A relatively high-affinity inhibitor of FIKK kinase from the malaria parasite Plasmodium vivax was identified by in vitro assay of recombinant kinase. The FIKK kinase family is unique to parasitic organisms of the Apicomplexan order and has been shown to be critical in malaria parasites. The recombinant kinase domain was expressed and screened against a small molecule library, revealing a number of tyrosine kinase inhibitors that block FIKK kinase activity. A family of tyrphostins was further investigated, to begin exploring the FIKK kinase pharmacophore. Finally, emodin was identified as a relatively high-affinity FIKK kinase inhibitor, identifying this family of anthraquinones as potential lead compounds for the development of antimalarials targeting the FIKK kinase.

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The understanding of the molecular basis of sea urchin behavior and sensory and motor systems lags far behind that of many other animal species. To investigate whole-animal behavior pharmacologically, we first demonstrated that immersion in drug solution is an effective drug administration route for sea urchins, whereas oral drug administration was found to be ineffective. Although intracoelomic injection was found to be effective at administering drugs, it was also found that injection itself can disrupt normal sea urchin behavior. Using the drug immersion procedure, we demonstrate that sea urchin locomotion and the sea urchin righting response are inhibited in a dose-dependent manner by the phosphodiesterase inhibitor theophylline and the transient receptor potential channel inhibitor 2-aminoethoxydiphenyl borate. The sea urchin righting response was also inhibited by the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and the Ca channel inhibitor diltiazem, which, along with theophylline and 2-aminoethoxydiphenyl borate, would all be expected to disrupt smooth muscle function, based on studies in other animals. In addition, the removal of extracellular Ca also inhibited the righting response, whereas an inhibitor of intracellular Ca release, thapsigargin, did not affect the righting response, indicating that extracellular Ca rather than intracellular Ca stores are required for righting.

The development of antimalarial drugs remains a public health priority, and the orotidine 5 0 -monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) has great potential as a drug target. The crystallization of PfOMPDC with substrate bound represents an important advance for structurebased drug-design efforts [Tokuoka et al. (2008), J. Biochem. 143, 69-78]. The complex of the enzyme bound to the substrate OMP (PDB entry 2za1) would be of particular utility in this regard. However, re-refinement of this structure of the Michaelis complex shows that the bound ligand is the product rather than the substrate. Here, the re-refinement of a set of three structures, the apo enzyme and two versions of the product-bound form (PDB entries 2za1, 2za2 and 2za3), is reported. The improved geometry and fit of these structures to the observed electron density will enhance their utility in antimalarial drug design.