Journal of Medicinal Chemistry, volume 61, issue 9, pages 4165-4175
Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes
Publication type: Journal Article
Publication date: 2018-04-18
Journal:
Journal of Medicinal Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 7.3
ISSN: 00222623, 15204804
Drug Discovery
Molecular Medicine
Abstract
Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure-guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (AI), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix-turn-helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-AI selective PrfA inhibitors with potent antivirulence properties.
Citations by journals
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Citations by publishers
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4
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American Chemical Society (ACS)
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4 publications, 19.05%
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2 publications, 9.52%
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Elsevier
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2 publications, 9.52%
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Wiley
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2 publications, 9.52%
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Royal Society of Chemistry (RSC)
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2 publications, 9.52%
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Bentham Science
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1 publication, 4.76%
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Public Library of Science (PLoS)
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Public Library of Science (PLoS)
1 publication, 4.76%
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Multidisciplinary Digital Publishing Institute (MDPI)
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Multidisciplinary Digital Publishing Institute (MDPI)
1 publication, 4.76%
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Proceedings of the National Academy of Sciences (PNAS)
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Proceedings of the National Academy of Sciences (PNAS)
1 publication, 4.76%
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Kulén M. et al. Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 9. pp. 4165-4175.
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Kulén M., Lindgren M., Hansen S., Cairns A. G., Grundström C., Begum A., Van Der Lingen I., Brännström K., Hall M. N., Sauer U., Johansson J., Sauer-Eriksson A. E., Almqvist F. Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 9. pp. 4165-4175.
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TY - JOUR
DO - 10.1021/acs.jmedchem.8b00289
UR - https://doi.org/10.1021%2Facs.jmedchem.8b00289
TI - Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes
T2 - Journal of Medicinal Chemistry
AU - Kulén, Martina
AU - Lindgren, Marie
AU - Hansen, Sabine
AU - Cairns, Andrew G.
AU - Begum, Afshan
AU - Van Der Lingen, Ingeborg
AU - Brännström, Kristoffer
AU - Almqvist, Fredrik
AU - Grundström, Christin
AU - Hall, Michael N.
AU - Sauer, Uwe
AU - Johansson, Jörgen
AU - Sauer-Eriksson, A. Elisabeth
PY - 2018
DA - 2018/04/18 00:00:00
PB - American Chemical Society (ACS)
SP - 4165-4175
IS - 9
VL - 61
SN - 0022-2623
SN - 1520-4804
ER -
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@article{2018_Kulén,
author = {Martina Kulén and Marie Lindgren and Sabine Hansen and Andrew G. Cairns and Afshan Begum and Ingeborg Van Der Lingen and Kristoffer Brännström and Fredrik Almqvist and Christin Grundström and Michael N. Hall and Uwe Sauer and Jörgen Johansson and A. Elisabeth Sauer-Eriksson},
title = {Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {apr},
url = {https://doi.org/10.1021%2Facs.jmedchem.8b00289},
number = {9},
pages = {4165--4175},
doi = {10.1021/acs.jmedchem.8b00289}
}
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Kulén, Martina, et al. “Structure-Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes.” Journal of Medicinal Chemistry, vol. 61, no. 9, Apr. 2018, pp. 4165-4175. https://doi.org/10.1021%2Facs.jmedchem.8b00289.