000145176 001__ 145176
000145176 005__ 20241003094705.0
000145176 0247_ $$2doi$$a10.1021/jacsau.4c00633
000145176 0248_ $$2sideral$$a139986
000145176 037__ $$aART-2024-139986
000145176 041__ $$aeng
000145176 100__ $$aCompañón, Ismael
000145176 245__ $$aRational Design of Dual-Domain Binding Inhibitors for N-Acetylgalactosamine Transferase 2 with Improved Selectivity over the T1 and T3 Isoforms
000145176 260__ $$c2024
000145176 5060_ $$aAccess copy available to the general public$$fUnrestricted
000145176 5203_ $$aThe 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.
000145176 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E34-R17$$9info:eu-repo/grantAgreement/ES/DGA/LMP58-18$$9info:eu-repo/grantAgreement/ES/MICINN AEI/PID2022-136362NB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-137973NB-I00
000145176 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000145176 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000145176 700__ $$aBallard, Collin J.
000145176 700__ $$aLira-Navarrete, Erandi
000145176 700__ $$aSantos, Tanausú
000145176 700__ $$aMonaco, Serena
000145176 700__ $$aMuñoz-García, Juan C.
000145176 700__ $$aDelso, Ignacio
000145176 700__ $$aAngulo, Jesus
000145176 700__ $$aGerken, Thomas A.
000145176 700__ $$aSchjoldager, Katrine T.
000145176 700__ $$aClausen, Henrik
000145176 700__ $$0(orcid)0000-0003-3433-6701$$aTejero, Tomás$$uUniversidad de Zaragoza
000145176 700__ $$0(orcid)0000-0002-2202-3460$$aMerino, Pedro$$uUniversidad de Zaragoza
000145176 700__ $$aCorzana, Francisco
000145176 700__ $$0(orcid)0000-0002-3122-9401$$aHurtado-Guerrero, Ramon
000145176 700__ $$aGhirardello, Mattia
000145176 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDpto. Química Orgánica$$cÁrea Química Orgánica
000145176 773__ $$g4, 9 (2024), 3649-3656$$tJACS Au$$x2691-3704
000145176 8564_ $$s3359660$$uhttps://zaguan.unizar.es/record/145176/files/texto_completo.pdf$$yVersión publicada
000145176 8564_ $$s3225669$$uhttps://zaguan.unizar.es/record/145176/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000145176 909CO $$ooai:zaguan.unizar.es:145176$$particulos$$pdriver
000145176 951__ $$a2024-10-03-08:56:28
000145176 980__ $$aARTICLE