Abstract
Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.
Highlights
Significant progress has been made with regards to worldwide malaria control and eradication, this infectious disease continues to have devastating effects, especially in developing countries
Two additional parasitic targets were identified for imidazopyridazines: class 1 compounds inhibited P. falciparum protein kinase G (Pf protein kinase G (PKG)) and class 2 compounds inhibited Pf HSP90. These results suggest that the activity of imidazopyridazines against erythrocytic P. falciparum parasites is primarily due to inhibition of Pf PKG and Pf HSP90, rather than
Three of the five malarial kinases that cluster within this group, namely adenosine monophosphate-dependent protein kinase A (PKA), cyclic guanosine monophosphate-dependent protein kinase G (PKG) and protein kinase B (PKB) have been characterised [13]. cAMP, cGMP- and calcium-mediated signalling pathways are closely linked within the malaria parasite
Summary
Significant progress has been made with regards to worldwide malaria control and eradication, this infectious disease continues to have devastating effects, especially in developing countries. In order to eliminate and eventually eradicate malaria, the focus needs to shift from mainly providing curative treatment to blocking disease transmission [8] Achieving this goal requires a new generation of cost-effective antimalarial agents that are safe and well-tolerated in a wide range of recipients, including vulnerable populations such as pregnant women and infants [8]. The plasmodial kinome contains protein kinases that have no mammalian orthologues (orphan kinases) or display homology with more than one of the established ePK groups (composite or hybrid kinases) [9] These differences can be exploited for selective antimalarial drug development. 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]. The P. berghei orthologue (PbCDPK6) signals to sporozoites when to stop migration and initiate invasion of hepatocytes [35]
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