Bioorthogonal "labeling after Recognition" Affording an FRET-Based Luminescent Probe for Detecting and Imaging Caspase-3 via Photoluminescence Lifetime Imaging

Article abstract of DOI:10.1021/jacs.9b12191

Bis-labeling with a luminescent energy donor/acceptor pair onto biological substrates affords probes which give FRET readouts for the detection of interaction partners. However, the covalently bound luminophores bring about steric hindrance and nonspecific interaction, which probably perturb the biological recognition. Herein, we designed a highly sensitive and specific "labeling after recognition" sensing approach, where luminophore labeling occurred after the biological recognition. Taking the cutting enzyme caspase-3 as an example, we demonstrated the detection of its catalytic activity in solution and apoptotic cells using the tetrapeptide motif Asp-Glu-Val-Asp (DEVD) as the cleavable substrate, and an iridium(III) complex and a rhodamine derivative as the energy donor/acceptor pair. The DEVD tetrapeptide was modified with an azide and a GK-norbornylene groups at the amino and carboxyl terminuses, respectively, which allowed donor/acceptor bis-labeling via two independent catalysis-free bioorthogonal reactions. The phosphorescence lifetime of the iridium(III) complex was quenched upon bis-labeling owing to the intracellular FRET to the rhodamine derivative, and significantly elongated upon the peptide being catalytically cleaved by caspase-3. Interestingly, the sensitivity and efficiency of the lifetime responses were much higher in the "labeling after recognition" sensing approach. Molecular docking analysis showed that the steric hindrance and nonspecific interactions partially inhibited the biological recognition of the DEVD substrate by caspase-3. The imaging of the catalytic activity of caspase-3 in apoptotic cells was demonstrated via photoluminescence lifetime imaging microscopy. Lifetime analysis not only confirmed the occurrence of intracellular bioorthogonal bis-labeling and catalytic cleavage, but also showed the extent to which the two dynamic processes occurred.

Full text of DOI:10.1021/jacs.9b12191

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Article
Bioorthogonal “Labeling after Recognition” Affording
an FRET-based Luminescent Probe for Detecting and
Imaging Caspase-3 via Photoluminescence Lifetime Imaging
Qi Wu, Kenneth Yin Zhang, Peiling Dai, Hengyu Zhu, Yun Wang,
Linna Song, Ling Wang, Shujuan Liu, Qiang Zhao, and Wei Huang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12191 • Publication Date (Web): 17 Dec 2019
Downloaded from pubs.acs.org on December 18, 2019
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ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
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ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
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ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
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ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
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ACS Paragon Plus Environment

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Page 8 of 9
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ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
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