Plasmodium kinase disruption: new hopes for anti-malarial drug discovery.

Abstract

Protein kinase/phosphatase signalling pathways regulate many eukaryote cell functions, including metabolism, cell division, cell death and protein production, among others (Cohen & Alessi, 2013). The development of targeting drugs against eukaryote protein kinase took off in the 1990s with the first human clinical trials for different therapeutic applications (Cohen, 2002). In the Kingdom Protista, Plasmodium falciparum is a member of the phylum Apicomplexa, a large group of parasitic eukaryotes. Its genome encodes about 5300 genes (Gardner, et al, 2002) but only 85 putative protein kinases (PKs) have been reported (Ward, et al, 2004). Among this P. falciparum kinome, a novel family of 20 PKs, called FIKK because of the phenylalanine, isoleucine, lysine, lysine motif, was identified (Schneider & Mercereau-Puijalon, 2005). Eighteen of the 20 FIKK kinase genes are proposed to encode fully functional kinases, and 16 of them should be exported at the surface of infected erythrocyte cells due to the presence of a PEXEL motif (Schneider & Mercereau-Puijalon, 2005; Nunes, et al, 2007; Nunes, et al, 2010). This FIKK family was not found to have any orthologous kinases families in other eukaryotic organisms (Srinivasan & Krupa, 2005). Therefore, the potential for anti-malarial drug development specifically targeting these Pf kinases is clearly noteworthy in association with their crucial roles in mediation the differentiation of certain life cycle stages. In this issue of the journal, Siddiqui et al. (2019) report the importance of FIKK kinases in P. falciparum survival and their localization within the parasite. The authors used elegant targeted gene-knockdown or gene disruption approaches (targeted deletion or epitope-tagged transgenic parasite lines). The authors conclude that five FIKKs were essential (FIKKs 3, 9·1, 9·5, 10·1 and 10·2) but only FIKK10·2, FIKK9·1 and FIKK10·1 were exported at the erythrocyte surface, specifically through Maurer's cleft trafficking system (Mundwiler-Pachlatko & Beck, 2013) for FIKK9·1 and FIKK10·1. The topology of the different proteins in the infected host-cell highlighted the fact that they play different roles in the erythrocytic parasite life cycle. The remodelling of erythrocytes was clearly associated with the virulence and the pathogenesis of Plasmodium spp. (Russell & Cooke, 2017). Several previous studies have showed that Plasmodium kinases have many essential functions during the Plasmodium life cycle and not only in the blood stage (Zhang, et al, 2013). The importance of the targeting methodology used by Siddiqui et al. (2019) showed that global mutagenesis approaches can miss essential genes and the fact that the parasite fitness cost for some targeting genes can be different between different P. falciparum strains and obviously for other Plasmodium species. Do FIKK kinases play a role in dormancy for the erythrocytic stage? The role of Plasmodium kinase was described in latency of sporozoites (Holmes, et al, 2017) and in the blood stage with Artemisinin treatment (Zhang, et al, 2017). In this context, the role of FIKK kinases in drug-induced dormancy during blood stage should be meticulously explored. Can FIKK kinase disruption be crucial for drug development against non-falciparum species? Interestingly, only one FIKK kinase copy has been found in non-Laverania subgenus. A recent study identified a compound that can specifically target this FIKK kinase in Plasmodium vivax (Lin, et al, 2017). The absence of in vitro long-term culture for P. vivax rendered the genetic content of this parasite very challenging (Russell, et al, 2012; Rangel, et al, 2018). To circumvent this major issue, Chua et al (2019) recently published an alternative for P. vivax culture by using P. cynomolgi, the sister species (Tachibana, et al, 2012), in monkey red blood cells to establish a powerful platform for drug screening and potentially genome content. This work highlighted the fact that the drug inhibitory effect can be species-dependent and that anti-malarial drug discovery cannot be conducted only on P. falciparum. In conclusion, the study reported by Siddiqui et al (2019) in this issue of the British Journal of Haematology should encourage further studies to identify more essential parasite kinases for the development of new anti-malarial drug compounds in the context of anti-malarial drug resistance.