Journal articles
Exploiting the S4–S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis
Carla Guarino
1
Natalia Gruba
2
Renata Grzywa
3
Edyta Dyguda-Kazimierowicz
4
Yveline Hamon
5, 1
Monika Łȩgowska
2
Marcin Skoreński
3
Sandrine Dallet-Choisy
6, 1
Adam Marchand-Adam
1
Christine Kellenberger
7
Dieter Jenne
8
Marcin Sieńczyk
3
Adam Lesner
9, 2
Francis Gauthier
1
Brice Korkmaz
10, 1
10
CEPR. Equipe 2 - Centre d'Etude des Pathologies Respiratoires (CEPR), UMR 1100. Equipe 2
CEPR - Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100
Carla Guarino 1
Author
Natalia Gruba 2
Author
Renata Grzywa 3
Author
Edyta Dyguda-Kazimierowicz 4
Author
Yveline Hamon 5, 1
Author
Monika Łȩgowska 2
Author
Marcin Skoreński 3
Author
Sandrine Dallet-Choisy 6, 1
Author
Adam Marchand-Adam 1
Author
Christine Kellenberger 7
Author
Dieter Jenne 8
Author
Marcin Sieńczyk 3
Author
1
Pathologies Respiratoires : Protéolyse et Aérosolthérapie (Faculté de Médecine - Bâtiment 47C - 10 Boulevard Tonnellé 37032 Tours Cedex 1 - France)
- Université de Tours : EA6305 (60 rue du Plat d'Étain, 37020 Tours cedex 1 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1100 (101, rue de Tolbiac, 75013 Paris - France)
2
UG - University of Gdańsk ( Wita Stwosza 57, 80952 Gdańsk - Poland)
3
UWr - University of Wrocław [Poland] (Pl. Uniwersytecki 1
50-137 Wrocław - Poland)
4
Wroclaw University of Science and Technology (27 Wybrzeże Wyspiańskiego St
50-370 Wrocław - Poland)
5
Comprehensive Pneumology Center - Institute of Lung Biology and Disease (iLBD) (Germany)
- German Center for Lung Research (Germany)
6
Université Francois Rabelais [Tours] (60 Rue du Plat d'Étain, 37000 Tours - France)
7
AFMB - Architecture et fonction des macromolécules biologiques (Faculté des Sciences de Luminy - ESIL 163 avenue de Luminy CP 925 13288 MARSEILLE CEDEX 09 - France)
- CNRS - Centre National de la Recherche Scientifique : UMR7257 (France)
- AMU - Aix Marseille Université : UMR7257 (Aix-Marseille Université Jardins du Pharo 58 Boulevard Charles Livon 13284 Marseille cedex 7 - France)
- INRA - Institut National de la Recherche Agronomique : USC1408 (France)
8
Department of Neuroimmunology (Max-Planck-Institute of Neurobiology, Martinsried, Munich - Germany)
- Max-Planck-Institut (Germany)
9
Faculty of Chemistry (Haifa 32000 - Israel)
- Technion - Israel Institute of Technology [Haifa] (Technion City, Haifa 3200003 - Israel)
10
CEPR. Equipe 2 - Centre d'Etude des Pathologies Respiratoires (CEPR), UMR 1100. Equipe 2 (Faculté de Médecine 10, boulevard Tonnellé 37032 TOURS CEDEX 1 - France)
- CEPR - Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (Faculté de Médecine 10, boulevard Tonnellé 37032 TOURS CEDEX 1 - France)
- Université de Tours (60 rue du Plat d'Étain, 37020 Tours cedex 1 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale (101, rue de Tolbiac, 75013 Paris - France)
Abstract : The neutrophilic serine protease proteinase 3 (PR3) is involved in inflammation and immune response and thus appears as a therapeutic target for a variety of infectious and inflammatory diseases. Here we combined kinetic and molecular docking studies to increase the potency of peptidyl-diphenyl phosphonate PR3 inhibitors. Occupancy of the S1 subsite of PR3 by a nVal residue and of the S4-S5 subsites by a biotinylated Val residue as obtained in biotin-VYDnVP(O-C6H4-4-Cl)2 enhanced the second-order inhibition constant kobs/[I] toward PR3 by more than 10 times ( kobs/[I] = 73000 ± 5000 M-1 s-1) as compared to the best phosphonate PR3 inhibitor previously reported. This inhibitor shows no significant inhibitory activity toward human neutrophil elastase and resists proteolytic degradation in sputa from cystic fibrosis patients. It also inhibits macaque PR3 but not the PR3 from rodents and can thus be used for in vivo assays in a primate model of inflammation.
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Journal articles
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https://hal-amu.archives-ouvertes.fr/hal-02094546
Contributor : Yves Bourne <>
Submitted on : Tuesday, April 9, 2019 - 7:25:30 PM
Last modification on : Tuesday, December 8, 2020 - 10:55:04 AM
Contributor : Yves Bourne <>
Submitted on : Tuesday, April 9, 2019 - 7:25:30 PM
Last modification on : Tuesday, December 8, 2020 - 10:55:04 AM
Identifiers
- HAL Id : hal-02094546, version 1
- DOI : 10.1021/acs.jmedchem.7b01416
- PUBMED : 29442501
Collections
UNIV-AMU | INRA | CNRS | UNIV-TOURS | INRAE
Citation
Carla Guarino, Natalia Gruba, Renata Grzywa, Edyta Dyguda-Kazimierowicz, Yveline Hamon, et al.. Exploiting the S4–S5 Specificity of Human Neutrophil Proteinase 3 to Improve the Potency of Peptidyl Di(chlorophenyl)-phosphonate Ester Inhibitors: A Kinetic and Molecular Modeling Analysis. Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (5), pp.1858-1870. ⟨10.1021/acs.jmedchem.7b01416⟩. ⟨hal-02094546⟩
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