Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity

Antoni R. Blaazer, Abhimanyu K. Singh, Erik De Heuvel, Ewald Edink, Kristina M. Orrling, Johan J.N. Veerman, Toine Van Den Bergh, Chimed Jansen, Erin Balasubramaniam, Wouter J. Mooij, Hans Custers, Maarten Sijm, Daniel N.A. Tagoe, Titilola D. Kalejaiye, Jane C. Munday, Hermann Tenor, An Matheeussen, Maikel Wijtmans, Marco Siderius, Chris De Graaf & 7 others Louis Maes, Harry P. De Koning, David S. Bailey, Geert Jan Sterk, Iwan J.P. De Esch, David G. Brown, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

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 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.

LanguageEnglish
Pages3870-3888
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Issue number9
Early online date19 Apr 2018
DOIs
Publication statusPublished - 10 May 2018

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Phosphodiesterase Inhibitors
Phosphoric Diester Hydrolases
Parasites
African Trypanosomiasis
Trypanosoma brucei brucei
Trypanosomiasis
Cyclic Nucleotides
Cyclic AMP
Inhibitory Concentration 50
Pharmacology
Ligands
Trypanosoma brucei PDEB1 protein
Enzymes
Pharmaceutical Preparations
neodymium pyrocatechin disulfonate
Therapeutics

Cite this

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. ; Custers, Hans ; Sijm, Maarten ; Tagoe, Daniel N.A. ; Kalejaiye, Titilola D. ; Munday, Jane C. ; Tenor, Hermann ; Matheeussen, An ; Wijtmans, Maikel ; Siderius, Marco ; De Graaf, Chris ; Maes, Louis ; De Koning, Harry P. ; Bailey, David S. ; Sterk, Geert Jan ; De Esch, Iwan J.P. ; Brown, David G. ; Leurs, Rob. / Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 9. pp. 3870-3888.
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title = "Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity",
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 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.",
author = "Blaazer, {Antoni R.} and Singh, {Abhimanyu K.} and {De Heuvel}, Erik and Ewald Edink and Orrling, {Kristina M.} and Veerman, {Johan J.N.} and {Van Den Bergh}, Toine and Chimed Jansen and Erin Balasubramaniam and Mooij, {Wouter J.} and Hans Custers and Maarten Sijm and Tagoe, {Daniel N.A.} and Kalejaiye, {Titilola D.} and Munday, {Jane C.} and Hermann Tenor and An Matheeussen and Maikel Wijtmans and Marco Siderius and {De Graaf}, Chris and Louis Maes and {De Koning}, {Harry P.} and Bailey, {David S.} and Sterk, {Geert Jan} and {De Esch}, {Iwan J.P.} and Brown, {David G.} and Rob Leurs",
year = "2018",
month = "5",
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Blaazer, AR, Singh, AK, De Heuvel, E, Edink, E, Orrling, KM, Veerman, JJN, Van Den Bergh, T, Jansen, C, Balasubramaniam, E, Mooij, WJ, Custers, H, Sijm, M, Tagoe, DNA, Kalejaiye, TD, Munday, JC, Tenor, H, Matheeussen, A, Wijtmans, M, Siderius, M, De Graaf, C, Maes, L, De Koning, HP, Bailey, DS, Sterk, GJ, De Esch, IJP, Brown, DG & Leurs, R 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, vol. 61, no. 9, pp. 3870-3888. https://doi.org/10.1021/acs.jmedchem.7b01670

Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity. / 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.; Custers, Hans; Sijm, Maarten; Tagoe, Daniel N.A.; Kalejaiye, Titilola D.; Munday, Jane C.; Tenor, Hermann; Matheeussen, An; Wijtmans, Maikel; Siderius, Marco; De Graaf, Chris; Maes, Louis; De Koning, Harry P.; Bailey, David S.; Sterk, Geert Jan; De Esch, Iwan J.P.; Brown, David G.; Leurs, Rob.

In: Journal of Medicinal Chemistry, Vol. 61, No. 9, 10.05.2018, p. 3870-3888.

Research output: Contribution to JournalArticleAcademicpeer-review

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

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SP - 3870

EP - 3888

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -