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

  • ChemMedChem. 2022 Sep 16;17(18):e202100622. doi: 10.1002/cmdc.202100622.
Muhammad Murtaza Hassan  1  2 ,  Abootaleb Sedighi  1  2 ,  Olasunkanmi O Olaoye  1  2 ,  Cécile Häberli  3  4 ,  Annika Merz  5 ,  Elizabeth Ramos-Morales  6  7 ,  Elvin D de Araujo  1 ,  Christophe Romier  6  7 ,  Manfred Jung  5 ,  Jennifer Keiser  3  4 ,  Patrick T Gunning  1  2
Affiliations
  • 1. Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON L5L 1C6, Canada.
  • 2. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada.
  • 3. Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland.
  • 4. University of Basel, 4003, Basel, Switzerland.
  • 5. Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104, Freiburg, Germany.
  • 6. Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104, U 1258, 67400, Illkirch, France.
  • 7. Department of Integrated Structural Biology IGBMC, 1 rue Laurent Fries, B.P. 10142, 67404, Illkirch Cedex, France.
PMID: 35983937 DOI: 10.1002/cmdc.202100622
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 μM; MMH259, IC50 =2.3 μM) and adult S. mansoni (MMH258, IC50 =2.1 μM; MMH373, IC50 =3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.

Keywords
HDAC inhibitors; HDAC8 selective; Schistosoma mansoni; epigenetic therapy; schistosomiasis.
Products