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3-Oxo-β-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling

  • Luís A. R. Carvalho*
    Luís A. R. Carvalho
    Department of Medicinal Chemistry, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
    *E-mail: [email protected] (L. A. R. Carvalho).
  • Vanessa T. Almeida
    Vanessa T. Almeida
    Biological Chemistry Division, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Av. da República, 2780-157 Oeiras, Portugal
  • José A. Brito
    José A. Brito
    Biological Chemistry Division, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Av. da República, 2780-157 Oeiras, Portugal
  • Kenneth M. Lum
    Kenneth M. Lum
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
  • Tânia F. Oliveira
    Tânia F. Oliveira
    Biological Chemistry Division, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Av. da República, 2780-157 Oeiras, Portugal
  • Rita C. Guedes
    Rita C. Guedes
    Department of Medicinal Chemistry, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
  • Lídia M. Gonçalves
    Lídia M. Gonçalves
    Department of Medicinal Chemistry, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
  • Susana D. Lucas
    Susana D. Lucas
    Department of Medicinal Chemistry, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
  • Benjamin F. Cravatt
    Benjamin F. Cravatt
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
  • Margarida Archer
    Margarida Archer
    Biological Chemistry Division, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Av. da República, 2780-157 Oeiras, Portugal
  • , and 
  • Rui Moreira*
    Rui Moreira
    Department of Medicinal Chemistry, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
    *E-mail: [email protected] (R. Moreira).
    More by Rui Moreira
Cite this: ACS Chem. Biol. 2020, 15, 4, 878–883
Publication Date (Web):March 16, 2020
https://doi.org/10.1021/acschembio.0c00090
Copyright © 2020 American Chemical Society

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    Abstract

    Abstract Image

    3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-β-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.0c00090.

    • Complete library of compounds, characterization and NMR spectra; full crystallographic data; full DFT computational results and methods; enzymatic assays; gel-based ABPP and ABPP-MudPIT complementary assays and procedures (PDF)

    • Full proteomics dataset (XLSX)

    Accession Codes

    The following Protein Databank (www.rcsb.org) codes were noted in this work: PPE:5, 6QBU; PPE:6, 6QEN; PPE:7, 6QEO; and HNE:8, 6SMA

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    Cited By

    This article is cited by 11 publications.

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    2. Keisuke Tokunaga, Mami Sato, Keiko Kuwata, Chizuru Miura, Hirokazu Fuchida, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo, Naoya Shindo, Akio Ojida. Bicyclobutane Carboxylic Amide as a Cysteine-Directed Strained Electrophile for Selective Targeting of Proteins. Journal of the American Chemical Society 2020, 142 (43) , 18522-18531. https://doi.org/10.1021/jacs.0c07490
    3. Noémi Csorba, Péter Ábrányi-Balogh, György M. Keserű. Covalent fragment approaches targeting non-cysteine residues. Trends in Pharmacological Sciences 2023, 44 (11) , 802-816. https://doi.org/10.1016/j.tips.2023.08.014
    4. Brittney Racioppo, Nan Qiu, Alexander Adibekian. Serine Hydrolase Activity‐Based Probes for Use in Chemical Proteomics. Israel Journal of Chemistry 2023, 63 (3-4) https://doi.org/10.1002/ijch.202300016
    5. Weishan Wang, Jiafang Deng, Yan Zhang, Jinbo Li. A Small‐Molecule Probe with a Dual Function of miRNA Inhibition and Target identification. Chemistry – A European Journal 2023, 29 (3) https://doi.org/10.1002/chem.202202013
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    9. Péter Ábrányi-Balogh, György Miklós Keserű. Warheads for designing covalent inhibitors and chemical probes. 2022, 47-73. https://doi.org/10.1016/B978-0-12-821433-6.00007-6
    10. Josefa Anaya, Ramón M. Sánchez. Four-membered ring systems. 2021, 53-91. https://doi.org/10.1016/B978-0-323-98410-2.00004-7
    11. György M. Keserű, Daniel A. Erlanson. The future of covalent inhibition. 2021, 267-284. https://doi.org/10.1016/bs.armc.2020.10.003

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