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

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.

• Authors: 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 Graaf, Louis Maes, Harry P de Koning, David S Bailey, Geert Jan Sterk, Iwan J P de Esch, David G Brown, Rob Leurs
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 9 Pg. 3870-3888 (05 10 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29672041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Phosphodiesterase Inhibitors
• Protozoan Proteins
• Trypanocidal Agents
• 3',5'-Cyclic-AMP Phosphodiesterases
• PDEB1 protein, Trypanosoma brucei

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors, chemistry)
• Amides (chemistry, pharmacology)
• Catalytic Domain
• Inhibitory Concentration 50
• Models, Molecular
• Molecular Targeted Therapy
• Phosphodiesterase Inhibitors (chemistry, pharmacology)
• Protozoan Proteins (antagonists & inhibitors, chemistry)
• Structure-Activity Relationship
• Trypanocidal Agents (chemistry, pharmacology)
• Trypanosoma brucei brucei (drug effects, enzymology)