Comparative analysis of the kinomes of Plasmodium falciparum, Plasmodium vivax and their host Homo sapiens

Abstract

Background Novel antimalarials should be effective across all species of malaria parasites that infect humans, especially the two species that bear the most impact, Plasmodium falciparum and Plasmodium vivax. Protein kinases encoded by pathogens, as well as host kinases required for survival of intracellular pathogens, carry considerable potential as targets for antimalarial intervention (Adderley et al. Trends Parasitol 37:508–524, 2021; Wei et al. Cell Rep Med 2:100423, 2021). To date, no comprehensive P. vivax kinome assembly has been conducted; and the P. falciparum kinome, first assembled in 2004, requires an update. The present study, aimed to fill these gaps, utilises a recently published structurally-validated multiple sequence alignment (MSA) of the human kinome (Modi et al. Sci Rep 9:19790, 2019). This MSA is used as a scaffold to assist the alignment of all protein kinase sequences from P. falciparum and P. vivax, and (where possible) their assignment to specific kinase groups/families. Results We were able to assign six P. falciparum previously classified as OPK or ‘orphans’ (i.e. with no clear phylogenetic relation to any of the established ePK groups) to one of the aforementioned ePK groups. Direct phylogenetic comparison established that despite an overall high level of similarity between the P. falciparum and P. vivax kinomes, which will help in selecting targets for intervention, there are differences that may underlie the biological specificities of these species. Furthermore, we highlight a number of Plasmodium kinases that have a surprisingly high level of similarity with their human counterparts and therefore not well suited as targets for drug discovery. Conclusions Direct comparison of the kinomes of Homo sapiens, P. falciparum and P. vivax sheds additional light on the previously documented divergence of many P. falciparum and P. vivax kinases from those of their human host. We provide the first direct kinome comparison between the phylogenetically distinct species of P. falciparum and P. vivax, illustrating the key similarities and differences which must be considered in the context of kinase-directed antimalarial drug discovery, and discuss the divergences and similarities between the human and Plasmodium kinomes to inform future searches for selective antimalarial intervention.

Update and elucidation of Plasmodium kinomes: Prioritization of kinases as potential drug targets for malaria

“…Our approach has enabled the update of the kinomes of six Plasmodium species and the elucidation for the first time of the kinomes of P. ovale and P. malariae, two species that also infect humans. Previous studies reported the kinomes of P. falciparum, P. yoelli, P. berghei, P. chabaudi, P. vivax, and P. knowlesi [29] , [30] , [31] , [32] , [33] and a comparative analysis of these and ours is available at supplemental material (Supp. Table S1 ).…”

Activation loop phosphorylation and cGMP saturation of PKG regulate egress of malaria parasites

“…Our finding that PfPKG activation loop phosphorylation is not essential in vitro but has significant effects in vivo , closely mimics properties of PKCδ. PKC belongs to the AGC family and there are 12 isoforms with important functions in eukaryotic cells, although PKC is absent in Plasmodium parasites ( 44 ). Most PKC isoforms are activated upon phosphorylation of the activation loop.…”

Hsp90 and Associated Co-Chaperones of the Malaria Parasite

“…Kinases are considered important therapeutic targets in both cancer (focusing on human kinases) and malaria, and kinase inhibitors form one of the largest classes of approved drugs. The P. falciparum kinome was recently updated, confirming that its kinome is considerably smaller (98 members compared to 497 members in the human kinome) and divergent (38% unique; 46% potentially unique; and 16% human homologs) from that of humans [ 120 ]. Therefore, the apparent lack of a Cdc37 ortholog, or the presence of a yet to be identified divergent Cdc37 ortholog or functional equivalent, is likely to reflect differences in the folding requirements of the P. falciparum kinome by the Cdc37–PfHsp90 co-chaperone–chaperone machinery.…”