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A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint

Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secr...

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Autores principales: Guay, Kevin P., Ibba, Roberta, Kiappes, J.L., Vasiljević, Snežana, Bonì, Francesco, De Benedictis, Maria, Zeni, Ilaria, Le Cornu, James D., Hensen, Mario, Chandran, Anu V., Kantsadi, Anastassia L., Caputo, Alessandro T., Blanco Capurro, Juan I., Bayo, Yusupha, Hill, Johan C., Hudson, Kieran, Lia, Andrea, Brun, Juliane, Withers, Stephen G., Martí, Marcelo, Biasini, Emiliano, Santino, Angelo, De Rosa, Matteo, Milani, Mario, Modenutti, Carlos P., Hebert, Daniel N., Zitzmann, Nicole, Roversi, Pietro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562782/
https://www.ncbi.nlm.nih.gov/pubmed/37822503
http://dx.doi.org/10.1016/j.isci.2023.107919
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author Guay, Kevin P.
Ibba, Roberta
Kiappes, J.L.
Vasiljević, Snežana
Bonì, Francesco
De Benedictis, Maria
Zeni, Ilaria
Le Cornu, James D.
Hensen, Mario
Chandran, Anu V.
Kantsadi, Anastassia L.
Caputo, Alessandro T.
Blanco Capurro, Juan I.
Bayo, Yusupha
Hill, Johan C.
Hudson, Kieran
Lia, Andrea
Brun, Juliane
Withers, Stephen G.
Martí, Marcelo
Biasini, Emiliano
Santino, Angelo
De Rosa, Matteo
Milani, Mario
Modenutti, Carlos P.
Hebert, Daniel N.
Zitzmann, Nicole
Roversi, Pietro
author_facet Guay, Kevin P.
Ibba, Roberta
Kiappes, J.L.
Vasiljević, Snežana
Bonì, Francesco
De Benedictis, Maria
Zeni, Ilaria
Le Cornu, James D.
Hensen, Mario
Chandran, Anu V.
Kantsadi, Anastassia L.
Caputo, Alessandro T.
Blanco Capurro, Juan I.
Bayo, Yusupha
Hill, Johan C.
Hudson, Kieran
Lia, Andrea
Brun, Juliane
Withers, Stephen G.
Martí, Marcelo
Biasini, Emiliano
Santino, Angelo
De Rosa, Matteo
Milani, Mario
Modenutti, Carlos P.
Hebert, Daniel N.
Zitzmann, Nicole
Roversi, Pietro
author_sort Guay, Kevin P.
collection PubMed
description Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGT(GT24) “WY” conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for CtUGGT(GT24)in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to CtUGGT(GT24) appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.
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spelling pubmed-105627822023-10-11 A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint Guay, Kevin P. Ibba, Roberta Kiappes, J.L. Vasiljević, Snežana Bonì, Francesco De Benedictis, Maria Zeni, Ilaria Le Cornu, James D. Hensen, Mario Chandran, Anu V. Kantsadi, Anastassia L. Caputo, Alessandro T. Blanco Capurro, Juan I. Bayo, Yusupha Hill, Johan C. Hudson, Kieran Lia, Andrea Brun, Juliane Withers, Stephen G. Martí, Marcelo Biasini, Emiliano Santino, Angelo De Rosa, Matteo Milani, Mario Modenutti, Carlos P. Hebert, Daniel N. Zitzmann, Nicole Roversi, Pietro iScience Article Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a CtUGGT(GT24) “WY” conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for CtUGGT(GT24)in vitro as measured by ligand-enhanced fluorescence. In cellula, 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to CtUGGT(GT24) appears to be mutually exclusive to M5-9 glycan binding in an in vitro competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors. Elsevier 2023-09-20 /pmc/articles/PMC10562782/ /pubmed/37822503 http://dx.doi.org/10.1016/j.isci.2023.107919 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Guay, Kevin P.
Ibba, Roberta
Kiappes, J.L.
Vasiljević, Snežana
Bonì, Francesco
De Benedictis, Maria
Zeni, Ilaria
Le Cornu, James D.
Hensen, Mario
Chandran, Anu V.
Kantsadi, Anastassia L.
Caputo, Alessandro T.
Blanco Capurro, Juan I.
Bayo, Yusupha
Hill, Johan C.
Hudson, Kieran
Lia, Andrea
Brun, Juliane
Withers, Stephen G.
Martí, Marcelo
Biasini, Emiliano
Santino, Angelo
De Rosa, Matteo
Milani, Mario
Modenutti, Carlos P.
Hebert, Daniel N.
Zitzmann, Nicole
Roversi, Pietro
A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
title A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
title_full A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
title_fullStr A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
title_full_unstemmed A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
title_short A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint
title_sort quinolin-8-ol sub-millimolar inhibitor of uggt, the er glycoprotein folding quality control checkpoint
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10562782/
https://www.ncbi.nlm.nih.gov/pubmed/37822503
http://dx.doi.org/10.1016/j.isci.2023.107919
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