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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2023
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| _version_ | 1797111469590970368 |
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| author | Guay, KP Ibba, R Kiappes, JL Vasiljević, S Bonì, F De Benedictis, M Zeni, I Le Cornu, JD Hensen, M Chandran, AV Kantsadi, AL Caputo, AT Blanco Capurro, JI Bayo, Y Hill, JC Hudson, K Lia, A Brun, J Withers, SG Martí, M Biasini, E Santino, A De Rosa, M Milani, M Modenutti, CP Hebert, DN Zitzmann, N Roversi, P |
| author_facet | Guay, KP Ibba, R Kiappes, JL Vasiljević, S Bonì, F De Benedictis, M Zeni, I Le Cornu, JD Hensen, M Chandran, AV Kantsadi, AL Caputo, AT Blanco Capurro, JI Bayo, Y Hill, JC Hudson, K Lia, A Brun, J Withers, SG Martí, M Biasini, E Santino, A De Rosa, M Milani, M Modenutti, CP Hebert, DN Zitzmann, N Roversi, P |
| author_sort | Guay, KP |
| collection | OXFORD |
| 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 CtUGGTGT24 “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 CtUGGTGT24 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 CtUGGTGT24 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. |
| first_indexed | 2024-03-07T08:09:20Z |
| format | Journal article |
| id | oxford-uuid:40dc158b-da1e-4742-bca9-5ce1b6a189ca |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:09:20Z |
| publishDate | 2023 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:40dc158b-da1e-4742-bca9-5ce1b6a189ca2023-11-20T15:23:49ZA quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpointJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:40dc158b-da1e-4742-bca9-5ce1b6a189caEnglishSymplectic ElementsCell Press2023Guay, KPIbba, RKiappes, JLVasiljević, SBonì, FDe Benedictis, MZeni, ILe Cornu, JDHensen, MChandran, AVKantsadi, ALCaputo, ATBlanco Capurro, JIBayo, YHill, JCHudson, KLia, ABrun, JWithers, SGMartí, MBiasini, ESantino, ADe Rosa, MMilani, MModenutti, CPHebert, DNZitzmann, NRoversi, PMisfolded 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 CtUGGTGT24 “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 CtUGGTGT24 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 CtUGGTGT24 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. |
| spellingShingle | Guay, KP Ibba, R Kiappes, JL Vasiljević, S Bonì, F De Benedictis, M Zeni, I Le Cornu, JD Hensen, M Chandran, AV Kantsadi, AL Caputo, AT Blanco Capurro, JI Bayo, Y Hill, JC Hudson, K Lia, A Brun, J Withers, SG Martí, M Biasini, E Santino, A De Rosa, M Milani, M Modenutti, CP Hebert, DN Zitzmann, N Roversi, P 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 |
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