Reactivity‐Tunable Fluorescent Platform for Selective and Biocompatible Modification of Cysteine or Lysine

Author:

Ren Xiaojie12,Li Haokun1,Peng Hui3,Yang Yang4,Su Hang2,Huang Chen1,Wang Xuan56,Zhang Jie1,Liu Zhiyang1,Wei Wenyu1,Cheng Ke1,Zhu Tianyang4,Lu Zhenpin1,Li Zhengqiu3,Zhao Qian4,Tang Ben Zhong7,Yao Shao Q.5ORCID,Song Xiangzhi2,Sun Hongyan1

Affiliation:

1. Department of Chemistry and Centre of Super‐Diamond and Advanced Films (COSDAF) City University of Hong Kong 83 Tat Chee Avenue, Kowloon Hong Kong 999077 China

2. College of Chemistry & Chemical Engineering Central South University Changsha Hunan 410083 China

3. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE) MOE Key Laboratory of Tumor Molecular Biology School of Pharmacy Jinan University Guangzhou Guangdong 510632 China

4. Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University Hung Hom, Kowloon Hong Kong 999077 China

5. Department of Chemistry National University of Singapore Singapore 117543 Singapore

6. School of Pharmaceutical Sciences (Shenzhen) Shenzhen Campus of Sun Yat‐sen University Shenzhen 518107 China

7. Department of Chemistry The Hong Kong University of Science and Technology Clear Water Bay, Kowloon Hong Kong 999077 China

Abstract

AbstractChemoselective modification of specific residues within a given protein poses a significant challenge, as the microenvironment of amino acid residues in proteins is variable. Developing a universal molecular platform with tunable chemical warheads can provide powerful tools for precisely labeling specific amino acids in proteins. Cysteine and lysine are hot targets for chemoselective modification, but current cysteine/lysine‐selective warheads face challenges due to cross‐reactivity and unstable reaction products. In this study, a versatile fluorescent platform is developed for highly selective modification of cysteine/lysine under biocompatible conditions. Chloro‐ or phenoxy‐substituted NBSe derivatives effectively labeled cysteine residues in the cellular proteome with high specificity. This finding also led to the development of phenoxy‐NBSe phototheragnostic for the diagnosis and activatable photodynamic therapy of GSH‐overexpressed cancer cells. Conversely, alkoxy‐NBSe derivatives are engineered to selectively react with lysine residues in the cellular environment, exhibiting excellent anti‐interfering ability against thiols. Leveraging a proximity‐driven approach, alkoxy‐NBSe probes are successfully designed to demonstrate their utility in bioimaging of lysine deacetylase activity. This study also achieves integrating a small photosensitizer into lysine residues of proteins in a regioselective manner, achieving photoablation of cancer cells activated by overexpressed proteins.

Funder

National Natural Science Foundation of China

Kementerian Pendidikan

Publisher

Wiley

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