STD NMR Epitope Perturbation by Mutation Unveils the Mechanism of YM155 as an Arginine-Glycosyltransferases Inhibitor Effective in Treating Enteropathogenic 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.
Authors
- Weston B. Struwe (ORCID: https://orcid.org/0000-0003-0594-226X)
- Samir El Qaidi
- Juan C. Muñoz–García (ORCID: https://orcid.org/0000-0003-2246-3236)
- Víctor Taleb (ORCID: https://orcid.org/0000-0001-9224-5854)
- Valeria Calvaresi (ORCID: https://orcid.org/0000-0002-1756-8853)
- Congrui Zhu (ORCID: https://orcid.org/0000-0002-0905-9979)
- Philip R. Hardwidge (ORCID: https://orcid.org/0000-0002-3540-7199)
- Jesús Angulo (ORCID: https://orcid.org/0000-0001-7250-5639)
- Ramón Hurtado‐Guerrero (ORCID: https://orcid.org/0000-0002-3122-9401)
- Jonathan Ramírez-Cárdenas (ORCID: https://orcid.org/0000-0003-4357-228X)
- Billy Veloz
- Kamrul Hasan
- Yingxin Zhang (ORCID: https://orcid.org/0009-0001-5214-7456)
Institutions
- University of Copenhagen (DK)
- Kansas State University (US)
- Universidad de Zaragoza (ES)
- University of Oxford (GB)
- Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES)
- Centro de Investigaciones Científicas Isla de la Cartuja (ES)
- Instituto de Investigaciones Químicas (ES)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- JACS Au
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1021/jacsau.4c01140
- Citations
- 2
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- UK Research and Innovation
- Ministerio de Ciencia, Innovación y Universidades
- European Regional Development Fund
- Agencia Estatal de Investigación
- Departamento de Educación, Cultura y Deporte, Gobierno de Aragón