Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development

Matthias Schiedel, Darius J B McArdle, Gilda Padalino, Anthony K N Chan, Josephine Forde-Thomas, Michael McDonough, Helen Whiteland, Manfred Beckmann, Rosa Cookson, Karl F Hoffmann, Stuart J Conway

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)15801-15822
Number of pages22
JournalJournal of Medicinal Chemistry
Volume66
Issue number23
Early online date04 Dec 2023
DOIs
Publication statusPublished - 14 Dec 2023

Keywords

  • Animals
  • Female
  • Humans
  • Ligands
  • Oviposition
  • Schistosoma mansoni
  • Schistosomiasis
  • Schistosomiasis mansoni/drug therapy

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