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

Xiaojie Ren, Haokun Li, Hui Peng, Yang Yang, Hang Su, Chen Huang, Xuan Wang, Jie Zhang, Zhiyang Liu, Wenyu Wei, Ke Cheng, Tianyang Zhu, Zhenpin Lu, Zhengqiu Li, Qian Zhao, Ben Zhong Tang, Shao Q. Yao*, Xiangzhi Song*, Hongyan Sun*

*Corresponding author for this work

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

1 Citation (Scopus)
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Abstract

Chemoselective 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. © 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH.
Original languageEnglish
Article number2402838
JournalAdvanced Science
Volume11
Issue number31
Online published19 Jun 2024
DOIs
Publication statusPublished - 21 Aug 2024

Funding

The authors are grateful for the financial support from National Natural Science Excellent Young Scientists Fund of China (Hong Kong and Macau) (Grant No. 32122003), Research Grants Council of Hong Kong (Grant Nos. 11305221, 11312422 and C6014-20W), Science Technology and Innovation Committee of Shenzhen Municipality (Grant Nos. JCYJ20180507181654823), National Natural Science Foundation of China (Grant No. 22078067 and No. 22178395), and the Ministry of Education (MOE T1; 22-5025-A0001; T2EP10222-0002) Singapore.

Research Keywords

  • chemoselective modification
  • cysteine
  • HDACs
  • lysine
  • PDT

Publisher's Copyright Statement

  • This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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