ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity
Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of To...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2017
|
| _version_ | 1797064073422045184 |
|---|---|
| author | Kiappes, JL Hill, ML Alonzi, DS Miller, JL Iwaki, R Sayce, AC Caputo, AT Kato, A Zitzmann, N |
| author_facet | Kiappes, JL Hill, ML Alonzi, DS Miller, JL Iwaki, R Sayce, AC Caputo, AT Kato, A Zitzmann, N |
| author_sort | Kiappes, JL |
| collection | OXFORD |
| description | Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy. ToP-DNJ inhibits ER α-glucosidase II at low micromolar concentrations and selectively accumulated in the liver in vivo. In cellular assays, the drug showed efficacy exclusively in immune cells of the myeloid lineage. Taken together, these data demonstrate that inclusion of a native metabolite into an iminosugar provides selectivity with respect to target enzyme, target cell and target tissue. |
| first_indexed | 2024-03-06T21:09:04Z |
| format | Journal article |
| id | oxford-uuid:3d840605-2e42-412b-bd67-cba4d43cc08d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:09:04Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:3d840605-2e42-412b-bd67-cba4d43cc08d2022-03-26T14:19:53ZToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3d840605-2e42-412b-bd67-cba4d43cc08dEnglishSymplectic Elements at OxfordAmerican Chemical Society2017Kiappes, JLHill, MLAlonzi, DSMiller, JLIwaki, RSayce, ACCaputo, ATKato, AZitzmann, NIminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy. ToP-DNJ inhibits ER α-glucosidase II at low micromolar concentrations and selectively accumulated in the liver in vivo. In cellular assays, the drug showed efficacy exclusively in immune cells of the myeloid lineage. Taken together, these data demonstrate that inclusion of a native metabolite into an iminosugar provides selectivity with respect to target enzyme, target cell and target tissue. |
| spellingShingle | Kiappes, JL Hill, ML Alonzi, DS Miller, JL Iwaki, R Sayce, AC Caputo, AT Kato, A Zitzmann, N ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity |
| title | ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity |
| title_full | ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity |
| title_fullStr | ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity |
| title_full_unstemmed | ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity |
| title_short | ToP-DNJ, a selective inhibitor of endoplasmic reticulum α-glucosidase II exhibiting anti-flaviviral activity |
| title_sort | top dnj a selective inhibitor of endoplasmic reticulum α glucosidase ii exhibiting anti flaviviral activity |
| work_keys_str_mv | AT kiappesjl topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT hillml topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT alonzids topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT millerjl topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT iwakir topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT sayceac topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT caputoat topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT katoa topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity AT zitzmannn topdnjaselectiveinhibitorofendoplasmicreticulumaglucosidaseiiexhibitingantiflaviviralactivity |