Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation

View ORCID ProfileG. Padalino, C. A. Celatka, H. Y. Rienhoff Jr., J. H. Kalin, P. A. Cole, View ORCID ProfileD. Lassalle, View ORCID ProfileC. Grunau, View ORCID ProfileI. W. Chalmers, View ORCID ProfileA. Brancale, K. F. Hoffmann
doi: https://doi.org/10.1101/2020.09.17.301184
G. Padalino
1Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, SY23 3DA, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for G. Padalino
C. A. Celatka
2Imago BioSciences, 2729 Debbie Court, San Carlos, CA 94070, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
H. Y. Rienhoff Jr.
2Imago BioSciences, 2729 Debbie Court, San Carlos, CA 94070, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. H. Kalin
3Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P. A. Cole
3Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D. Lassalle
4IHPE, Univ. Montpellier, CNRS, Ifremer, University Perpignan, Via Domitia, 58 Av Paul Alduy, 66860 Perpigna, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for D. Lassalle
C. Grunau
4IHPE, Univ. Montpellier, CNRS, Ifremer, University Perpignan, Via Domitia, 58 Av Paul Alduy, 66860 Perpigna, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for C. Grunau
I. W. Chalmers
1Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, SY23 3DA, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for I. W. Chalmers
A. Brancale
5School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for A. Brancale
K. F. Hoffmann
1Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, SY23 3DA, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: krh@aber.ac.uk
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Schistosomiasis is a chronically-debilitating neglected tropical disease (NTD) that predominantly affects people living in resource-poor communities of tropical and subtropical countries. Schistosoma mansoni, one of three species responsible for most human infections, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic- and epigenetic- processes. As inhibition of S. mansoni epigenetic machinery components has been shown to impair key transitions throughout the parasite’s digenetic lifecycle, this knowledge is currently fuelling the search for new epi-drug - based anthelmintics.

In this study, the anti-schistosomal activity of 39 re-purposed Homo sapiens Lysine Specific Demethylase 1 (HsLSD1) inhibitors was investigated on key life cycle stages associated with both definitive (schistosomula, juvenile worms, sexually-mature adults) and intermediate host (miracidia) infection. The most active compound (compound 33; e.g. schistosomula phenotype EC50 = 4.370 µM; adult worm motility EC50 = 2.137 µM) was subsequently used to provide further insight into the critical role of S. mansoni lysine specific demethylase 1 (SmLSD1) in adult worm oviposition and stem cell proliferation. Here, compound 33 treatment of adult schistosomes led to significant defects in egg production, intra-egg vitellocyte/ovum packaging and gonadal/neoblast stem cell proliferation. A greater abundance of H3K4me2 marks accompanied these phenotypes and supported specific inhibition of SmLSD1 in adult schistosomes by compound 33. In silico screening indicated that compound 33 likely inhibits SmLSD1 activity by covalently reacting with the FAD cofactor.

This work suggests that evaluation of HsLSD1 - targeting epi-drugs could have utility in the search for next-generation anti-schistosomals. The ability of compound 33 to inhibit parasite survival, oviposition, H3K4me2 demethylation and stem cell proliferation warrants further investigations of this compound and its epigenetic target. This data further highlights the importance of histone methylation in S. mansoni lifecycle transitions.

Author summary Affecting over 200 million people, schistosomiasis is a chronic disease caused by the parasitic worm Schistosoma mansoni. The frontline drug for schistosomiasis treatment is praziquantel. Owing to the concern surrounding praziquantel insensitivity or resistance developing, current research is directed towards the identification of novel drugs. We have focused our search for compounds that affect essential aspects of schistosome biology including parasite movement, fertility, cell proliferation and survival. Since all of these functions are potentially influenced by epigenetic regulation of gene expression, we investigated the activity of compounds that alter histone methylation status. In this report, we show that S. mansoni Lysine Specific Demethylase 1 (SmLSD1), a histone demethylase, is critical to miracidia-to-sporocyst transitioning, adult worm motility, egg production and parasite survival. Inhibition of SmLSD1 with compounds developed to inhibit the human paralog show promising potential as novel anti-schistosomal agents.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted September 17, 2020.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation
G. Padalino, C. A. Celatka, H. Y. Rienhoff Jr., J. H. Kalin, P. A. Cole, D. Lassalle, C. Grunau, I. W. Chalmers, A. Brancale, K. F. Hoffmann
bioRxiv 2020.09.17.301184; doi: https://doi.org/10.1101/2020.09.17.301184
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation
G. Padalino, C. A. Celatka, H. Y. Rienhoff Jr., J. H. Kalin, P. A. Cole, D. Lassalle, C. Grunau, I. W. Chalmers, A. Brancale, K. F. Hoffmann
bioRxiv 2020.09.17.301184; doi: https://doi.org/10.1101/2020.09.17.301184

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Microbiology
Subject Areas
All Articles
  • Animal Behavior and Cognition (2653)
  • Biochemistry (5289)
  • Bioengineering (3698)
  • Bioinformatics (15837)
  • Biophysics (7284)
  • Cancer Biology (5644)
  • Cell Biology (8126)
  • Clinical Trials (138)
  • Developmental Biology (4786)
  • Ecology (7558)
  • Epidemiology (2059)
  • Evolutionary Biology (10611)
  • Genetics (7749)
  • Genomics (10171)
  • Immunology (5230)
  • Microbiology (13974)
  • Molecular Biology (5402)
  • Neuroscience (30899)
  • Paleontology (217)
  • Pathology (885)
  • Pharmacology and Toxicology (1527)
  • Physiology (2262)
  • Plant Biology (5039)
  • Scientific Communication and Education (1045)
  • Synthetic Biology (1400)
  • Systems Biology (4160)
  • Zoology (815)