Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion

Abstract

Polymerization of the cytosolic protein actin is critical to cell movement and host-cell invasion by the malaria parasite, Plasmodium falciparum. Any disruption to actin polymerization dynamics will render the parasite incapable 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 key interaction features with actin. This truncated core was synthesised and subjected to preliminary structure-activity relationship studies to generate a focused set of analogues. Biochemical analyses of these analogues demonstrate their 6-fold increased activity compared 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-based drug design of chemotherapeutics against malaria.

Multiple essential functions of Plasmodium falciparum actin-1 during malaria blood-stage development

“…Therefore, whilst cross-comparison between these two species has certainly guided understanding, future comparative studies will be important for defining conserved versus evolutionary niche-specific adaptations of the core molecules required for motility and host cell invasion. Mechanistic dissection of PfACT1 involvement in P. falciparum development is not only of biological interest, but owing to the divergence of parasite actin from mammalian actins, can realistically form the basis for development of therapeutics targeting its function towards specific intervention against apicomplexan diseases [ 62 ].…”

Targeting malaria parasite invasion of red blood cells as an antimalarial strategy

“…1979; Cooper 1987; Johnson et al . 2016). Latrunculins bind to actin's monomeric form (G-actin) near the Adenosine Triphosphate (ATP) binding site and prevent polymerisation to filamentous actin (F-actin).…”

Single-molecule nanopore sensing of actin dynamics and drug binding

“…Based on the assumption that actin is fully unfolded at 6 M urea, a threshold of 40 nm 3 for the excluded volume at 6 M was used to dene the transition between folded (<40 nm 3 ) and unfolded (>40 nm 3 ) actin. This value is around 10 nm 3 less than reported at 0 M urea with no applied voltage as we see a slight decrease in excluded volume upon addition of voltage ( Fig.…”