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, 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.
Original language | English |
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Pages (from-to) | 15801-15822 |
Number of pages | 22 |
Journal | Journal of Medicinal Chemistry |
Volume | 66 |
Issue number | 23 |
Early online date | 04 Dec 2023 |
DOIs | |
Publication status | Published - 14 Dec 2023 |
Keywords
- Animals
- Female
- Humans
- Ligands
- Oviposition
- Schistosoma mansoni
- Schistosomiasis
- Schistosomiasis mansoni/drug therapy