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The Li Lab focuses on the development of protein-based chemical tools for live-cell research. By integrating chemical protein synthesis with cytosolic protein delivery technologies, we construct functional protein tools with tunable bioactivity and cell permeability. This approach enables the investigation of complex, dynamic molecular processes in living cells.
Leveraging synthetic chemistry, the lab strives to expand the functional repertoire of proteins and advance the application of synthetic protein tools for in situ functional interrogation in live cells. These endeavors lay a solid foundation for deciphering disease mechanisms, designing novel molecular probes, and exploring potential therapeutic intervention strategies.
RESEARCH
Our laboratory has long-standing research interests in protein chemical biology as well as peptide and protein chemical synthesis. Our work focus on chemical semi-synthesis of proteins, cytosolic protein delivery, and the construction of cell-permeable protein probes, along with their applications in live-cell research. We aim to develop structurally well-defined, functionally tunable and cell-permeable protein-based chemical tools to elucidate the molecular regulatory mechanisms underlying complex biological processes in living cells.
We have a particular focus on biologically important protein post-translational modifications, including ubiquitination, ubiquitin-like modifications, and histone modifications. Leveraging chemical protein synthesis and chemical ligation strategies, we have constructed functionalized, cell-permeable protein probes, such as photocaged probes, activity-based probes, and photoaffinity probes. These chemical tools empower the exploration of protein function and molecular interactomes in living cells.
Based on these established methodological platforms, our lab strives to further integrate chemical protein synthesis with live-cell functional studies. We seek to provide robust chemical tools for the in situ dissection of key biological processes, and lay new methodological foundations for modulating intracellular protein function, deciphering disease mechanisms, and exploring potential therapeutic intervention strategies.
Main Research Directions
* Construction of cell-permeable protein probes (with a focus on ubiquitin- and histone-associated probes)
* In situ interrogation of protein interactions in living cells
* Proteins chemical semi-synthesis
* Development of cytosolic protein delivery technologies
PUBLICATIONS
Prof. Li has published more than 60 research articles as a corresponding author in journals including Nature Chemical Biology, Nature Communications, Chem, Journal of the American Chemical Society, Angewandte Chemie International Edition, JACS Au, and CCS Chemistry. Selected representative publications in recent years are listed below:
1.Hua X.; Guo Y.; Li P.; Wang Y.; Han X.; Chen J.; Li J.; Chu G.; Shi J.; Liu L.*; Li, Y.-M.*. Reversible Surface Modifications of Functional Proteins for Accelerated Cytosolic Delivery via Cell-Penetrating Peptide Clusters. Nature Commun. 2026, 17, 3341.
2.Wang, Y.; Fan, J.; Meng, X.; Shu, Q.; Wu, Y.; Chu, G.; Ji, R., Ye, Y. S.; Wu, X. W.; Shi, J.; Deng, H.; Liu, L.*; Li, Y.-M.* Development of Nucleus-Targeted Histone-Tail-Based Photoaffinity Probes to Profile the Epigenetic Interactome in Native Cells. Nature Commun. 2025, 16, 415.
3.Zhao R.; Han D.; Tang J.; Gao Y.; Shu Q.; Chu G.; Luo J.; Shi C.; Shi P.; Shi J.*; Li, Y.-M.*, Liu L.*. Single-Shot Solid-Phase Synthesis of Insulins and Their A/B-Chain Heterodimeric Analogs. Chem 2026, 12, 103022.
4.Wang, Y.; Liu, L.; Zheng, Q.Y.; Wu, Y.; Su, Z.; Yuan, R.J.; Xia, Q.; Wang, B.; Yu, Y.*; Li, Y.-M.* Synergizing Structure-Guided Photocaged Linear Diubiquitin-Dha with Biotinylated Linear-Fab for Time-Resolved Profiling of Interactors in Living Cells. J. Am. Chem. Soc. 2025, 147, 47299.
5.Zhao R., Shi P., Cui J. B., Shi C. W., Wei X. X., Luo J., Xia Z. M., Shi W. W., Zhou Y. X., Tang J. H., Tian C. L., Meininghaus M., Bierer D., Shi J.*, Li Y.-M.*, Liu L.*, Single-Shot Solid-Phase Synthesis of Full-Length H2 Relaxin Disulfide Surrogates. Angew. Chem. Int. Ed. 2023, 62, e202216365.
6.Chu, G. C.; Li, Y.-M.* Lighting Up Kinase Contacts in Situ. Nature Chem. Biol. 2024, 20, 544.
7.Wang, Y.; Chen, J. N.; Hua, X.; Meng, X. B.; Cai, H. Y.; Wang, R. T.; Shi, J.; Deng, H. T.; Liu, L.; Li, Y.-M.* Photocaging of Cell-permeable Activity-Based Ubiquitin Probes via a C-Terminal Backbone Modification Strategy. Angew. Chem. Int. Ed. 2022, 61, e202203792.
8.Zheng, Q. Y.; Wang, T.; Chu, G. C.; Zuo, C.; Zhao, R.; Sui X.; Ye, L.; Yu, Y., Chen, J Zhang, W.; Deng, H.; Shi, J.; Pan, M.*; Li, Y.-M.*; Liu, L.* An E1-Catalyzed Chemoenzymatic Strategy to Isopeptide-N-Ethylated Deubiquitylase-Resistant Ubiquitin Probes, Angew. Chem. Int. Ed. 2020, 59, 13496.
9.Wang, Y.; Chen, C. C.; Meng, X.; Fan, J.; Pan, M.; Chen, J; Deng, H.; Shi, J.*; Liu, L.; Li, Y.-M.* Chemical Synthesis of diSUMO Photoaffinity Probes for the Identification of PolySUMO-Chain Specific Interacting Proteins. CCS Chem. 2020, 3, 1157.
10.Chu, G. C.; Pan, M.; Li, J.; Liu, S.; Zuo, C.; Tong, Z.-B.; Bai, J.-S.; Gong, Q.; Ai, H.; Fan, J.; Meng, X.; Huang, Y.; Shi, J.; Deng, H.; Tian, C.*; Li, Y.-M.*; Liu, L.* Cysteine-Aminoethylation Assisted Chemical Ubiquitination of Recombinant Histones, J. Am. Chem. Soc. 2019, 141, 3654.
11.Li, Y. T.; Yi, C.; Chen, C. C.; Lan, H.; Pan, M.; Zhang, S. J.; Huang, Y. C.; Guan, C. J.; Li, Y.-M.*; Yu, L.*; Liu, L.* A Semisynthetic Atg3 Reveals That Acetylation Promotes Atg3 Membrane Binding and Atg8 Lipidation. Nature Commun. 2017, 8, 14846.
CONTACT
Email: ymli@hfut.edu.cn
Office: Room 1110, Shisheng Building
Master’s Program Admissions: Organic Chemistry, Biochemistry, Pharmacy
Doctoral Program Admissions: Organic Chemistry, Biochemistry, Cell Biology
The lab has stable annual openings for both academic Ph.D. and professional engineering doctoral students. Highly motivated students with a keen interest in fundamental research are strongly encouraged to apply.
