Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity

Antoni R. Blaazer, Abhimanyu K. Singh, Erik De Heuvel, Ewald Edink, Kristina M. Orrling, Johan J.N. Veerman, Toine Van Den Bergh, Chimed Jansen, Erin Balasubramaniam, Wouter J. Mooij, Hans Custers, Maarten Sijm, Daniel N.A. Tagoe, Titilola D. Kalejaiye, Jane C. Munday, Hermann Tenor, An Matheeussen, Maikel Wijtmans, Marco Siderius, Chris De GraafLouis Maes, Harry P. De Koning, David S. Bailey, Geert Jan Sterk, Iwan J.P. De Esch, David G. Brown*, Rob Leurs

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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, and 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 μM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.

Original languageEnglish
Pages (from-to)3870-3888
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Issue number9
Early online date19 Apr 2018
DOIs
Publication statusPublished - 10 May 2018

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