Title :

Structure-Based Design and Synthesis of Novel Inhibitors targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis

Author(s) :

Heimburg, Tino [Auteur]
Chakrabarti, Alokta [Auteur]
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Marek, Martin [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Melesina, Jelena [Auteur]
Hauser, Alexander-Thomas [Auteur]
Shaik, Tajith [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Duclaud, Sylvie [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Robaa, Dina [Auteur]
Erdmann, Frank [Auteur]
Schmidt, Matthias [Auteur]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Jung, Manfred [Auteur]
Sippl, Wolfgang [Auteur]

Journal title :

Journal of Medicinal Chemistry

Pages :

2423-2435

Publisher :

American Chemical Society

Publication date :

2016-03-24

ISSN :

0022-2623

English keyword(s) :

Schistosoma mansoni
smHDAC8
histone deacetylase
co-crystallization
docking
anti-parasitic inhibitors

HAL domain(s) :

Chimie/Chimie thérapeutique

English abstract : [en]

Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this ...
Show more >Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates was prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amido-benzohydroxamates. The newly-designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range and some of them showed selectivity towards smHDAC8 compared to the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant, dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL