STD NMR Epitope Perturbation by Mutation Unveils the Mechanism of YM155 as an Arginine-Glycosyltransferases Inhibitor Effective in Treating Enteropathogenic Diseases
Jonathan Ramírez-CárdenasVíctor TalebValeria CalvaresiWeston B. StruweSamir El QaidiCongrui ZhuKamrul HasanYingxin ZhangPhilip R. HardwidgeBilly VelozJuan C. Muñoz-García, Ramón Hurtado-Guerrero*and Jesús Angulo*. JACS Au. *joint corresponding authorship
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.
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.