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Targeting a subpocket in Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) enables the structure-based discovery of selective inhibitors with trypanocidal activity

DOI: 10.1021/acs.jmedchem.7b01670 DOI Help

Authors: Antoni R. Blaazer (Vrije Universiteit Amsterdam) , Abhimanyu K. Singh (University of Kent) , Erik De Heuvel (Vrije Universiteit Amsterdam) , Ewald Edink (Vrije Universiteit Amsterdam) , Kristina M. Orrling (Vrije Universiteit Amsterdam) , Johan J. N. Veerman (Mercachem) , Toine Van Den Bergh (Mercachem) , Chimed Jansen (Vrije Universiteit Amsterdam) , Erin Balasubramaniam (University of Kent) , Wouter J. Mooij (Vrije Universiteit Amsterdam) , Hans Custers (Vrije Universiteit Amsterdam) , Maarten Sijm (Vrije Universiteit Amsterdam) , Daniel N. A. Tagoe (University of Glasgow) , Titilola D. Kalejaiye (University of Glasgow) , Jane C. Munday (University of Glasgow) , Hermann Tenor (Topadur Pharma AG) , An Matheeussen (University of Antwerp) , Maikel Wijtmans (Vrije Universiteit Amsterdam) , Marco Siderius (Vrije Universiteit Amsterdam) , Chris De Graaf (Vrije Universiteit Amsterdam) , Louis Maes (University of Antwerp) , Harry P. De Koning (University of Glasgow) , David S. Bailey (IOTA Pharmaceuticals) , Geert Jan Sterk (Vrije Universiteit Amsterdam) , Iwan J. P. De Esch (Vrije Universiteit Amsterdam) , David G. Brown (University of Kent) , Rob Leurs (Vrije Universiteit Amsterdam)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: April 2018

Abstract: Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, pharmacological evaluation, and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent (Ki = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC50 = 5.5 and 6.7 ┬ÁM, respectively). Treatment of parasites with 8 caused an increase in intracellular cAMP levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography