Targeting phase II detoxification enzyme inhibition in Plasmodium for malaria treatment

Despite multidimensional and multi-stakeholder efforts towards finding effective treatment options, malaria's global endemicity persists. Consequently, researchers continue to seek new drug targets to address the enormous burden that malaria treatment places on humans. Plasmodium parasites have progressively become resistant to almost all antimalarials. They do this by evading their therapeutic mode of action, hence necessitating research into novel therapeutics with distinct modes of action. Drug discovery in the face of resistant/multidrug-resistant Plasmodium parasite essentially requires characterizing the enzyme(s) implicated in the parasite's xenobiotic metabolism. In this review, we explored the inhibition of Plasmodium's detoxification enzyme, given the critical and unique role that Glutathione S-Transferase (GST) plays in the parasite's survival. This is because targeting the inhibition of this enzyme is novel in antimalarial drug discovery efforts, given the established understanding of GSTs' use in Plasmodium for detoxifying many substances intracellularly. The inactivation and conversion of diverse exogenous and endogenous toxic molecules through the phase II biotransformation/detoxification process to less toxic, soluble compounds are reviewed here as a potential antimalarial drug discovery route. Given these reasons, we opined that the inhibition of Plasmodium falciparum and vivax GSTs, vis-à-vis their therapeutic implications, holds a promising key to finding new antimalarials.