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Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 May 10; Vol. 61 (9), pp. 3870-3888. Date of Electronic Publication: 2018 May 01. - Publication Year :
- 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, 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 ( K <subscript>i</subscript> = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC <subscript>50</subscript> = 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.
- Subjects :
- 3',5'-Cyclic-AMP Phosphodiesterases chemistry
Amides chemistry
Amides pharmacology
Catalytic Domain
Inhibitory Concentration 50
Models, Molecular
Molecular Targeted Therapy
Protozoan Proteins chemistry
Structure-Activity Relationship
3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors
Phosphodiesterase Inhibitors chemistry
Phosphodiesterase Inhibitors pharmacology
Protozoan Proteins antagonists & inhibitors
Trypanocidal Agents chemistry
Trypanocidal Agents pharmacology
Trypanosoma brucei brucei drug effects
Trypanosoma brucei brucei enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29672041
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01670