Hassan, M. M. and Sedighi, A. and Olaoye, O. O. and Haberli, C. and Merz, A. and Ramos-Morales, E. and de Araujo, E. D. and Romier, C. and Jung, M. and Keiser, J. and Gunning, P. T.. (2022) Phenotypic screening of histone deacetylase (HDAC) inhibitors against Schistosoma mansoni. ChemMedChem. e202100622.
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Official URL: https://edoc.unibas.ch/90531/
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Abstract
Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with >10-fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100 nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50 =1.5 muM; MMH259, IC50 =2.3 muM) and adult S. mansoni (MMH258, IC50 =2.1 muM; MMH373, IC50 =3.4 muM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.
Faculties and Departments: | 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Helminth Drug Development (Keiser) |
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UniBasel Contributors: | Häberli, Cécile and Keiser, Jennifer |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
ISSN: | 1860-7187 (Electronic)1860-7179 (Linking) |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Identification Number: |
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Last Modified: | 27 Dec 2022 09:38 |
Deposited On: | 27 Dec 2022 09:38 |
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