Journal of Medicinal Chemistry, volume 61, issue 8, pages 3350-3369
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors
Maude Giroud
1
,
Uwe Dietzel
2
,
Lilli Anselm
3
,
David Banner
3
,
Andreas Kuglstatter
3
,
J. Benz
3
,
Jean-Baptiste Blanc
3
,
Delphine Gaufreteau
3
,
Haixia Liu
4
,
XianFeng Lin
4
,
August Stich
5
,
Bernd Kuhn
3
,
Franz Schuler
3
,
Marcel Kaiser
6, 7
,
Reto Brun
6, 7
,
T. Schirmeister
8
,
C. T. Kisker
2
,
Francois Diederich
1
,
W. Haap
3
4
Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, 720 Cailun Road, Pudong, Shanghai 201203, China
|
5
Department of Tropical Medicine, Medical Mission Institute, Salvatorstrasse 7, 97074 Würzburg, Germany
|
Publication type: Journal Article
Publication date: 2018-03-29
Journal:
Journal of Medicinal Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 7.3
ISSN: 00222623, 15204804
Drug Discovery
Molecular Medicine
Abstract
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
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Citations by publishers
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6 publications, 20.69%
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1 publication, 3.45%
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1 publication, 3.45%
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1 publication, 3.45%
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1 publication, 3.45%
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- We do not take into account publications 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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Giroud M. et al. Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 8. pp. 3350-3369.
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Giroud M., Dietzel U., Anselm L., Banner D., Kuglstatter A., Benz J., Blanc J., Gaufreteau D., Liu H., Lin X., Stich A., Kuhn B., Schuler F., Kaiser M., Brun R., Schirmeister T., Kisker C. T., Diederich F., Haap W. Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 8. pp. 3350-3369.
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TY - JOUR
DO - 10.1021/acs.jmedchem.7b01869
UR - https://doi.org/10.1021/acs.jmedchem.7b01869
TI - Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors
T2 - Journal of Medicinal Chemistry
AU - Giroud, Maude
AU - Dietzel, Uwe
AU - Anselm, Lilli
AU - Banner, David
AU - Kuglstatter, Andreas
AU - Blanc, Jean-Baptiste
AU - Gaufreteau, Delphine
AU - Lin, XianFeng
AU - Stich, August
AU - Brun, Reto
AU - Diederich, Francois
AU - Haap, W.
AU - Benz, J.
AU - Liu, Haixia
AU - Kuhn, Bernd
AU - Schuler, Franz
AU - Kaiser, Marcel
AU - Schirmeister, T.
AU - Kisker, C. T.
PY - 2018
DA - 2018/03/29 00:00:00
PB - American Chemical Society (ACS)
SP - 3350-3369
IS - 8
VL - 61
SN - 0022-2623
SN - 1520-4804
ER -
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@article{2018_Giroud,
author = {Maude Giroud and Uwe Dietzel and Lilli Anselm and David Banner and Andreas Kuglstatter and Jean-Baptiste Blanc and Delphine Gaufreteau and XianFeng Lin and August Stich and Reto Brun and Francois Diederich and W. Haap and J. Benz and Haixia Liu and Bernd Kuhn and Franz Schuler and Marcel Kaiser and T. Schirmeister and C. T. Kisker},
title = {Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {mar},
url = {https://doi.org/10.1021/acs.jmedchem.7b01869},
number = {8},
pages = {3350--3369},
doi = {10.1021/acs.jmedchem.7b01869}
}
Cite this
MLA
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Giroud, Maude, et al. “Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.” Journal of Medicinal Chemistry, vol. 61, no. 8, Mar. 2018, pp. 3350-3369. https://doi.org/10.1021/acs.jmedchem.7b01869.