pätsi,Maija K. Lahtela-Kakkonen,Erik A. A. Wallén,Khaled Arja,Samuli Auno,Timo T. Myöhänen,Pyry M. J. Dillemuth,Tommi P. Kilpeläinen

doi:10.1021/acsmedchemlett.1c00399

Abstract

Different five-membered nitrogen-containing heteroaromatics in the position of the typical electrophilic group in prolyl oligopeptidase (PREP) inhibitors were investigated and compared to tetrazole. The 2-imidazoles were highly potent inhibitors of the proteolytic activity. The binding mode for the basic imidazole was studied by molecular docking as it was expected to differ from the acidic tetrazole. A new putative noncovalent binding mode with an interaction to His680 was found for the 2-imidazoles. Inhibition of the proteolytic activity did not correlate with the modulating effect on protein–protein-interaction-derived functions of PREP (i.e., dimerization of alpha-synuclein and autophagy). Among the highly potent PREP inhibiting 2-imidazoles, only one was also a potent modulator of PREP-catalyzed alpha-synuclein dimerization, indicating that the linker length on the opposite side of the molecule from the five-membered heteroaromatic is critical for the disconnected structure–activity relationships.

Highlights

Different five-membered nitrogen-containing heteroaromatics in the position of the typical electrophilic group in prolyl oligopeptidase (PREP) inhibitors were investigated and compared to tetrazole
We have recently shown that PREP can regulate alphasynuclein and protein phosphatase 2A (PP2A) via direct protein−protein interactions (PPIs), leading to increased αSyn aggregation[10] and decreased autophagy,[11,12] respectively
We have demonstrated that the effects of PREP ligands on αSyn dimerization and autophagy have no direct correlation to their IC50 values.[15,16]

Summary

Sar tetrazolyl

ALuminescence signal percentage of DMSO control with SEM. bGFP signal percentage of DMSO control with SEM. cJarho et al.,[26] measured with porcine brain homogenate. dKilpelaï nen et al.[15] eKilpelaï nen et al.[16] fConfidence interval could not be determined as IC50 value is higher than the maximum concentration used. gFirst reported by Tsutsumi et al.[18] hPREP activity at 1 nM inhibitor concentration compared to control.

Author Contributions

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES