Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics
Abstract Sulfur‐fluoride exchange (SuFEx) reaction is an emerging class of click chemistry reaction. Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody‐molecular glue drug conjugate nanoagent is re...
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| Format: | Article |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412273 |
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| author | Wenhui Gao Xiaoyuan Yang Qingrong Li Yingchun Liu Wei Huang Xuelin Xia Deyue Yan |
| author_facet | Wenhui Gao Xiaoyuan Yang Qingrong Li Yingchun Liu Wei Huang Xuelin Xia Deyue Yan |
| author_sort | Wenhui Gao |
| collection | DOAJ |
| description | Abstract Sulfur‐fluoride exchange (SuFEx) reaction is an emerging class of click chemistry reaction. Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody‐molecular glue drug conjugate nanoagent is reported, which can irreversibly bind with its target protein through proximity‐enabled SuFEx reaction. As a proof of concept, a latent bioreactive unnatural amino acid fluorosulfate‐L‐tyrosine (FSY) is first introduced at site 36 of the affibody with cysteine mutation (ZHER2:342‐Cys) to produce ZHER2:342‐36FSY‐Cys. Subsequently, ZHER2:342‐36FSY‐Cys is coupled with a molecular glue drug (CR8) to yield an amphiphilic conjugate of ZHER2:342‐36FSY‐CR8, which can self‐assemble into affibody–drug conjugate nanoagent (ZHER2:342‐36FSY‐CR8 ADCN) in PBS. When ZHER2:342‐36FSY‐CR8 ADCN specific binds to human epidermal growth factor receptor 2 (HER2) on cancer cells, the FSY36 of ZHER2:342 approaches to the His490 of HER2 and ultimately reacts with each other to form a covalent bond via SuFEx reaction. Such a covalent binding mode endows ZHER2:342‐36FSY‐CR8 ADCN with permanent binding ability to effectively increase the concentration of drugs in tumor. Eventually, the covalent ZHER2:342‐36FSY‐CR8 ADCN exhibits an outstanding tumor inhibition ratio of 90.03 ± 4.29% in HER2‐positive ovary tumor models, strikingly higher than that of the noncovalent one (64.25 ± 7.71%). |
| format | Article |
| id | doaj-art-e9b48f3377e84ca1a4a9382dc1a47d45 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-e9b48f3377e84ca1a4a9382dc1a47d452025-08-20T02:23:12ZengWileyAdvanced Science2198-38442025-03-011210n/an/a10.1002/advs.202412273Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive TherapeuticsWenhui Gao0Xiaoyuan Yang1Qingrong Li2Yingchun Liu3Wei Huang4Xuelin Xia5Deyue Yan6School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaSchool of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaSchool of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaSchool of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaSchool of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaSchool of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaSchool of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 ChinaAbstract Sulfur‐fluoride exchange (SuFEx) reaction is an emerging class of click chemistry reaction. Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody‐molecular glue drug conjugate nanoagent is reported, which can irreversibly bind with its target protein through proximity‐enabled SuFEx reaction. As a proof of concept, a latent bioreactive unnatural amino acid fluorosulfate‐L‐tyrosine (FSY) is first introduced at site 36 of the affibody with cysteine mutation (ZHER2:342‐Cys) to produce ZHER2:342‐36FSY‐Cys. Subsequently, ZHER2:342‐36FSY‐Cys is coupled with a molecular glue drug (CR8) to yield an amphiphilic conjugate of ZHER2:342‐36FSY‐CR8, which can self‐assemble into affibody–drug conjugate nanoagent (ZHER2:342‐36FSY‐CR8 ADCN) in PBS. When ZHER2:342‐36FSY‐CR8 ADCN specific binds to human epidermal growth factor receptor 2 (HER2) on cancer cells, the FSY36 of ZHER2:342 approaches to the His490 of HER2 and ultimately reacts with each other to form a covalent bond via SuFEx reaction. Such a covalent binding mode endows ZHER2:342‐36FSY‐CR8 ADCN with permanent binding ability to effectively increase the concentration of drugs in tumor. Eventually, the covalent ZHER2:342‐36FSY‐CR8 ADCN exhibits an outstanding tumor inhibition ratio of 90.03 ± 4.29% in HER2‐positive ovary tumor models, strikingly higher than that of the noncovalent one (64.25 ± 7.71%).https://doi.org/10.1002/advs.202412273affibody‐molecular glue drug conjugatecovalent nanoagentproximity‐enabled reactive therapeuticsSuFEx reaction |
| spellingShingle | Wenhui Gao Xiaoyuan Yang Qingrong Li Yingchun Liu Wei Huang Xuelin Xia Deyue Yan Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics Advanced Science affibody‐molecular glue drug conjugate covalent nanoagent proximity‐enabled reactive therapeutics SuFEx reaction |
| title | Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics |
| title_full | Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics |
| title_fullStr | Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics |
| title_full_unstemmed | Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics |
| title_short | Covalent Affibody‐Molecular Glue Drug Conjugate Nanoagent for Proximity‐Enabled Reactive Therapeutics |
| title_sort | covalent affibody molecular glue drug conjugate nanoagent for proximity enabled reactive therapeutics |
| topic | affibody‐molecular glue drug conjugate covalent nanoagent proximity‐enabled reactive therapeutics SuFEx reaction |
| url | https://doi.org/10.1002/advs.202412273 |
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