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Peer-reviewedCC BY 3.0RSC Chemical Biology

BODIPY-tagged β-lactams as selective quenched activity-based probes to target human neutrophil elastase

  • Rita Felix1,2
  • Luís Carvalho3
  • Ismael Rufino1,2
  • Rita Guedes1,2
  • Ana Margarida Madureira1,2
  • Ana Mallo-Abreu4,5
  • Lídia Gonçalves1,2
  • Olga Genilloud6
  • Rosario Fernandez-Godino6
  • Maria C. Ramos6
  • Rui Moreira1,2
6 affiliations
  1. 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa Lisboa Portugal
  2. 2Faculty of Pharmacy, Universidade de Lisboa Lisboa Portugal
  3. 3The Francis Crick Institute 1 Midland Road London NW1 1AT UK
  4. 4Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela 15782 Santiago de Compostela Spain
  5. 5Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela 15782 Santiago de Compostela Spain
  6. 6Fundación MEDINA Av. Conocimiento 34, Health Sciences Technology Park 18016 Granada Spain
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Abstract

Activity-based probes are indispensable tools for interrogating protease function, and quenched fluorescent variants enable dynamic, real-time imaging of enzymatic activity. Despite these advances, very few quenched activity-based probes (qABPs) have been reported for serine proteases, which constitute the largest and most diverse mechanistic class of proteases. β-Lactams have been extensively used to develop molecular tools and drugs designed to bind or be hydrolysed by serine-dependent bacterial enzymes. Here, we report the first monocyclic β-lactam-containing qABPs for detecting serine proteases. Both the enzyme-triggered activation mechanism and intrinsic reactivity of the probes were highly dependent on the relative position of the BODIPY-FL fluorophore and quencher moiety at the β-lactam core. qABPs displaying the most efficient turn-on mechanism were shown to selectively target human neutrophil elastase (HNE) in different human cell lysates. The most successful qABP was rapidly internalised and targeted HNE in U937 cells and human neutrophils. These results demonstrate the potential of the modular β-lactam warhead to develop turn-on probes to track neutrophil serine proteases in live cells.

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Cite

BibTeXRIS
BibTeX
@article{felix2026bodipytagged,
  title = {{BODIPY-tagged β-lactams as selective quenched activity-based probes to target human neutrophil elastase}},
  author = {Rita Felix and Luís Carvalho and Ismael Rufino and Rita Guedes and Ana Margarida Madureira and Ana Mallo-Abreu and Lídia Gonçalves and Olga Genilloud and Rosario Fernandez-Godino and Maria C. Ramos and Rui Moreira},
  journal = {RSC Chemical Biology},
  year = {2026},
  month = oct,
  doi = {10.1039/d6cb00206d},
  url = {https://doi.org/10.1039/d6cb00206d},
  note = {CC BY 3.0},
}
RIS
TY  - JOUR
TI  - BODIPY-tagged β-lactams as selective quenched activity-based probes to target human neutrophil elastase
AU  - Rita Felix
AU  - Luís Carvalho
AU  - Ismael Rufino
AU  - Rita Guedes
AU  - Ana Margarida Madureira
AU  - Ana Mallo-Abreu
AU  - Lídia Gonçalves
AU  - Olga Genilloud
AU  - Rosario Fernandez-Godino
AU  - Maria C. Ramos
AU  - Rui Moreira
PY  - 2026
DA  - 2026/10/29
JO  - RSC Chemical Biology
DO  - 10.1039/d6cb00206d
UR  - https://doi.org/10.1039/d6cb00206d
AB  - Activity-based probes are indispensable tools for interrogating protease function, and quenched fluorescent variants enable dynamic, real-time imaging of enzymatic activity. Despite these advances, very few quenched activity-based probes (qABPs) have been reported for serine proteases, which constitute the largest and most diverse mechanistic class of proteases. β-Lactams have been extensively used to develop molecular tools and drugs designed to bind or be hydrolysed by serine-dependent bacterial enzymes. Here, we report the first monocyclic β-lactam-containing qABPs for detecting serine proteases. Both the enzyme-triggered activation mechanism and intrinsic reactivity of the probes were highly dependent on the relative position of the BODIPY-FL fluorophore and quencher moiety at the β-lactam core. qABPs displaying the most efficient turn-on mechanism were shown to selectively target human neutrophil elastase (HNE) in different human cell lysates. The most successful qABP was rapidly internalised and targeted HNE in U937 cells and human neutrophils. These results demonstrate the potential of the modular β-lactam warhead to develop turn-on probes to track neutrophil serine proteases in live cells.
SN  - 2633-0679
ER  -