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, Schistosoma mansoni . Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected Sm 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 Sm BRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of Sm BRD3 [ Sm BRD3(2)] enabled rational design of a quinoline-based ligand ( 15 ) with an ITC K d = 364 ± 26.3 nM for Sm BRD3(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.