Copper assisted sequence-specific chemical protein conjugation at a single backbone amide

Mengzhun Guo, Kai Zhao, Liang Guo, Rui Zhou, Qiuju He, Kuan Lu, Tian Li, Dandan Liu, Jinfeng Chen, Jing Tang, Xin Fu, Jinyun Zhou, Bei Zheng, Samuel I. Mann, Yongdeng Zhang, Jing Huang, Bing Yang, Ting Zhou (), Yingjie Lei () and Bobo Dang ()
Additional contact information
Mengzhun Guo: Fudan University
Kai Zhao: Westlake Laboratory of Life Sciences and Biomedicine
Liang Guo: Westlake Laboratory of Life Sciences and Biomedicine
Rui Zhou: The Second Affiliated Hospital of Zhejiang University School of Medicine
Qiuju He: Westlake Laboratory of Life Sciences and Biomedicine
Kuan Lu: Westlake Laboratory of Life Sciences and Biomedicine
Tian Li: Westlake Laboratory of Life Sciences and Biomedicine
Dandan Liu: Zhejiang University
Jinfeng Chen: Westlake Laboratory of Life Sciences and Biomedicine
Jing Tang: Westlake Laboratory of Life Sciences and Biomedicine
Xin Fu: Westlake Laboratory of Life Sciences and Biomedicine
Jinyun Zhou: The Second Affiliated Hospital of Zhejiang University School of Medicine
Bei Zheng: Westlake Laboratory of Life Sciences and Biomedicine
Samuel I. Mann: University of California at San Francisco
Yongdeng Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Jing Huang: Westlake Laboratory of Life Sciences and Biomedicine
Bing Yang: Zhejiang University
Ting Zhou: Westlake Laboratory of Life Sciences and Biomedicine
Yingjie Lei: Westlake Laboratory of Life Sciences and Biomedicine
Bobo Dang: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Direct, site-specific methods of protein functionalization are highly desirable for biotechnology. However, such methods are challenging due to the difficulty of chemically differentiating a single site within a large protein. Herein, we propose “metal binding targeting” strategy and develop a Copper Assisted Sequence-specific conjugation Tag (CAST) method to achieve rapid (second order rate 8.1 M−1 s−1), site-specific protein backbone chemical modification with pinpoint accuracy. We demonstrate the versatility of CAST conjugation by preparing various on-demand modified recombinant proteins, including a homogeneous antibody-drug conjugate with high plasma stability and potent efficacy in vitro and in vivo. Thus, CAST provides an efficient and quantitative method to site-specifically attach payloads on large, native proteins.

Date: 2023
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DOI: 10.1038/s41467-023-43753-7

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