Discovery of Potent Degraders of the Dengue Virus Envelope Protein
Abstract Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E‐...
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| Format: | Article |
| Language: | English |
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Wiley
2024-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405829 |
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| author | Zhengnian Li Han‐Yuan Liu Zhixiang He Antara Chakravarty Ryan P. Golden Zixuan Jiang Inchul You Hong Yue Katherine A. Donovan Guangyan Du Jianwei Che Jason Tse Isaac Che Wenchao Lu Eric S. Fischer Tinghu Zhang Nathanael S. Gray Priscilla L. Yang |
| author_facet | Zhengnian Li Han‐Yuan Liu Zhixiang He Antara Chakravarty Ryan P. Golden Zixuan Jiang Inchul You Hong Yue Katherine A. Donovan Guangyan Du Jianwei Che Jason Tse Isaac Che Wenchao Lu Eric S. Fischer Tinghu Zhang Nathanael S. Gray Priscilla L. Yang |
| author_sort | Zhengnian Li |
| collection | DOAJ |
| description | Abstract Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E‐degraders are developed by linking two previously reported E‐binding small molecules, GNF‐2, and CVM‐2‐12‐2, to a glutarimide‐based recruiter of the CRL4CRBN ligase to effect proteosome‐mediated degradation of the E protein. ZXH‐2‐107 (based on GNF‐2) is an E‐degrader with ABL inhibitory activity while ZXH‐8‐004 (based on CVM‐2‐12‐2) is a selective and potent E‐degrader. These two compounds provide proof of concept that difficult‐to‐drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class of direct‐acting antiviral drugs. |
| format | Article |
| id | doaj-art-d886eb34b9c74a7eabd320cf5081d214 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d886eb34b9c74a7eabd320cf5081d2142025-08-20T02:11:59ZengWileyAdvanced Science2198-38442024-10-011140n/an/a10.1002/advs.202405829Discovery of Potent Degraders of the Dengue Virus Envelope ProteinZhengnian Li0Han‐Yuan Liu1Zhixiang He2Antara Chakravarty3Ryan P. Golden4Zixuan Jiang5Inchul You6Hong YueKatherine A. Donovan7Guangyan Du8Jianwei Che9Jason Tse10Isaac Che11Wenchao Lu12Eric S. Fischer13Tinghu Zhang14Nathanael S. Gray15Priscilla L. Yang16Department of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Microbiology and Immunology Stanford University School of Medicine 279 Campus Drive Palo Alto CA 94305 USADepartment of Cancer Biology Dana‐Farber Cancer Institute 450 Brookline Avenue Boston 02215 USADepartment of Microbiology and Immunology Stanford University School of Medicine 279 Campus Drive Palo Alto CA 94305 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Biological Chemistry and Molecular Pharmacology Harvard Medical School 240 Longwood Avenue Boston 02115 USADepartment of Cancer Biology Dana‐Farber Cancer Institute 450 Brookline Avenue Boston 02215 USADepartment of Cancer Biology Dana‐Farber Cancer Institute 450 Brookline Avenue Boston 02215 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Cancer Biology Dana‐Farber Cancer Institute 450 Brookline Avenue Boston 02215 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Chemical and Systems Biology Chem‐H and Stanford Cancer Institute Stanford Medicine Stanford University 290 Jane Stanford Way Stanford CA 94305 USADepartment of Microbiology and Immunology Stanford University School of Medicine 279 Campus Drive Palo Alto CA 94305 USAAbstract Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E‐degraders are developed by linking two previously reported E‐binding small molecules, GNF‐2, and CVM‐2‐12‐2, to a glutarimide‐based recruiter of the CRL4CRBN ligase to effect proteosome‐mediated degradation of the E protein. ZXH‐2‐107 (based on GNF‐2) is an E‐degrader with ABL inhibitory activity while ZXH‐8‐004 (based on CVM‐2‐12‐2) is a selective and potent E‐degrader. These two compounds provide proof of concept that difficult‐to‐drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class of direct‐acting antiviral drugs.https://doi.org/10.1002/advs.202405829antiviralsdengueenvelope proteininfectionprotein degradation |
| spellingShingle | Zhengnian Li Han‐Yuan Liu Zhixiang He Antara Chakravarty Ryan P. Golden Zixuan Jiang Inchul You Hong Yue Katherine A. Donovan Guangyan Du Jianwei Che Jason Tse Isaac Che Wenchao Lu Eric S. Fischer Tinghu Zhang Nathanael S. Gray Priscilla L. Yang Discovery of Potent Degraders of the Dengue Virus Envelope Protein Advanced Science antivirals dengue envelope protein infection protein degradation |
| title | Discovery of Potent Degraders of the Dengue Virus Envelope Protein |
| title_full | Discovery of Potent Degraders of the Dengue Virus Envelope Protein |
| title_fullStr | Discovery of Potent Degraders of the Dengue Virus Envelope Protein |
| title_full_unstemmed | Discovery of Potent Degraders of the Dengue Virus Envelope Protein |
| title_short | Discovery of Potent Degraders of the Dengue Virus Envelope Protein |
| title_sort | discovery of potent degraders of the dengue virus envelope protein |
| topic | antivirals dengue envelope protein infection protein degradation |
| url | https://doi.org/10.1002/advs.202405829 |
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