Small Molecule Ligands of the BET-like Bromodomain, Sm BRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development
Year: 2023
Type: article
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.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: GlaxoSmithKline, St. Hugh's College, University of Oxford, University of Oxford, European Commission, Deutsche Forschungsgemeinschaft, Life Sciences Research Network Wales, University of California, Los Angeles, Horizon 2020 Framework Programme, Biotechnology and Biological Sciences Research Council
OpenAlex ID: W4389302791