Emerging antimalarial drug targets to combat drug-resistant malaria parasites

The emergence and rapid spread of multidrug resistance in Plasmodium parasites, particularly in the Greater Mekong region and increasingly in Sub-Saharan Africa. Resistance has led to an urgent need to develop novel anti-malaria therapies with an effective mechanism. Several non-classical targets, including Na⁺⁺ pump PfATP4 (Plasmodium falciparum ATPase 4), PI4K (Phosphatidylinositol 4-kinase) and PfNCR1(Plasmodium falciparum Niemann-Pick Type C1-Related protein), are highly active against the asexual stage of Plasmodium. We summarise the progress achieved on key emerging targets over past decade and emerging pipeline of artemisinin-combination therapies (ACTs). Other targets, such as dihydroorotate dehydrogenase (PfDHODH) for pyrimidine biosynthesis, ion transporters, mitochondrial electron transport chain, and apicoplast metabolic pathways, have demonstrated significant therapeutic potential due to their essential roles in parasite physiology and minimal homology to human counterparts. Combating drug-resistant malaria parasites and strengthening the global antimalarial drug pipeline for long-term disease control can be achieved by developing new ways to target parasites. This comprehensive review discusses the current status of novel antimalarial drug targets, recent discoveries and future of novel therapies in the following innovation areas: Protein synthesis machinery as drug targets, hemoglobin metabolism targets, transport proteins therapeutic targets, Kinase targets, Organelles and cell targets, and mitochondrial targets, which fill critical gaps in the existing therapeutic arsenal.