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

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...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 61; no. 8; pp. 3350 - 3369
Main Authors:	Giroud, Maude, Dietzel, Uwe, Anselm, Lilli, Banner, David, Kuglstatter, Andreas, Benz, Jörg, Blanc, Jean-Baptiste, Gaufreteau, Delphine, Liu, Haixia, Lin, Xianfeng, Stich, August, Kuhn, Bernd, Schuler, Franz, Kaiser, Marcel, Brun, Reto, Schirmeister, Tanja, Kisker, Caroline, Diederich, François, Haap, Wolfgang
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 26-04-2018
Subjects:	Animals Binding Sites Blood-Brain Barrier - metabolism Cathepsin L - antagonists & inhibitors Cell Line Cysteine Endopeptidases - chemistry Cysteine Endopeptidases - metabolism Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - chemistry Cysteine Proteinase Inhibitors - pharmacokinetics Cysteine Proteinase Inhibitors - pharmacology Drug Repositioning Humans Lactams, Macrocyclic - chemical synthesis Lactams, Macrocyclic - chemistry Lactams, Macrocyclic - pharmacokinetics Lactams, Macrocyclic - pharmacology Ligands Male Mice, Inbred C57BL Molecular Structure Rats Structure-Activity Relationship Swine Trypanocidal Agents - chemical synthesis Trypanocidal Agents - chemistry Trypanocidal Agents - pharmacokinetics Trypanocidal Agents - pharmacology Trypanosoma brucei rhodesiense - drug effects
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Summary:	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 (K i < 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.7b01869