Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases.

Cyclin dependent protein kinases (CDKs) are pursued as drug targets for several eukaryotic pathogens. In this study, we identified thiophene and benzene sulfonamides as potent inhibitors of Pfmrk, a Plasmodium falciparum CDK with sequence homology to human CDK7. Several of the compounds demonstrated inhibitor selectivity for CDK7 over CDK1, CDK2, and CDK6.

Exploring novel targets for antimalarial drug discovery: plasmodial protein kinases.

Protein kinases are pursued drug targets in numerous diseases including parasitic infections such as malaria. Plasmodium falciparum, the deadliest malarial parasite, relies on numerous protein kinases to regulate growth and differentiation through a complex life cycle that alternates between an invertebrate and vertebrate host. Many of the protein kinases are uncharacterized, however genetic and biochemical approaches have identified homologues of known eukaryotic kinases families as well as unique families of plasmodial kinases.

The malarial CDK Pfmrk and its effector PfMAT1 phosphorylate DNA replication proteins and co-localize in the nucleus.

Cyclin-dependent kinases (CDKs) have an established role in metazoans and yeast in DNA replication, transcription and cell cycle regulation. Several CDKs and their effectors have been identified in the malaria parasite Plasmodium falciparum and their biological functions are beginning to be investigated. Here we report results from the functional characterization of Pfmrk and its effector PfMAT1.

Identification of an effector protein and gain-of-function mutants that activate Pfmrk, a malarial cyclin-dependent protein kinase.

Cyclin-dependent protein kinases (CDKs) are key regulators of cell cycle control. In humans, CDK7 performs dual roles as the CDK activating kinase (CAK) responsible for regulating numerous CDKs and as the RNA polymerase II carboxyl-terminal domain (CTD) kinase involved in the regulation of transcription. Binding of an effector protein, human MAT1, stimulates CDK7 kinase activity and influences substrate specificity.

Constitutive salicylic acid-dependent signaling in cpr1 and cpr6 mutants requires PAD4.

Salicylic acid (SA)-dependent signaling controls activation of a set of plant defense mechanisms that are important for resistance to a variety of microbial pathogens. Many Arabidopsis mutants that display altered SA-dependent signaling have been isolated. We used double mutant analysis to determine the relative positions of the pad4, cpr1, cpr5, cpr6, dnd1 and dnd2 mutations in the signal transduction network leading to SA-dependent activation of defense gene expression and disease resistance.