Structure‐Based Design, Synthesis, and ...
Document type :
Article dans une revue scientifique: Article original
DOI :
PMID :
Title :
Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors
Author(s) :
Kalinin, Dmitrii [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems [DZIF]
Universität Hamburg = University of Hamburg [UHH]
Jana, Sunit [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
Pfafenrot, Maxim [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
Chakrabarti, Alokta [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Melesina, Jelena [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Shaik, Tajith [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Sippl, Wolfgang [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Jung, Manfred [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Holl, Ralph [Auteur correspondant]
German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems [DZIF]
Universität Hamburg = University of Hamburg [UHH]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems [DZIF]
Universität Hamburg = University of Hamburg [UHH]
Jana, Sunit [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
Pfafenrot, Maxim [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
Chakrabarti, Alokta [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Melesina, Jelena [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Shaik, Tajith [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Lancelot, Julien [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Sippl, Wolfgang [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Jung, Manfred [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Holl, Ralph [Auteur correspondant]
German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems [DZIF]
Universität Hamburg = University of Hamburg [UHH]
Journal title :
ChemMedChem
Pages :
571-584
Publisher :
Wiley-VCH Verlag
Publication date :
2019-12-09
ISSN :
1860-7179
English keyword(s) :
Schistosoma mansoni
crystal structures
histone deacetylases
molecular docking studies
triazole derivatives
crystal structures
histone deacetylases
molecular docking studies
triazole derivatives
HAL domain(s) :
Sciences du Vivant [q-bio]/Microbiologie et Parasitologie/Parasitologie
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biologie structurale [q-bio.BM]
Sciences du Vivant [q-bio]/Sciences pharmaceutiques/Médicaments
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biologie structurale [q-bio.BM]
Sciences du Vivant [q-bio]/Sciences pharmaceutiques/Médicaments
English abstract : [en]
Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial ...
Show more >Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2 b (N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4-fluorophenoxy derivative 21 (1-[5-chloro-2-(4-fluorophenoxy)phenyl]-N-hydroxy-1H-1,2,3-triazole-4-carboxamide), a nanomolar smHDAC8 inhibitor (IC50 =0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole-based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.Show less >
Show more >Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2 b (N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4-fluorophenoxy derivative 21 (1-[5-chloro-2-(4-fluorophenoxy)phenyl]-N-hydroxy-1H-1,2,3-triazole-4-carboxamide), a nanomolar smHDAC8 inhibitor (IC50 =0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole-based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
European Project :
Source :
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