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 , Natalia Gruba , Renata Grzywa , Edyta Dyguda-Kazimierowicz , Yveline Hamon , Monika Łęgowska , Marcin Skoreński , Sandrine Dallet-Choisy , Sylvain Marchand-Adam , Christine Kellenberger , Dieter E. Jenne , Marcin Sieńczyk , Adam Lesner , Francis Gauthier , Brice Korkmaz

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.
Author Carla Guarino - [Université de Tours]
Carla Guarino,,
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, Natalia Gruba (FCh / DET / LBAN)
Natalia Gruba,,
- Laboratory of Biochemical Analytics and Nanodiagnostics
, Renata Grzywa - [Wrocław University of Science and Technology]
Renata Grzywa,,
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- Wrocław University of Science and Technology
, Edyta Dyguda-Kazimierowicz - [Wrocław University of Science and Technology]
Edyta Dyguda-Kazimierowicz,,
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- Wrocław University of Science and Technology
, Yveline Hamon - [Université de Tours]
Yveline Hamon,,
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, Monika Łęgowska (FCh / DMB / LBA)
Monika Łęgowska,,
- Laboratory of Biochemical Analytics
, Marcin Skoreński - [Wrocław University of Science and Technology]
Marcin Skoreński,,
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- Wrocław University of Science and Technology
, Sandrine Dallet-Choisy - [Université de Tours]
Sandrine Dallet-Choisy,,
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, Sylvain Marchand-Adam - [Université de Tours]
Sylvain Marchand-Adam,,
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, Christine Kellenberger - [CNRS Centre National de la Recherche Scientifique]
Christine Kellenberger,,
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- CNRS Centre National de la Recherche Scientifique
et al.`
Journal seriesJournal of Medicinal Chemistry, ISSN 0022-2623, [1520-4804], (A 45 pkt)
Issue year2018
Vol61
No5
Pages1858-1870
Publication size in sheets0.6
DOIDOI:10.1021/acs.jmedchem.7b01416
URL https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01416#
Languageen angielski
Score (nominal)45
ScoreMinisterial score = 45.0, ArticleFromJournal
Ministerial score (2013-2016) = 45.0, ArticleFromJournal
Publication indicators WoS Citations = 5; WoS Impact Factor: 2017 = 6.253 (2) - 2017=5.9 (5); Scopus Citations = 6
Citation count*7 (2020-05-24)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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