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Small molecule ligands of the BET-like bromodomain, SmBRD3, affect Schistosoma mansoni survival, oviposition, and development
Open accessPreprint — published as 10.1021/acs.jmedchem.3c01321 · Paper page
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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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Schiedel, M., McArdle, D., Padalino, G., Chan, A., Forde-Thomas, J., McDonough, M., Whiteland, H., Beckmann, M., Cookson, R., Hoffmann, K., & Conway, S.
- Affiliations
- University of Oxford (GB)
- Aberystwyth University (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- University of California, Los Angeles (US)
- Corresponding author
- Hoffmann, Karl
- Conway, Stuart
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2023-06-26
- Volume
- 66
- Issue
- 23
- Pages
- 15801-15822
- ISSN
- 0022-2623 (ISSN-L)
- 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
- hybrid
- doi.org
- 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
- Deutsche Forschungsgemeinschaft (SCHI 1408/1-1)
- GlaxoSmithKline
- 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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