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

Blaazer, A. R. et al. (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. (doi:10.1021/acs.jmedchem.7b01670) (PMID:29672041) (PMCID:PMC5949723)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:kalejaiye, Titilola and Munday, Dr Jane and De Koning, Professor Harry
Authors: Blaazer, A. R., Singh, A. K., de Heuvel, E., Edink, E., Orrling, K. M., Veerman, J. J. N., van den Bergh, T., Jansen, C., Balasubramaniam, E., Mooij, W. J., Custers, H., Sijm, M., Tagoe, D. N.A., kalejaiye, T. D., Munday, J. C., Tenor, H., Matheeussen, A., Wijtmans, M., Siderius, M., de Graaf, C., Maes, L., de Koning, H. P., Bailey, D. S., Sterk, G. J., de Esch, I. J. P., Brown, D. G., and Leurs, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN (Online):1520-4804
Published Online:19 April 2018
Copyright Holders:Copyright © 2018 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 61(9): 3870-3888
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620151PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - PARASITOLOGY

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