Rational Design of Dual-Domain Binding Inhibitors for N-Acetylgalactosamine Transferase 2 with Improved Selectivity over the T1 and T3 Isoforms

Compañón, Ismael ; Ballard, Collin J. ; Lira-Navarrete, Erandi ; Santos, Tanausú ; Monaco, Serena ; Muñoz-García, Juan C. ; Delso, Ignacio ; Angulo, Jesus ; Gerken, Thomas A. ; Schjoldager, Katrine T. ; Clausen, Henrik ; Tejero, Tomás (Universidad de Zaragoza) ; Merino, Pedro (Universidad de Zaragoza) ; Corzana, Francisco ; Hurtado-Guerrero, Ramon ; Ghirardello, Mattia

Resumen: The GalNAc-transferase (GalNAc-T) family, consisting of 20 isoenzymes, regulates the O-glycosylation process of mucin glycopeptides by transferring GalNAc units to serine/threonine residues. Dysregulation of specific GalNAc-Ts is associated with various diseases, making these enzymes attractive targets for drug development. The development of inhibitors is key to understanding the implications of GalNAc-Ts in human diseases. However, developing selective inhibitors for individual GalNAc-Ts represents a major challenge due to shared structural similarities among the isoenzymes and some degree of redundancy among the natural substrates. Herein, we report the development of a GalNAc-T2 inhibitor with higher potency compared to those of the T1 and T3 isoforms. The most promising candidate features bivalent GalNAc and thiophene moieties on a peptide chain, enabling binding to both the lectin and catalytic domains of the enzyme. The binding mode was confirmed by competitive saturation transfer difference NMR experiments and validated through molecular dynamics simulations. The inhibitor demonstrated an IC50 of 21.4 μM for GalNAc-T2, with 8- and 32-fold higher selectivity over the T3 and T1 isoforms, respectively, representing a significant step forward in the synthesis of specific GalNAc-T inhibitors tailored to the unique structural features of the targeted isoform.

Idioma: Inglés

DOI: 10.1021/jacsau.4c00633

Año: 2024

Publicado en: JACS Au 4, 9 (2024), 3649-3656
ISSN: 2691-3704

Financiación: info:eu-repo/grantAgreement/ES/DGA/E34-R17
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP58-18
Financiación: info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2022-137973NB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)