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With the inevitable selection of resistance to antimalarial drugs in treated populations, there is a need for new medicines to enter the clinic and new targets to progress through the drug discovery pipeline. In this study we set out to develop a transgenic rodent model for testing inhibitors of the  Plasmodium falciparum  cyclic GMP-dependent kinase  in vivo . A model was needed that would allow us to investigate whether differences in amino acid sequence of this enzyme between species influences  in vivo  efficacy. Here we report the successful development of a transgenic  P. berghei  line in which the cyclic GMP-dependent protein kinase (PKG) was replaced by the  P. falciparum  orthologue. We demonstrate that the  P. falciparum  orthologue was able to functionally complement the endogenous  P. berghei pkg  gene throughout blood stage development and early sexual development. However, subsequent development in the mosquito was severely compromised. We show that this is due to a defect in the female lineage of the transgenic by using genetic crosses with both male and female deficient  P. berghei  lines. This defect could be due to expression of a female-specific target in the mosquito stages of  P. berghei  that cannot be phosphorylated by the  P. falciparum  kinase. Using a previously reported anti-coccidial inhibitor of the cyclic GMP-dependent protein kinase, we show no difference in  in vivo  efficacy between the transgenic and control  P. berghei  lines. This  in vivo  model will be useful for screening future generations of cyclic GMP-dependent protein kinase inhibitors and allowing us to overcome any species-specific differences in the enzyme primary sequence that would influence  in vivo  efficacy in the rodent model. The approach will also be applicable to  in vivo  testing of other antimalarial compounds where the target is known.

plos one

Development of a Transgenic Plasmodium berghei Line (Pbpfpkg) Expressing the P. falciparum cGMP-Dependent Protein Kinase, a Novel Antimalarial Drug Target