Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.

Autor: Hassan MM; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON L5L 1C6, Canada.; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada., Sedighi A; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON L5L 1C6, Canada.; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada., Olaoye OO; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON L5L 1C6, Canada.; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada., Häberli C; Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland.; University of Basel, 4003, Basel, Switzerland., Merz A; Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104, Freiburg, Germany., Ramos-Morales E; Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104, U 1258, 67400, Illkirch, France.; Department of Integrated Structural Biology IGBMC, 1 rue Laurent Fries, B.P. 10142, 67404, Illkirch Cedex, France., de Araujo ED; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON L5L 1C6, Canada., Romier C; Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104, U 1258, 67400, Illkirch, France.; Department of Integrated Structural Biology IGBMC, 1 rue Laurent Fries, B.P. 10142, 67404, Illkirch Cedex, France., Jung M; Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104, Freiburg, Germany., Keiser J; Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland.; University of Basel, 4003, Basel, Switzerland., Gunning PT; Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON L5L 1C6, Canada.; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2022 Sep 16; Vol. 17 (18), pp. e202100622. Date of Electronic Publication: 2022 Aug 19.
DOI: 10.1002/cmdc.202100622
Abstrakt: 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 IC 50 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, IC 50 =1.5 μM; MMH259, IC 50 =2.3 μM) and adult S. mansoni (MMH258, IC 50 =2.1 μM; MMH373, IC 50 =3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.
(© 2022 Wiley-VCH GmbH.)
Databáze: MEDLINE
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