PeptidomimeticVinyl Heterocyclic Inhibitors of CruzainEffect Antitrypanosomal Activity
Figshare documentation (Figshare (United Kingdom))(2020)
摘要
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.
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关键词
inhibitors
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