Truncated latrunculins as actin inhibitors targeting plasmodium falciparum motility and host-cell invasion

摘要

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.