Increasing worldwide resistance of Plasmodium falciparum to traditional chemotherapy strategies such as chloroquine and mefloquine demonstrates the urgent need for the discovery of novel chemotherapeutic agents in the fight against malaria. The recent discovery of P. falciparum Protein Kinase 5 (PfPKE) invites the possibility of selectively targeting the life cycle of P. falciparum in order to prevent cerebral malaria. PfPK5 bears a high degree of sequence homology (>65%) to a structurally conserved family of mammalian kinases known as the cyclin-dependent kinases (CDKs). The CDKs are the key regulatory elements governing the ordered progression of the mammalian cell cycle. With numerous x-ray crystal structures of CDK2 to provide a structural template, we constructed a three-dimensional model of PfPK5 using computer-based homology modeling techniques, The 3D-coordinates of PfPK5 and those available for the mammalian CDKs, will enable us to utilize rational drug design strategies to design and synthesize novel and selective antimalarial agents. The overall objective of the proposed research is to computer design, chemically synthesize, and biologically evaluate a series of novel inhibitors of P. falciparum Protein Kinase 5 (PfPK5) as therapeutic agents for the treatment of cerebral malaria. Upon completion of the specific aims as detailed above, I hope to have discovered a potent and selective PfPK5 inhibitor that will provide safe and effective chemotherapeutic treatment of malaria. Furthermore the project breadth: from concept, to lead, offers an extensive range of training experiences that will contribute immensely to my postdoctoral training.
