GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins
Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific express...
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| Language: | English |
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Elsevier
2025-04-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525001339 |
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| author | Yuxin Fang Yaojin Zhu Wei Wang Zhewei Xia Shipeng He Guoqiang Dong Chunquan Sheng |
| author_facet | Yuxin Fang Yaojin Zhu Wei Wang Zhewei Xia Shipeng He Guoqiang Dong Chunquan Sheng |
| author_sort | Yuxin Fang |
| collection | DOAJ |
| description | Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets. |
| format | Article |
| id | doaj-art-79c1d75a3a1f4203be9961da3cd9d7d1 |
| institution | OA Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-79c1d75a3a1f4203be9961da3cd9d7d12025-08-20T01:51:13ZengElsevierActa Pharmaceutica Sinica B2211-38352025-04-011542156216910.1016/j.apsb.2025.02.037GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteinsYuxin Fang0Yaojin Zhu1Wei Wang2Zhewei Xia3Shipeng He4Guoqiang Dong5Chunquan Sheng6Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai 200444, ChinaCenter for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, ChinaCenter for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai 200444, China; Corresponding authors.Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China; Corresponding authors.Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China; Corresponding authors.Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets.http://www.sciencedirect.com/science/article/pii/S2211383525001339Glypican-3PD-L1Lysosomal degradationMembrane proteinTargeted protein degradation |
| spellingShingle | Yuxin Fang Yaojin Zhu Wei Wang Zhewei Xia Shipeng He Guoqiang Dong Chunquan Sheng GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins Acta Pharmaceutica Sinica B Glypican-3 PD-L1 Lysosomal degradation Membrane protein Targeted protein degradation |
| title | GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins |
| title_full | GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins |
| title_fullStr | GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins |
| title_full_unstemmed | GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins |
| title_short | GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins |
| title_sort | gpc3 mediated lysosome targeting chimeras gltacs for targeted degradation of membrane proteins |
| topic | Glypican-3 PD-L1 Lysosomal degradation Membrane protein Targeted protein degradation |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525001339 |
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