purfalcamine and Malaria

Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.

Topics: Antimalarials; Humans; Malaria; Plasmodium; Protein Kinase Inhibitors; Protein Kinases

Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum, calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii, which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.

Topics: Adenine; Animals; Antimalarials; Cell Line; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Cyclohexylamines; Drug Evaluation, Preclinical; Enzyme Activation; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Life Cycle Stages; Malaria; Male; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular Structure; Molecular Weight; Movement; Oligonucleotide Array Sequence Analysis; Parasitic Sensitivity Tests; Plasmodium falciparum; Protein Kinases; Protozoan Proteins; Recombinant Proteins; Small Molecule Libraries; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution