STD NMR Epitope Perturbation by Mutation Unveils the Mechanism of YM155 as an Arginine-Glycosyltransferases Inhibitor Effective in Treating Enteropathogenic Diseases

Ramírez-Cárdenas, Jonathan ; Taleb, Víctor ; Calvaresi, Valeria ; Struwe, Weston B. ; El Qaidi, Samir ; Zhu, Congrui ; Hasan, Kamrul ; Zhang, Yingxin ; Hardwidge, Philip R. ; Veloz, Billy (Universidad de Zaragoza) ; Muñoz-García, Juan C. ; Hurtado-Guerrero, Ramón ; Angulo, Jesús

Resumen: Enteropathogenic arginine-glycosyltransferases (Arg-GTs) alter higher eukaryotic proteins by attaching a GlcNAc residue to arginine acceptor sites, disrupting essential pathways such as NF-κB signaling, which promotes bacterial survival. These enzymes are potential drug targets for treating related diseases. In this study, we present a novel STD NMR Epitope Perturbation by Mutation spectroscopic approach that, in combination with hydrogen–deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations, shows that the highly potent broad-spectrum anticancer drug YM155 serves as a potential noncompetitive inhibitor of these enzymes. It induces a conformation of the arginine acceptor site unfavorable for GlcNAc transfer, which underlies the molecular mechanism by which this compound exerts its inhibitory function. Finally, we also demonstrate that YM155 effectively treats enteropathogenic diseases in a mouse model, highlighting its therapeutic potential. Overall, our data suggest that this compound can be repurposed to not only treat cancer but also infectious diseases.

Idioma: Inglés

DOI: 10.1021/jacsau.4c01140

Año: 2025

Publicado en: JACS Au 5, 3 (2025), 1279-1288
ISSN: 2691-3704

Financiación: info:eu-repo/grantAgreement/ES/AEI/AEI/PID2022-142879NB-I00
Financiación: info:eu-repo/grantAgreement/ES/DGA/E34-17R
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP58_18
Financiación: info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)