Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remaining class of effective antimalarial (artemisinin) in South East Asia may soon pose a significant threat. Hence, the identification of new antimalarial compounds with a novel mode of action is necessary to curb this problem. Protein kinase has been implicated as a valid target for drug development in diseases such as cancer and diabetes in humans. A similar approach is now recognized for the treatment of protozoan-related disease including malaria. Few Plasmodium protein kinases that are not only crucial for their survival but also have unique structural features have been identified as a potential target for drug development. In this review, studies on antimalarial drug development exploiting the size of Plasmodium protein kinase ATP gatekeeper over the past 15 years are mainly discussed. The ATP-binding site of Plasmodium protein kinases such as Pf CDPK1, Pf CDPK4, Pf PKG, Pf PK7, and Pf PI4K showed great potential for selective and multi-target inhibitions owing to their smaller or unique ATP-gatekeeper amino acid subunits compared to that of human protein kinase. Hence it is a feasible solution to identify a new class of active antimalarial agents with a novel mode of action and longer clinical life-span.

Aims: Glycogen synthase kinase-3 (GSK-3 (EC:2.7.11.1)) is one of the main therapeutic targets for treating cancer, diabetes, neurological illness and parasitic infection. Due to their distinctive structural characteristics and wide-ranging biological actions, small compounds from soil bacteria have been the most sought-after source for GSK-3 inhibitors. This study assessed the activities of soil actinomycetes isolated from Sabah, Malaysia, against human GSK-3β. Methodology and results: A total of 514 actinomycetes strains were isolated from 144 soil samples. The activities of the crude extracts were evaluated against GSK-3β and its upstream regulators (MKK1 and PP1/GLC7) using yeast-based assays. Eight actinomycetes extracts showed selective human GSK-3β inhibition without affecting MKK1 and PP1/GLC7. The extract from one of these eight isolates, FA013, also showed potent and selective anti-plasmodial activities against Plasmodium falciparum 3D7 strain (IC50 = 0.18 μg/mL, SI = 13,850) with a non-toxic effect against Chang liver cells. Conclusion, significance and impact of study This study identified FA013 as a potential isolate from Malaysian rainforest soil with inhibitory activities against GSK-3β and malaria parasites for future drug development.