Abstract
The ubiquitin-proteasome system (UPS)
is a potential pathway for
therapeutic intervention for pathogens such as
Plasmodium
, the causative agent of malaria. However, due to the essential nature
of this proteolytic pathway, proteasome inhibitors must avoid inhibition
of the host enzyme complex to prevent toxic side effects. The
Plasmodium
proteasome is poorly characterized, making rational
design of inhibitors that induce selective parasite killing difficult.
In this study, we developed a chemical probe that labels all catalytic
sites of the
Plasmodium
proteasome. Using this probe,
we identified several subunit selective small molecule inhibitors
of the parasite enzyme complex. Treatment with an inhibitor that is
specific for the β5 subunit during blood stage schizogony led
to a dramatic decrease in parasite replication while short-term inhibition
of the β2 subunit did not affect viability. Interestingly, coinhibition
of both the β2 and β5 catalytic subunits resulted in enhanced
parasite killing at all stages of the blood stage life cycle and reduced
parasite levels
in vivo
to barely detectable levels.
Parasite killing was achieved with overall low host toxicity, something
that has not been possible with existing proteasome inhibitors. Our
results highlight differences in the subunit dependency of the parasite
and human proteasome, thus providing a strategy for development of
potent antimalarial drugs with overall low host toxicity.