Polymerization of the cytosolic protein actin is c
ritical to cell movement and
host-cell invasion by the malaria parasite,
Plasmodium falciparum.
Any disruption to actin
polymerization dynamics will render the parasite in
capable of invading a host cell and
thereby unable to cause infection. Here, we explore
the potential of using truncated
latrunculins as potential chemotherapeutics for the
treatment of malaria. Exploration of the
binding interactions of the natural actin inhibitor
latrunculins, with actin revealed how a
truncated core of the inhibitor could retain its ke
y interaction features with actin. This
truncated core was synthesised and subjected to pre
liminary structure-activity relationship
studies to generate a focused set of analogues. Bio
chemical analyses of these analogues
demonstrate their 6-fold increased activity compare
d with latrunculin B against
Plasmodium
falciparum
and a 16-fold improved selectivity
ex vivo
. These data establish the latrunculin
core as a potential focus for future structure-base
d drug design of chemotherapeutics against
malaria.