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Compañón, Ismael, Ballard, Collin J., Lira-Navarrete, Erandi, Santos, Tanausú, Monaco, Serena, Muñoz-García, Juan C., Delso, Ignacio 
ORCID: https://orcid.org/0000-0001-8355-2289, Angulo, Jesus ORCID: https://orcid.org/0000-0001-7250-5639, Gerken, Thomas A., Schjoldager, Katrine T., Clausen, Henrik, Tejero, Tomás, Merino, Pedro, Corzana, Francisco, Hurtado-Guerrero, Ramon and Ghirardello, Mattia
(2024)
Rational design of dual-domain binding inhibitors for N-acetylgalactosamine transferase 2 with improved selectivity over the T1 and T3 isoforms.
JACS Au, 4 (9).
pp. 3649-3656.
ISSN 2691-3704
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Abstract
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.
| Item Type: | Article |
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| Additional Information: | Funding Information: Agencia Estatal de Investigación (AEI, PID2021-127622OB-I00 and PDC2022-133725-C21 to F.C., PID2022-136362NB-I00 to R.H.-G., PID2022137973NB-I00 to P.M.), Universidad de La Rioja (REGI22/16 Project), and Gobierno de Aragón (E34_R17 and LMP58_18) with FEDER (2014–2020) funds for ‘Building Europe from Aragón’ for financial support (to R.H.-G.). The support of the National Institutes of Health grant R01-GM113535 (to T.A.G.) is also acknowledged. M.G. and I.D. acknowledge the Marie Skłodowska-Curie fellowship program (grant agreement nos. 101034288 (M.G.) and 890779 (I.D.)) for financial support. J.A. and S.M. acknowledge support of BBSRC, grant BB/P010660/1. J.A. and J.C.M.-G. also acknowledge funding from the grant AEI/10.13039/501100011033/PID2022-142879NB-I00, cofunded by the European Regional Development Fund (ERDF), “A way of making Europe”, and T.S. thanks MICIU/AEI /10.13039/501100011033 and the European Union NextGenerationEU/PRTR for his Juan de la Cierva contract, JDC2022-048607-I. |
| Uncontrolled Keywords: | galnac,glycopeptide,glycosyltransferase,inhibitor,molecular dynamics,n-acetylgalactosamine transferase,std nmr,analytical chemistry,chemistry (miscellaneous),physical and theoretical chemistry,organic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1600/1602 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Pharmacy (former - to 2024) |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 15 Nov 2024 17:30 |
| Last Modified: | 18 Nov 2024 00:56 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97700 |
| DOI: | 10.1021/jacsau.4c00633 |
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