Abstract
Cruzain, an essential cysteine protease of the parasitic protozoan, Trypanosoma cruzi, is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(N-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (Ki* = 0.1-0.4 μM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of Trypanosoma brucei brucei (EC50 = 1-15 μM) and eliminated T. cruzi in infected murine cardiomyoblasts (EC50 = 5-8 μM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.
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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Cysteine Endopeptidases / metabolism
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / metabolism
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Cysteine Proteinase Inhibitors / pharmacology*
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Drug Design
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Enzyme Assays
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Humans
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Kinetics
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Mice
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Molecular Docking Simulation
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Myoblasts, Cardiac / drug effects
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Peptidomimetics / chemical synthesis
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Peptidomimetics / metabolism
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Peptidomimetics / pharmacology*
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Protein Binding
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / metabolism
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Pyridines / chemical synthesis
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Pyridines / metabolism
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Pyridines / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / metabolism
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Pyrimidines / pharmacology
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / metabolism
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei brucei / drug effects
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Trypanosoma cruzi / drug effects
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Vinyl Compounds / chemical synthesis
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Vinyl Compounds / metabolism
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Vinyl Compounds / pharmacology*
Substances
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Cysteine Proteinase Inhibitors
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Peptidomimetics
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Protozoan Proteins
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Pyridines
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Pyrimidines
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Trypanocidal Agents
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Vinyl Compounds
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Cysteine Endopeptidases
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cruzipain