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Cited by 4Protein Degradation and InhibitorsParasites and Host InteractionsTrypanosoma species research and implications

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Small Molecule Ligands of the BET-like Bromodomain, Sm BRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development

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Schiedel, Matthias, McArdle, Darius J. B., Padalino, Gilda, Chan, Anthony K. N., Forde-Thomas, Josephine, McDonough, Michael, Whiteland, Helen, Beckmann, Manfred, Cookson, Rosa, Hoffmann, Karl F., Conway, Stuart J.·2023·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.3c01321PMC PMC10726355

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Abstract

Schistosomiasis is a disease affecting over 200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, Schistosoma mansoni. Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected SmBRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening of 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for SmBRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rationale design of a quinoline-based ligand (15) with an ITC Kd value of 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays. This compound will form the basis for future studies into new treatments for schistosomiasis.

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Metadata

Authors
Schiedel, M., McArdle, D. J. B., Padalino, G., Chan, A. K. N., Forde-Thomas, J., McDonough, M., Whiteland, H., Beckmann, M., Cookson, R., Hoffmann, K. F., & Conway, S. J.
Affiliations
  • University of Oxford (GB)
  • Aberystwyth University (GB)
  • GlaxoSmithKline (United Kingdom) (GB)
  • University of California, Los Angeles (US)
Corresponding author
  • Hoffmann, Karl F.
  • Conway, Stuart J.
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2023-12-04
Volume
66
Issue
23
Pages
15801-15822
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.3c01321
PMC
PMC10726355
OpenAlex
W4389302791
Cited by
4
References
1
Citations by year
2025: 1 · 2024: 2 · 2023: 1
FWCI
0.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Medicinal Chemistry (publishedVersion, cc-by)
  • ChemRxiv (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cronfa (Swansea University) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Life Sciences Research Network Wales
  • University of California, Los Angeles
  • Deutsche Forschungsgemeinschaft (SCHI 1408/1-1)
  • GlaxoSmithKline
  • Horizon 2020 Framework Programme (660156)
  • St. Hugh's College, University of Oxford
  • Biotechnology and Biological Sciences Research Council (BB/S507015/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
  • Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
Keywords
bromodomain, small-molecule ligands, Schistosoma mansoni, schistosomiasis, parasite survival, oviposition, parasite development, antiparasitic drug discovery
MeSH terms
Aminoquinolines, Animals, Benzoates, Female, Humans, Ligands, Oviposition, Schistosoma mansoni, Schistosomiasis, Schistosomiasis mansoni

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