Identification of an RNA-binding perturbing characteristic for thiopurine drugs and their derivatives to disrupt CELF1-RNA interaction.
Nucleic Acids Res
; 2024 Sep 12.
Article
en En
| MEDLINE
| ID: mdl-39268573
ABSTRACT
RNA-binding proteins (RBPs) are attractive targets in human pathologies. Despite a number of efforts to target RBPs with small molecules, it is still difficult to develop RBP inhibitors, asking for a deeper understanding of how to chemically perturb RNA-binding activity. In this study, we found that the thiopurine drugs (6-mercaptopurine and 6-thioguanine) effectively disrupt CELF1-RNA interaction. The disrupting activity relies on the formation of disulfide bonds between the thiopurine drugs and CELF1. Mutating the cysteine residue proximal to the RNA recognition motifs (RRMs), or adding reducing agents, abolishes the disrupting activity. Furthermore, the 1,2,4-triazole-3-thione, a thiopurine analogue, was identified with 20-fold higher disrupting activity. Based on this analogue, we found that compound 9 disrupts CELF1-RNA interaction in living cells and ameliorates CELF1-mediated myogenesis deficiency. In summary, we identified a thiol-mediated binding mechanism for thiopurine drugs and their derivatives to perturb protein-RNA interaction, which provides novel insight for developing RBP inhibitors. Additionally, this work may benefit the pharmacological and toxicity research of thiopurine drugs.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Reino Unido