Blaazer, Antoni R., Singh, Abhimanyu K., de Heuvel, Erik, Edink, Ewald, Orrling, Kristina M., Veerman, Johan J. N., van den Bergh, Toine, Jansen, Chimed, Balasubramaniam, Erin, Mooij, Wouter J., and others. (2018) Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity. Journal of Medicinal Chemistry, 61 (9). pp. 3870-3888. ISSN 0022-2623. (doi:10.1021/acs.jmedchem.7b01670) (KAR id:67365)
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| Official URL: https://doi.org/10.1021/acs.jmedchem.7b01670 |
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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 ?M, 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.
| Item Type: | Article |
|---|---|
| DOI/Identification number: | 10.1021/acs.jmedchem.7b01670 |
| Subjects: |
Q Science Q Science > QR Microbiology |
| Divisions: | Divisions > Division of Natural Sciences > Biosciences |
| Depositing User: | David Brown |
| Date Deposited: | 19 Jun 2018 14:34 UTC |
| Last Modified: | 05 Nov 2024 11:07 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/67365 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Singh, Abhimanyu K..
| Creator's ORCID: | |
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| CReDIT Contributor Roles: |
Brown, David G..
| Creator's ORCID: |
 https://orcid.org/0000-0003-4605-4779
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| CReDIT Contributor Roles: |
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