Transition State Mimetics
of the Plasmodium Export Element Are
Potent Inhibitors of Plasmepsin V from P. falciparum and P. vivax
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Abstract
Following
erythrocyte invasion, malaria parasites export a catalogue
of remodeling proteins into the infected cell that enable parasite
development in the human host. Export is dependent on the activity
of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins
within the Plasmodium export element
(PEXEL; RxL↓xE/Q/D) in the parasite’s endoplasmic reticulum.
Here, we generated transition state mimetics of the native PEXEL substrate
that potently inhibit PMV isolated from Plasmodium
falciparum and Plasmodium vivax. Through optimization, we identified that the activity of the mimetics
was completely dependent on the presence of P<sub>1</sub> Leu and
P<sub>3</sub> Arg. Treatment of P. falciparum-infected erythrocytes with a set of optimized mimetics impaired
PEXEL processing and killed the parasites. The striking effect of
the compounds provides a clearer understanding of the accessibility
of the PMV active site and reaffirms the enzyme as an attractive target
for the design of future antimalarials