生物医药

一、发展化学生物学交叉技术，实现不同翻译后修饰（尤其是泛素化修饰）在重要信号通路及疾病发生、发展中的功能解析。具体包括：1）翻译后修饰构象识别抗体工具的开发及功能解码；2） 绘制翻译后修饰在组织特异性和疾病特异性的“指纹图谱”，用于开发选择性调控或监测分子试剂。
二、开发靶向蛋白酶体降解或者溶酶体降解技术，实现Protac，Lytac，ADC等药物开发及应用。

1. 通过合成精准的不同类型多聚泛素修饰样本，开发了多种链型多聚泛素修饰的构象识别抗体(Nat. Chem. Biol., 2021；J. Am. Chem. Soc., 2025；BioRxiv, 2025)，揭示了K29链型多聚泛素修饰在细胞周期和压力应激过程的调控功能及K27链型在Chaperone介导的蛋白稳态中的调控功能；

2. 揭示了N端降解机制执行E3酶—Ubr1对底物蛋白的进行K48链型泛素链化修饰的分子机制（Nature, 2021; Nat. Struct. Mol. Biol., 2021; Nat. Commun., 2021）；

3.开发了多种PROTAC平台，包括化学合成磷酸化泛素解锁Parkin以构建激活调控型PROTAC平台及膜蛋白靶向降解的应用（Angew. Chem. Int. Ed. 2025；Sci. China Chem. 2025）

1. Han, C.#, Weng, Y.#, Zheng, Q.#, Qu, Q.#, Erramilli, S, Su,Z., Duan,Y., Han,Y., Zhai,X., Kossiakoff, A., Pan,M., Zhao,M.*, Liu, L.*, Yu,Y.*,Conformation-specific Antibody Deciphers K27-linked Ubiquitination in Chaperone-Mediated Proteostasis, BioRxiv, 2025, doi: https://doi.org/10.64898/2025.12.18.695067

2. Wang, Y.#,Liu, L.#,Zheng, Q.#, Wu,Y., Su, Z., Yuan, R., Xia, Q. Wang, B., Yu, Y.*; Li, Y.*; 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, 51, 47299–47310.

3. Chen,F.#, Zhan,Q.#, Qu, Q.# Cui,S., Weng,Y., Pan,M., Zheng,Q.*, Hu,H.*, Yu, Y.*Chemically Synthesized Phosphorylated Ubiquitin Unlocks Parkin for Activation-Controlled PROTAC Platforms.Sci. China Chem. 2025, 68, 5881-5891.

4. Cui, J. #, Zheng, Q. #, Weng, Y. #, Zhai, X., Su, Z., Du, Y., Wei, X., Yu, Y. *, Qu, Q. *, and Pan, M. * Structure-Guided Development of Chemically Tailored Peptide Binders of RNF43/ZNRF3 to Enable Versatile Design of Membrane Protein-Targeting PROTACs. Angew. Chem. Int. Ed. 2025, 64, e202501488.

5. Zheng, Q. #; Su, Z. #; Yu, Y. *; Liu, L.* Recent progress in dissecting ubiquitin signals with chemical biology tools. Curr. Opin. Chem. Biol.2022,70:102187.

6. Pan, M; Zheng, Q.; Wang, T.; Liang, L.; Mao, J.; Zuo, C.; Ding, R.; Ai, H.; Xie, Y.; Si, D.; Yu, Y. *; Liu, L.; * Zhao, M. *Structural Insights Into the Initiation and Elongation of Ubiquitination by Ubr1. Nature, 2021, 600, 334-338.

7. Yu, Y. #; Zheng, Q. #; Erramilli S.K.#; Pan, M. #; et.al. Liu, L.*; Zhao, M.* K29-Linked Ubiquitin Signaling Regulates Proteotoxic Stress Response and Cell Cycle. Nat. Chem. Biol. 2021,17, 896-905.

8. Yu, Y. #; Li, J. #; Jiang, L.; Zhang, J.*; Zu, L.* Catalytic Enantioselective Aza-pinacol Rearrangement. Angew. Chem. Int. Ed. 2017, 129, 9345-9349.

9. Yu, Y. #; Li, G. #; Jiang, L.; Zu, L.* An Indoxyl-Based Strategy for the Synthesis of Indolines and Indolenines. Angew. Chem. Int. Ed. 2015, 54, 12627-12631.

10. Pan, M. #; Yu, Y. #; Ai, H.; Zheng, Q.; Xie, Y.; Liu L. *; & Zhao, M.* Mechanistic insight into substrate processing and allosteric inhibition of human p97. Nat. Struct. Mol. Biol., 2021, 28, 614-625.

11. Pan, M. #; Zheng, Q. #; Yu, Y. #; et. al. Liu, L. *; Zhao, M. * Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. Nat.Commun. 2021, doi: 10.1038/s41467-020-20359-x

12. Yu, Y.; Wang, C.; He, X.; Yao, X.; Zu, L.* Efficient Assembly of Polysubstituted Pyrroles via a (3+2) Cycloaddition/Skeletal Rearrangement/Redox Isomerization Cascade Reaction. Org. Lett. 2014, 16, 3580-3583.

13. Yu, Y.; Li, G.; Zu, L.* The Development of Aza-Pinacol and Aza-Semipinacol Rearrangements for the Synthesis of Nitrogen-Containing Molecules. Synlett. 2016, 27, 1303-1309. (invited Synpacts)

合作专利：一种基于PARKIN的靶向蛋白泛素化降解剂及其制备方法和应用，专利号为：ZL 202311769549.2，授权时间为2024年9月24日。

2023.1-2025.12，国家自然科学基金优秀青年基金（海外），基于合成蛋白工具的泛素化修饰功能探索与机制解析，主持，在研；
2023.1-2025.12，国家自然科学基金青年项目，K27链型多聚泛素抗体工具的开发及应用，22207070，主持，在研；
2025.1-2028.12, 国家自然科学基金面上项目，基于构象识别的ISG15功能调控工具的开发及应用，22477076，主持，在研；
2023.12-2026.11, 国家重点研发计划, 中枢感染免疫和药物干预策略研究，2023YFC2306500 ，骨干参与，在研。

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