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<p>The chemical modification of natural proteins in living systems is highly desirable as cutting-edge research at the chemistry–biology interface. Recent advances in bio-orthogonal protein modification have enabled the production of chemically functionalized proteins in cultured cell systems. However, a limited number of methods are applicable in vivo because of the complexity of the three-dimensional constructs of living systems with diverse, heterogeneous cell populations and flow systems filled with tissue fluids. Here we report a genetic-engineering-free method to modify receptor proteins with various probes in the living mouse brain by combining in-brain ligand-directed chemistry with bio-orthogonal click chemistry, and propose a chemical guideline for the reaction design. The rapid and selective tethering of a set of fluorescent peptides to AMPA-type glutamate receptors allowed the synthesis of receptor-based fluorescent sensors. These probes enabled mapping of the activity of matrix metalloproteinase-9 proximal to AMPA-type glutamate receptors in the living brain to be realized with high spatial resolution.</p><p></p>

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In-brain synthesis of receptor-based protease sensors by coupling ligand-directed chemistry and click chemistry

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月2日

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  • Seiji Sakamoto,
  • Kazuki Shiraiwa,
  • Mengchu Wang,
  • Mamoru Ishikawa,
  • Hiroshi Nonaka,
  • Itaru Hamachi

摘要

The chemical modification of natural proteins in living systems is highly desirable as cutting-edge research at the chemistry–biology interface. Recent advances in bio-orthogonal protein modification have enabled the production of chemically functionalized proteins in cultured cell systems. However, a limited number of methods are applicable in vivo because of the complexity of the three-dimensional constructs of living systems with diverse, heterogeneous cell populations and flow systems filled with tissue fluids. Here we report a genetic-engineering-free method to modify receptor proteins with various probes in the living mouse brain by combining in-brain ligand-directed chemistry with bio-orthogonal click chemistry, and propose a chemical guideline for the reaction design. The rapid and selective tethering of a set of fluorescent peptides to AMPA-type glutamate receptors allowed the synthesis of receptor-based fluorescent sensors. These probes enabled mapping of the activity of matrix metalloproteinase-9 proximal to AMPA-type glutamate receptors in the living brain to be realized with high spatial resolution.