Targeting a Large Active Site : Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim..
Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas' disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Chemistry (Weinheim an der Bergstrasse, Germany) - 25(2019), 49 vom: 02. Sept., Seite 11416-11421 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
De Gasparo, Raoul [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.10.2019 Date Revised 08.01.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/chem.201901664 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM300183062 |
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| 520 | |a © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. | ||
| 520 | |a Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas' disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies | ||
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| 700 | 1 | |a Diederich, François |e verfasserin |4 aut | |
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