Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain

Gallinamide A, originally isolated
with a modest antimalarial activity,
was subsequently reisolated and characterized as a potent, selective,
and irreversible inhibitor of the human cysteine protease cathepsin
L. Molecular docking identified potential modifications to improve
binding, which were synthesized as a suite of analogs. Resultingly,
this current study produced the most potent gallinamide analog yet
tested against cathepsin L (10, Ki = 0.0937 ± 0.01 nM and kinact/Ki = 8 730 000). From
a protein structure and substrate preference perspective, cruzain,
an essential Trypanosoma cruzi cysteine
protease, is highly homologous. Our investigations revealed that gallinamide
and its analogs potently inhibit cruzain and are exquisitely toxic
toward T. cruzi in the intracellular
amastigote stage. The most active compound, 5, had an
IC50 = 5.1 ± 1.4 nM, but was relatively inactive to
both the epimastigote (insect stage) and the host cell, and thus represents
a new candidate for the treatment of Chagas disease.