TY - JOUR
T1 - Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity
AU - Blaazer, Antoni R.
AU - Singh, Abhimanyu K.
AU - De Heuvel, Erik
AU - Edink, Ewald
AU - Orrling, Kristina M.
AU - Veerman, Johan J.N.
AU - Van Den Bergh, Toine
AU - Jansen, Chimed
AU - Balasubramaniam, Erin
AU - Mooij, Wouter J.
AU - Custers, Hans
AU - Sijm, Maarten
AU - Tagoe, Daniel N.A.
AU - Kalejaiye, Titilola D.
AU - Munday, Jane C.
AU - Tenor, Hermann
AU - Matheeussen, An
AU - Wijtmans, Maikel
AU - Siderius, Marco
AU - De Graaf, Chris
AU - Maes, Louis
AU - De Koning, Harry P.
AU - Bailey, David S.
AU - Sterk, Geert Jan
AU - De Esch, Iwan J.P.
AU - Brown, David G.
AU - Leurs, Rob
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.7b01670
DO - 10.1021/acs.jmedchem.7b01670
M3 - Article
AN - SCOPUS:85046411469
SN - 0022-2623
VL - 61
SP - 3870
EP - 3888
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -