Calcium-dependent Protein Kinases in Malaria Parasite Development and Infection

Abstract

Apicomplexan parasites have challenged researchers for nearly a century. A major challenge to developing efficient treatments and vaccines is the parasite’s ability to change its cellular and molecular makeup to develop intracellular and extracellular niches in its hosts. Ca2+ signaling is an important messenger for the egress of the malaria parasite from the infected erythrocyte, gametogenesis, ookinete motility in the mosquito, and sporozoite invasion of mammalian hepatocytes. Calcium-dependent protein kinases (CDPKs) have crucial functions in calcium signaling at various stages of the parasite’s life cycle; this therefore makes them attractive drug targets against malaria. Here, we summarize the functions of the various CDPK isoforms in relation to the malaria life cycle by emphasizing the molecular mechanism of developmental progression within host tissues. We also discuss the current development of anti-malarial drugs, such as how specific bumped kinase inhibitors (BKIs) for parasite CDPKs have been shown to reduce infection in Toxoplasma gondii, Cryptosporidium parvum, and Plasmodium falciparum. Our suggested combinations of BKIs, artemisinin derivatives with peroxide bridge, and inhibitors on the Ca(2+)-ATPase PfATP6 as a potential target should be inspected further as a treatment against malaria.

Taming the Boys for Global Good: Contraceptive Strategy to Stop Malaria Transmission

“…Whatever the challenges, the potential epidemiological impact of deployment of a transmission-blocking drug in malaria-endemic areas should include a considerable decrease in clinical malaria cases, direct economic benefits, and eventual eradication. Increasing interest in insecticides that address mosquito resistance and the identification of new molecules as potential transmission-blocking therapeutics emphasizes the urgency of establishing this alternative malaria control strategy [47,[82][83][84]. Newly developed assay protocols are increasing the possibilities of high throughput screening of pharmaceutical libraries for potential malaria transmission-blocking leads [47,82].…”

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

“…Enzymes from the classical Ca 2+ /calmodulin-dependent protein kinase (CaMK) group seem to be rare in the P. falciparum kinome [15]. However, the kinome contains calcium-dependent protein kinases (CDPKs) which have a C-terminal calmodulin-like domain that is highly homologous to the CaMK group [16]. CDPKs comprise a unique family of serine/threonine kinases only found in plants, protozoans (including apicomplexan parasites) and some algae [17].…”

“…These enzymes play an important role in calcium signalling during the various life stages of the Plasmodium parasite [15]. Seven members of the CDPK family (Pf CDPK1 to Pf CDPK7) have been identified in P. falciparum [16]. Pf CDPK1 is expressed at all stages of the Plasmodium parasite life cycle.…”

“…The CDPKs are promising drug targets for the development of new antiplasmodial agents as there are no CDPK orthologues in the human host [16]. A unique structural feature of many parasitic CDPKs is the small gatekeeper residue at the hinge region [36].…”

Plasmodium falciparum protein kinase as a potential therapeutic target for antimalarial drugs development

“…Moreover, typical mammalian kinase group such as tyrosine kinase (TyrK) and (STE) are missing and exist in a low number in malaria kinome, respectively. Instead, most malaria kinome contains kinases such as FIKK (lacking the canonical glycine-rich motif in its ATP binding site, replaced with FIKK motif) and CDPKs that cannot be found in mammalian cells (Lin et al, 2017;Ghartey-Kwansah et al, 2020). Besides, the size of the ATP-gatekeeper in Plasmodium kinase is mostly guarded by small amino acid subunits, exposing its hydrophobic pocket in the ATP-binding site (Huang et al, 2010;Tewari et al, 2010;Bansal et al, 2016).…”