Download MendeleyTargeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.
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., Leurs, R.(2018) J Med Chem 61: 3870-3888
- PubMed: 29672041
- DOI: https://doi.org/10.1021/acs.jmedchem.7b01670
- Primary Citation of Related Structures:
5G2B, 5G57, 5G5V, 5L8C, 5L8Y, 5L9H, 5LAQ, 5LBO - PubMed 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 i = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC 50 = 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.
Organizational Affiliation:
Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems , Vrije Universiteit Amsterdam , 1081 HZ Amsterdam , The Netherlands.
