Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)

Plasmepsins
represent novel antimalarial drug targets. However,
plasmepsin-based antimalarial drug discovery efforts in the past 2
decades have generally suffered some drawbacks including lack of translatability
of target inhibition to potent parasite inhibition in vitro and in vivo as well as poor selectivity over the
related human aspartic proteases. Most studies reported in this period
have over-relied on the use of hemoglobinase plasmepsins I–IV
(particularly I and II) as targets for the new inhibitors even though
these are known to be nonessential at the asexual stage of parasite
development. Therefore, future antimalarial drug discovery efforts
seeking to identify plasmepsin inhibitors should focus on incorporating
non-hemoglobinase plasmepsins such as V, IX, and X in their screening
in order to maximize chances of success. Additionally, there is need
to go beyond just target enzymatic activity profiling to establishing
cellular activity, physicochemical as well as drug metabolism and
pharmacokinetics properties and finally in vivo proof-of-concept
while ensuring selectivity over related human host proteases.