Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:61 |
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| Enthalten in: |
Journal of medicinal chemistry - 61(2018), 9 vom: 10. Mai, Seite 3870-3888 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Blaazer, Antoni R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.05.2019 Date Revised 28.12.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.7b01670 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM283201371 |
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| 100 | 1 | |a Blaazer, Antoni R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity |
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| 500 | |a Date Revised 28.12.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Phosphodiesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Protozoan Proteins |2 NLM | |
| 650 | 7 | |a Trypanocidal Agents |2 NLM | |
| 650 | 7 | |a 3',5'-Cyclic-AMP Phosphodiesterases |2 NLM | |
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| 650 | 7 | |a PDEB1 protein, Trypanosoma brucei |2 NLM | |
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| 700 | 1 | |a Singh, Abhimanyu K |e verfasserin |4 aut | |
| 700 | 1 | |a de Heuvel, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a Edink, Ewald |e verfasserin |4 aut | |
| 700 | 1 | |a Orrling, Kristina M |e verfasserin |4 aut | |
| 700 | 1 | |a Veerman, Johan J N |e verfasserin |4 aut | |
| 700 | 1 | |a van den Bergh, Toine |e verfasserin |4 aut | |
| 700 | 1 | |a Jansen, Chimed |e verfasserin |4 aut | |
| 700 | 1 | |a Balasubramaniam, Erin |e verfasserin |4 aut | |
| 700 | 1 | |a Mooij, Wouter J |e verfasserin |4 aut | |
| 700 | 1 | |a Custers, Hans |e verfasserin |4 aut | |
| 700 | 1 | |a Sijm, Maarten |e verfasserin |4 aut | |
| 700 | 1 | |a Tagoe, Daniel N A |e verfasserin |4 aut | |
| 700 | 1 | |a Kalejaiye, Titilola D |e verfasserin |4 aut | |
| 700 | 1 | |a Munday, Jane C |e verfasserin |4 aut | |
| 700 | 1 | |a Tenor, Hermann |e verfasserin |4 aut | |
| 700 | 1 | |a Matheeussen, An |e verfasserin |4 aut | |
| 700 | 1 | |a Wijtmans, Maikel |e verfasserin |4 aut | |
| 700 | 1 | |a Siderius, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a de Graaf, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Maes, Louis |e verfasserin |4 aut | |
| 700 | 1 | |a de Koning, Harry P |e verfasserin |4 aut | |
| 700 | 1 | |a Bailey, David S |e verfasserin |4 aut | |
| 700 | 1 | |a Sterk, Geert Jan |e verfasserin |4 aut | |
| 700 | 1 | |a de Esch, Iwan J P |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, David G |e verfasserin |4 aut | |
| 700 | 1 | |a Leurs, Rob |e verfasserin |4 aut | |
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