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Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.
Journal article

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

  • Giroud M Laboratorium für Organische Chemie , ETH Zurich , Vladimir-Prelog-Weg 3 , 8093 Zürich , Switzerland.
  • Dietzel U Rudolf-Virchow Center for Experimental Biomedicine , University of Würzburg , Josef-Schneider-Strasse 2 , 97080 Würzburg , Germany.
  • Anselm L Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Banner D Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Kuglstatter A Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Benz J Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Blanc JB Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Gaufreteau D Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Liu H Roche Pharma Research and Early Development , Roche Innovation Center Shanghai , 720 Cailun Road , Pudong , Shanghai 201203 , China.
  • Lin X Roche Pharma Research and Early Development , Roche Innovation Center Shanghai , 720 Cailun Road , Pudong , Shanghai 201203 , China.
  • Stich A Department of Tropical Medicine , Medical Mission Institute , Salvatorstrasse 7 , 97074 Würzburg , Germany.
  • Kuhn B Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Schuler F Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • Kaiser M Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4051 Basel , Switzerland.
  • Brun R Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4051 Basel , Switzerland.
  • Schirmeister T Institut für Pharmazie und Biochemie , Johannes Gutenberg-Universität Mainz , Staudinger Weg 5 , 55128 Mainz , Germany.
  • Kisker C Rudolf-Virchow Center for Experimental Biomedicine , University of Würzburg , Josef-Schneider-Strasse 2 , 97080 Würzburg , Germany.
  • Diederich F Laboratorium für Organische Chemie , ETH Zurich , Vladimir-Prelog-Weg 3 , 8093 Zürich , Switzerland.
  • Haap W Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
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  • 2018-03-30
Published in:
  • Journal of medicinal chemistry. - 2018
Animals
Binding Sites
Blood-Brain Barrier
Cathepsin L
Cell Line
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors
Drug Repositioning
Humans
Lactams, Macrocyclic
Ligands
Male
Mice, Inbred C57BL
Molecular Structure
Rats
Structure-Activity Relationship
Swine
Trypanocidal Agents
Trypanosoma brucei rhodesiense
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/274448
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