Exploring Novel Targets for Antimalarial Drug Discovery: Plasmodial Protein Kinases

Dayadevi      Jirage; Susan      M. Keenan; Norman      C. Waters

Abstract

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. Several classes of protein kinases have been studied, revealing that not only are these kinases essential for parasite viability, but that structure-based drug design strategies can be applicable to identify protein kinase inhibitors as antimalarial agents. In this review, we profile plasmodial protein kinases that have been characterized. Such a profile allows comparison across the plasmodial kinome and aids in placing these kinases within signaling networks responsible for biological activity but also provides a rationale to develop inhibitors that target multiple plasmodial kinases. With widespread malaria drug resistance, coupled by a parasite that can develop resistance quickly to new drugs, the development of multi-kinase inhibitors may be extremely efficacious and reduce the likelihood for resistance.

Keywords: Protein kinases, Plasmodium falciparum, antimalarial agents, plasmodial protein kinases, kinase family, antimalarial drug targets