Small molecule ligands of the BET-like bromodomain, SmBRD3, affect Schistosoma mansoni survival, oviposition, and development

26 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Schistosoma mansoni
medicinal chemistry

Supplementary materials

Supplementary Information
Supplementary figures and tables. Experimental details and methods. NMR spectra and HPLC traces for biologically tested compound.


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