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| Higher Order Protein Catenation Leads to an Artificial Antibody with Enhanced Affinity and In Vivo Stability | |
| Wu, Wen-Hao1; Bai, Xilin1; Shao, Yu1; Yang, Chao2; Wei, Jingjing2; Wei, Wei3; Zhang, Wen-Bin1 | |
| 2021-11-03 | |
| Source Publication | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| ISSN | 0002-7863 |
| Volume | 143Issue:43Pages:18029-18040 |
| Abstract | The chemical topology is a unique dimension for protein engineering, yet the topological diversity and architectural complexity of proteins remain largely untapped. Herein, we report the biosynthesis of complex topological proteins using a rationally engineered, cross-entwining peptide heterodimer motif derived from p53dim (an entangled homodimeric mutant of the tetramerization domain of the tumor suppressor protein p53). The incorporation of an electrostatic interaction at specific sites converts the p53dim homodimer motif into a pair of heterodimer motifs with high specificity for directing chain entanglement upon folding. Its combination with split-intein-mediated ligation and/or SpyTag/SpyCatcher chemistry facilitates the programmed synthesis of protein heterocatenane or [n]catenanes in cells, leading to a general and modular approach to complex protein catenanes containing various proteins of interest. Concatenation enhances not only the target protein's affinity but also the in vivo stability as shown by its prolonged circulation time in blood. As a proof of concept, artificial antibodies have been developed by embedding a human epidermal growth factor receptor 2-specific affibody onto the [n]catenane scaffolds and shown to exhibit a higher affinity and a better pharmacokinetic profile than the wild-type affibody. These results suggest that topology engineering holds great promise in the development of therapeutic proteins. |
| DOI | 10.1021/jacs.1c06169 |
| Language | 英语 |
| WOS Keyword | HETERODIMERIC COILED-COILS ; LASSO PEPTIDES ; DESIGN ; TOPOLOGY ; BIOSYNTHESIS ; CATENANES ; THERAPY ; MODULES ; RINGS |
| Funding Project | National Key R&D Program of China[2020YFA0908100] ; National Natural Science Foundation of China[21925102] ; National Natural Science Foundation of China[21991132] ; National Natural Science Foundation of China[92056118] ; Beijing Municipal Natural Science Foundation[L182003] ; Beijing National Laboratory for Molecular Sciences[BNLMS-CXXM-202006] ; Clinical Medicine Plus X project of Peking University ; Fundamental Research Funds for the Central Universities ; State Key Laboratory of Biochemical Engineering[2018KF-01] ; China Postdoctoral Science Foundation[2020TQ0005] ; National Center for Protein Sciences at Peking University |
| WOS Research Area | Chemistry |
| WOS Subject | Chemistry, Multidisciplinary |
| Funding Organization | National Key R&D Program of China ; National Natural Science Foundation of China ; Beijing Municipal Natural Science Foundation ; Beijing National Laboratory for Molecular Sciences ; Clinical Medicine Plus X project of Peking University ; Fundamental Research Funds for the Central Universities ; State Key Laboratory of Biochemical Engineering ; China Postdoctoral Science Foundation ; National Center for Protein Sciences at Peking University |
| WOS ID | WOS:000715845900022 |
| Publisher | AMER CHEMICAL SOC |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.ipe.ac.cn/handle/122111/50878 |
| Collection | 中国科学院过程工程研究所 |
| Corresponding Author | Wei, Wei; Zhang, Wen-Bin |
| Affiliation | 1.Peking Univ, Beijing Natl Lab Mol Sci, Key Lab Polymer Chem & Phys, Minist Educ,Ctr Soft Matter Sci & Engn,Coll Chem, Beijing 100871, Peoples R China 2.Anyang Inst Technol, Coll Chem & Environm Engn, Anyang 455000, Henan, Peoples R China 3.Chinese Acad Sci, State Key Lab Biochem Engn, Inst Proc Engn, Beijing 100190, Peoples R China |
| Recommended Citation GB/T 7714 | Wu, Wen-Hao,Bai, Xilin,Shao, Yu,et al. Higher Order Protein Catenation Leads to an Artificial Antibody with Enhanced Affinity and In Vivo Stability[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2021,143(43):18029-18040. |
| APA | Wu, Wen-Hao.,Bai, Xilin.,Shao, Yu.,Yang, Chao.,Wei, Jingjing.,...&Zhang, Wen-Bin.(2021).Higher Order Protein Catenation Leads to an Artificial Antibody with Enhanced Affinity and In Vivo Stability.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,143(43),18029-18040. |
| MLA | Wu, Wen-Hao,et al."Higher Order Protein Catenation Leads to an Artificial Antibody with Enhanced Affinity and In Vivo Stability".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 143.43(2021):18029-18040. |
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