Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4
The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE...
| Κύριοι συγγραφείς: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Μορφή: | Journal article |
| Γλώσσα: | English |
| Έκδοση: |
Elsevier
2016
|
| _version_ | 1826311866965557248 |
|---|---|
| author | Warfield, KL Plummer, EM Sayce, AC Alonzi, DS Tang, W Tyrrell, BE Hill, ML Caputo, AT Killingbeck, SS Beatty, PR Harris, E Iwaki, R Kinami, K Ide, D Kiappes, JL Kato, A Buck, MD King, K Eddy, W Khaliq, M Sampath, A Treston, AM Dwek, RA Enterlein, SG Miller, JL Zitzmann, N Ramstedt, U Shresta, S |
| author_facet | Warfield, KL Plummer, EM Sayce, AC Alonzi, DS Tang, W Tyrrell, BE Hill, ML Caputo, AT Killingbeck, SS Beatty, PR Harris, E Iwaki, R Kinami, K Ide, D Kiappes, JL Kato, A Buck, MD King, K Eddy, W Khaliq, M Sampath, A Treston, AM Dwek, RA Enterlein, SG Miller, JL Zitzmann, N Ramstedt, U Shresta, S |
| author_sort | Warfield, KL |
| collection | OXFORD |
| description | The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10–20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease. |
| first_indexed | 2024-03-07T08:17:36Z |
| format | Journal article |
| id | oxford-uuid:b53e5705-7a3f-44b7-a1b5-017b1c450a7c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:17:36Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:b53e5705-7a3f-44b7-a1b5-017b1c450a7c2024-01-10T18:46:27ZInhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b53e5705-7a3f-44b7-a1b5-017b1c450a7cEnglishSymplectic Elements at OxfordElsevier2016Warfield, KLPlummer, EMSayce, ACAlonzi, DSTang, WTyrrell, BEHill, MLCaputo, ATKillingbeck, SSBeatty, PRHarris, EIwaki, RKinami, KIde, DKiappes, JLKato, ABuck, MDKing, KEddy, WKhaliq, MSampath, ATreston, AMDwek, RAEnterlein, SGMiller, JLZitzmann, NRamstedt, UShresta, SThe antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10–20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease. |
| spellingShingle | Warfield, KL Plummer, EM Sayce, AC Alonzi, DS Tang, W Tyrrell, BE Hill, ML Caputo, AT Killingbeck, SS Beatty, PR Harris, E Iwaki, R Kinami, K Ide, D Kiappes, JL Kato, A Buck, MD King, K Eddy, W Khaliq, M Sampath, A Treston, AM Dwek, RA Enterlein, SG Miller, JL Zitzmann, N Ramstedt, U Shresta, S Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4 |
| title | Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4 |
| title_full | Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4 |
| title_fullStr | Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4 |
| title_full_unstemmed | Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4 |
| title_short | Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4 |
| title_sort | inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar uv 4 |
| work_keys_str_mv | AT warfieldkl inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT plummerem inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT sayceac inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT alonzids inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT tangw inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT tyrrellbe inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT hillml inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT caputoat inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT killingbeckss inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT beattypr inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT harrise inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT iwakir inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT kinamik inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT ided inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT kiappesjl inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT katoa inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT buckmd inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT kingk inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT eddyw inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT khaliqm inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT sampatha inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT trestonam inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT dwekra inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT enterleinsg inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT millerjl inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT zitzmannn inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT ramstedtu inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 AT shrestas inhibitionofendoplasmicreticulumglucosidasesisrequiredforinvitroandinvivodengueantiviralactivitybytheiminosugaruv4 |