145176 20260219090939.0 doi 10.1021/jacsau.4c00633 sideral 139986 ART-2024-139986 eng Compañón, Ismael Rational Design of Dual-Domain Binding Inhibitors for N-Acetylgalactosamine Transferase 2 with Improved Selectivity over the T1 and T3 Isoforms 2024 Access copy available to the general public Unrestricted 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. info:eu-repo/grantAgreement/ES/DGA/E34-R17 info:eu-repo/grantAgreement/ES/DGA/LMP58-18 info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00 info:eu-repo/grantAgreement/ES/MICINN/PID2022-137973NB-I00 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es 8.7 2024 2.944 2024 Analytical Chemistry 2024 Q1 Physical and Theoretical Chemistry 2024 Q1 Organic Chemistry 2024 Q1 Chemistry (miscellaneous) 2024 Q1 12.4 2024 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 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 (orcid)0000-0003-3433-6701 Merino, Pedro Universidad de Zaragoza (orcid)0000-0002-2202-3460 Corzana, Francisco Hurtado-Guerrero, Ramon (orcid)0000-0002-3122-9401 Ghirardello, Mattia 2013 765 Universidad de Zaragoza Dpto. Química Orgánica Área Química Orgánica 4, 9 (2024), 3649-3656 JACS Au 2691-3704 3359660 http://zaguan.unizar.es/record/145176/files/texto_completo.pdf Versión publicada 3225669 http://zaguan.unizar.es/record/145176/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:145176 articulos driver 2026-02-19-09:00:42 ARTICLE