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

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 2023-12, Vol.66 (23), p.15801-15822
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Female
Humans
Ligands
Oviposition
Schistosoma mansoni
Schistosomiasis
Schistosomiasis mansoni - drug therapy
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Summary: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, . Having identified 29 putative bromodomains (BRDs) in 22 proteins, we selected BRD3, 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 BRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of BRD3 [ BRD3(2)] enabled rational design of a quinoline-based ligand ( ) with an ITC = 364 ± 26.3 nM for BRD3(2). The ethyl ester pro-drug of compound (compound ) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in assays.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c01321