Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development

Schiedel, Matthias; B., Darius J.; Padalino, Gilda; N., Anthony K.; Forde-Thomas, Josephine; McDonough, Michael; Whiteland, Helen; Beckmann, Manfred; Cookson, Rosa; Hoffmann, Karl F.; Conway, Stuart J.

doi:10.1021/acs.jmedchem.3c01321

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Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development

Matthias Schiedel

, 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,...

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Published in:	Journal of Medicinal Chemistry
ISSN:	0022-2623 1520-4804
Published:	American Chemical Society (ACS) 2023
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa65218
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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). 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spelling	v2 65218 2023-12-05 Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false 2023-12-05 PHAR 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. Journal Article Journal of Medicinal Chemistry 66 23 15801 15822 American Chemical Society (ACS) 0022-2623 1520-4804 14 12 2023 2023-12-14 10.1021/acs.jmedchem.3c01321 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University Another institution paid the OA fee 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. 2024-04-09T16:17:23.3445872 2023-12-05T11:50:51.9027928 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Matthias Schiedel 0000-0001-7365-3617 1 Darius J. B. McArdle 2 Gilda Padalino 0000-0001-8580-1293 3 Anthony K. N. Chan 0000-0002-7091-1294 4 Josephine Forde-Thomas 5 Michael McDonough 6 Helen Whiteland 7 Manfred Beckmann 8 Rosa Cookson 9 Karl F. Hoffmann 0000-0002-3932-5502 10 Stuart J. Conway 0000-0002-5148-117x 11 65218__29374__fea72e6ca74a499cb686d8324059492a.pdf 65218.pdf 2024-01-04T12:10:14.5342549 Output 12110977 application/pdf Version of Record true This publication is licensed under the terms of a CC-BY 4.0. license. true eng https://creativecommons.org/licenses/by/4.0/
title	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
spellingShingle	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development Gilda Padalino
title_short	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
title_full	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
title_fullStr	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
title_full_unstemmed	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
title_sort	Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
author_id_str_mv	7e5526209f02734f57ba19b0d17604ec
author_id_fullname_str_mv	7e5526209f02734f57ba19b0d17604ec_***_Gilda Padalino
author	Gilda Padalino
author2	Matthias Schiedel 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
format	Journal article
container_title	Journal of Medicinal Chemistry
container_volume	66
container_issue	23
container_start_page	15801
publishDate	2023
institution	Swansea University
issn	0022-2623 1520-4804
doi_str_mv	10.1021/acs.jmedchem.3c01321
publisher	American Chemical Society (ACS)
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
document_store_str	1
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description	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.
published_date	2023-12-14T16:17:19Z
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Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development

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