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Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
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Darius J. B. McArdle,
Gilda Padalino ,
Anthony K. N. Chan ,
Josephine Forde-Thomas,
Michael McDonough,
Helen Whiteland,
Manfred Beckmann,
Rosa Cookson,
Karl F. Hoffmann ,
Stuart J. Conway
Journal of Medicinal Chemistry, Volume: 66, Issue: 23, Pages: 15801 - 15822
Swansea University Author:
Gilda Padalino
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DOI (Published version): 10.1021/acs.jmedchem.3c01321
Abstract
Schistosomiasis is a disease affecting >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,...
| Published in: | Journal of Medicinal Chemistry |
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| ISSN: | 0022-2623 1520-4804 |
| Published: |
American Chemical Society (ACS)
2023
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65218 |
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| Abstract: |
Schistosomiasis is a disease affecting >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 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 rational design of a quinoline-based ligand (15) with an ITC Kd = 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. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
M.S. was supported by the Deutsche Forschungsgemeinschaft (SCHI 1408/1-1). D.M. thanks the BBSRC and GSK for studentship support (BB/S507015/1). A.K.N.C. received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements No 660156. S.J.C. thanks St Hugh’s College, Oxford, for research support. S.J.C. is grateful to Michael and Alice Jung for endowing the Jung Chair in Medicinal Chemistry and Drug Discovery at UCLA, which partially supported this work. K.F.H. and the DLS coauthors thanks the Life Sciences National Research Network Wales for funding. |
| Issue: |
23 |
| Start Page: |
15801 |
| End Page: |
15822 |