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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Blood-Brain Barrier / metabolism
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Cathepsin L / antagonists & inhibitors*
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Cell Line
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacokinetics
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Cysteine Proteinase Inhibitors / pharmacology*
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Drug Repositioning
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Humans
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Lactams, Macrocyclic / chemical synthesis
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / pharmacokinetics
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Lactams, Macrocyclic / pharmacology*
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Ligands
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Male
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Mice, Inbred C57BL
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Molecular Structure
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Rats
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Structure-Activity Relationship
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Swine
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry
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Trypanocidal Agents / pharmacokinetics
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei rhodesiense / drug effects*
Substances
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Cysteine Proteinase Inhibitors
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Lactams, Macrocyclic
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Ligands
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Trypanocidal Agents
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Cysteine Endopeptidases
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rhodesain
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CTSL protein, human
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Cathepsin L