Peptidomimetic Vinyl Heterocyclic Inhibitors of Cruzain Effect Antitrypanosomal Activity
| Autor: | Jana Gomez, Jair L. Siqueira-Neto, Drake M. Mellott, Jorge Cruz-Reyes, Emily Desormeaux, Claudia Calvet Alvarez, Jean A. Bernatchez, Thomas D. Meek, Linfeng Li, Xiang Zhai, Elizabeth Alvarez Hernandez, Balachandra Chenna, James H. McKerrow |
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| Rok vydání: | 2020 |
| Předmět: |
Chagas disease
Vinyl Compounds Pyridines Stereochemistry Peptidomimetic Trypanosoma cruzi Trypanosoma brucei brucei Protozoan Proteins Plasma protein binding Cysteine Proteinase Inhibitors Trypanosoma brucei Vinyl sulfone 01 natural sciences Article Mice 03 medical and health sciences chemistry.chemical_compound parasitic diseases Drug Discovery medicine Animals Humans Enzyme Assays 030304 developmental biology 0303 health sciences Dipeptide biology Chemistry biology.organism_classification medicine.disease Trypanocidal Agents Cysteine protease 0104 chemical sciences Molecular Docking Simulation Cysteine Endopeptidases Kinetics 010404 medicinal & biomolecular chemistry Pyrimidines Drug Design Molecular Medicine Peptidomimetics Myoblasts Cardiac Protein Binding |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 (K(i)* = 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 (EC(50) = 1–15 μM) and eliminated T. cruzi in infected murine cardiomyoblasts (EC(50) = 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. |
| Databáze: | OpenAIRE |
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