The Plasmodium proteasome
represents a potential
antimalarial drug target for compounds with activity against multiple
life cycle stages. We screened a library of human proteasome inhibitors
(peptidyl boronic acids) and compared activities against purified P. falciparum and human 20S proteasomes. We chose four hits
that potently inhibit parasite growth and show a range of selectivities
for inhibition of the growth of P. falciparum compared
with human cell lines. P. falciparum was selected
for resistance in vitro to the clinically used
proteasome inhibitor, bortezomib, and whole genome sequencing was
applied to identify mutations in the proteasome β5 subunit.
Active site profiling revealed inhibitor features that enable retention
of potent activity against the bortezomib-resistant line. Substrate
profiling reveals P. falciparum 20S proteasome active
site preferences that will inform attempts to design more selective
inhibitors. This work provides a starting point for the identification
of antimalarial drug leads that selectively target the P.
falciparum proteasome.
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5′-monophosphate–mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid–sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite
Plasmodium falciparum
, namely tyrosine RS (
Pf
YRS). ML901 exerts whole-life-cycle–killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.
The NK1 receptor research has led to the clinical introduction of aprepitant in 2003 and its water soluble injectable form, fosaprepitant dimeglumine, in 2009 by Merck for the prevention of postoperative nausea and vomiting and for inhibiting chemotherapy-induced nausea and vomiting. In addition, maropitant citrate received approval in 2007 for veterinary use.
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