A comprehensive review on classifying fast-acting and slow-acting antimalarial agents based on time of action and target organelle of Plasmodium sp.

The clinical resistance towards malarial parasites has rendered many antimalarials ineffective, likely due to a lack of understanding of time of action and stage specificity of all life stages. Therefore, to tackle this problem a more incisive comprehensive analysis of the fast- and slow-acting profile of antimalarial agents relating to parasite time-kill kinetics and the target organelle on the progression of blood-stage parasites was carried out. It is evident from numerous findings that drugs targeting food vacuole, nuclear components, and endoplasmic reticulum mainly exhibit a fast-killing phenotype within 24 h affecting first-cycle activity. Whereas drugs targeting mitochondria, apicoplast, microtubules, parasite invasion, and egress exhibit a largely slow-killing phenotype within 96-120 h, affecting second-cycle activity with few exemptions as moderately fast-killing. It is essential to understand the susceptibility of drugs on rings, trophozoites, schizonts, merozoites, and the appearance of organelle at each stage of the 48-h intraerythrocytic parasite cycle. Therefore, these parameters may facilitate the paradigm for understanding the timing of antimalarials action in deciphering its precise mechanism linked with time. Thus, classifying drugs based on the time of killing may promote designing new combination regimens against varied strains of Plasmodium falciparum and evaluating potential clinical resistance.

Mammalian host microRNA response to plasmodial infection: role as therapeutic target and potential biomarker.

The appearance of increasing drug resistance in apicomplexan intracellular Plasmodium falciparum presents a significant challenge. P. falciparum infection results in cerebral malaria (CM), causing irreversible damage to the brain leading to high mortality cases. To enhance the clinical outcome of the disease, further research is required to identify new molecular targets involved in disease manifestations. Presently, the role of non-coding microRNAs (miRNAs) derived from different cells implicated in CM pathogenesis is still barely understood. Despite the absence of miRNA machinery in Plasmodium, host-parasite interactions can lead to disease severity or impart resistance to malaria. Cytoadherence and sequestration of parasitized RBCs dysregulate the miRNA profile of brain endothelial cells, leukocytes, monocytes, and platelets, disrupting blood-brain barrier integrity and activating inflammatory signaling pathways. The abundance of miRNA in blood plasma samples of CM patients directly correlates to cerebral symptoms compared to non-CM patients and healthy individuals. Moreover, the differential host-miRNA signatures distinguish P. falciparum from P. vivax infection. Here, we review the diverse functions of host-miRNA, either protective, pathogenic, or a combination of the two, which may act as prognostic markers and novel antimalarial drug targets.