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


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
Carla Guarino,,
, Natalia Gruba (FCh / DET / LBAN)
Natalia Gruba,,
- Laboratory of Biochemical Analytics and Nanodiagnostics
, Renata Grzywa
Renata Grzywa,,
, Edyta Dyguda-Kazimierowicz
Edyta Dyguda-Kazimierowicz,,
, Yveline Hamon
Yveline Hamon,,
, Monika Łęgowska (FCh / DMB / LBA)
Monika Łęgowska,,
- Laboratory of Biochemical Analytics
, Marcin Skoreński
Marcin Skoreński,,
, Sandrine Dallet-Choisy
Sandrine Dallet-Choisy,,
, Sylvain Marchand-Adam
Sylvain Marchand-Adam,,
, Christine Kellenberger
Christine Kellenberger,,
et al.`
Journal seriesJournal of Medicinal Chemistry, ISSN 0022-2623, [1520-4804], (A 45 pkt)
Issue year2018
Publication size in sheets0.6
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 = 1; WoS Impact Factor: 2017 = 6.253 (2) - 2017=5.9 (5)
Citation count*4 (2019-07-17)
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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.