Abstract
The trypanosomal cathepsin TbcatB is essential for parasite survival and is an attractive therapeutic target. Herein we report the structure-guided development of TbcatB inhibitors with specificity relative to rhodesain and human cathepsins B and L. Inhibitors were tested for enzymatic activity, trypanocidal activity, and general cytotoxicity. These data chemically validate TbcatB as a drug target and demonstrate that it is possible to potently and selectively inhibit TbcatB relative to trypanosomal and human homologues.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cathepsin B / antagonists & inhibitors
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Cathepsin B / metabolism
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Cathepsin L / antagonists & inhibitors
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Cathepsin L / metabolism
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Cell Line
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism*
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Drug Discovery
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Humans
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Models, Molecular
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology*
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Protein Conformation
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Purines / chemistry
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Substrate Specificity
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Trypanocidal Agents / chemistry*
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei brucei / drug effects
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Trypanosoma brucei brucei / enzymology
Substances
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Protease Inhibitors
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Purines
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Trypanocidal Agents
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Cysteine Endopeptidases
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TbcatB protein, Trypanosoma brucei
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rhodesain
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Cathepsin B
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Cathepsin L