Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i>
Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH<sup>+</sup> and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant def...
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MDPI AG
2021-01-01
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| Series: | Molecules |
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| author | Cecilia Ortíz Francesca Moraca Marc Laverriere Allan Jordan Niall Hamilton Marcelo A. Comini |
| author_facet | Cecilia Ortíz Francesca Moraca Marc Laverriere Allan Jordan Niall Hamilton Marcelo A. Comini |
| author_sort | Cecilia Ortíz |
| collection | DOAJ |
| description | Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH<sup>+</sup> and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In <i>Trypanosoma cruzi</i>, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent <i>T. cruzi</i> G6PDH inhibitors than the corresponding β-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit μM EC<sub>50</sub> against infective <i>T. brucei</i> and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH<sup>+</sup>-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis. |
| first_indexed | 2024-03-09T05:05:55Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T05:05:55Z |
| publishDate | 2021-01-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-523a400c62a14a129093f53b8d75ab5a2023-12-03T12:54:44ZengMDPI AGMolecules1420-30492021-01-0126235810.3390/molecules26020358Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i>Cecilia Ortíz0Francesca Moraca1Marc Laverriere2Allan Jordan3Niall Hamilton4Marcelo A. Comini5Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, UruguayDipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, ItalyInstituto de Investigaciones Biotecnológicas, Instituto Tecnológico de Chascomus (IIB-INTECH, UNSAM-CONICET), Av. General Paz 5445, INTI, San Martín 1650, Pcia de Buenos Aires, ArgentinaDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, UKDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, UKRedox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, UruguayGlucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH<sup>+</sup> and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In <i>Trypanosoma cruzi</i>, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent <i>T. cruzi</i> G6PDH inhibitors than the corresponding β-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit μM EC<sub>50</sub> against infective <i>T. brucei</i> and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH<sup>+</sup>-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.https://www.mdpi.com/1420-3049/26/2/358androstaneredox<i>Trypanosoma brucei</i><i>Trypanosoma cruzi</i>pentose phosphate pathway |
| spellingShingle | Cecilia Ortíz Francesca Moraca Marc Laverriere Allan Jordan Niall Hamilton Marcelo A. Comini Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i> Molecules androstane redox <i>Trypanosoma brucei</i> <i>Trypanosoma cruzi</i> pentose phosphate pathway |
| title | Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i> |
| title_full | Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i> |
| title_fullStr | Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i> |
| title_full_unstemmed | Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i> |
| title_short | Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream <i>Trypanosoma brucei</i> |
| title_sort | glucose 6 phosphate dehydrogenase from trypanosomes selectivity for steroids and chemical validation in bloodstream i trypanosoma brucei i |
| topic | androstane redox <i>Trypanosoma brucei</i> <i>Trypanosoma cruzi</i> pentose phosphate pathway |
| url | https://www.mdpi.com/1420-3049/26/2/358 |
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