Slow-binding inhibitors of prolyl oligopeptidase with different functional groups at the P1 site

The Biochemical Journal
Jarkko I VenäläinenPekka T Männistö

Abstract

POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied. In the present study, we examined the effect of different functional groups at the P1 site of the parent inhibitor isophthalic acid bis-(L-prolylpyrrolidine) amide on the binding kinetics to POP. Addition of CHO, CN or COCH(2)OH groups to the P1 site increased the inhibitory potency by two orders of magnitude (K(i)=11.8-0.1 nM) and caused a clear slow-binding inhibition. The inhibitor containing a CHO group had the lowest association rate constant, k(on)=(2.43+/-0.12) x 10(5) M(-1) x s(-1), whereas the inhibitor with a CN group exhibited the fastest binding, k(on)=(12.0+/-0.08)x10(5) M(-1) x s(-1). In addition, the dissociation rate was found to be crucially dependent on the type of the functional group. Compounds with COCH(...Continue Reading

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Citations

Dec 22, 2009·SAR and QSAR in Environmental Research·K KaszubaA Bunker
Sep 13, 2013·Future Medicinal Chemistry·Abraham LópezErnest Giralt
Jan 13, 2006·Biochemical Pharmacology·Jarkko I VenäläinenPekka T Männistö
Jan 8, 2017·Protein Engineering, Design & Selection : PEDS·R Van ElzenA M Lambeir
Mar 3, 2018·Nature Communications·Justin M Di TraniAnthony K Mittermaier
May 5, 2011·Expert Opinion on Therapeutic Patents·Abraham LópezErnest Giralt
Jan 12, 2010·Journal of Medicinal Chemistry·Janice LawandiNicolas Moitessier

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