Protoberberine alkaloids berberine and palmatine employ PfPgh-1 transporter to enter the digestive vacuole and kill the malaria parasite by inhibiting heme biocrystallization

Introduction With Plasmodium falciparum devising means of evading antimalarial agents and in the absence of a vaccine that can be used across all age groups, malaria continues to ravage large parts of the tropical and sub-tropical regions of the world. Hence improved drugs with novel scaffolds are constantly needed to replenish the antimalarial chemotherapeutic arsenal. Medicinal plants have afforded some of the best antimalarials of which members of the alkaloid class are the ones that have made the most significant contributions. Protoberberine alkaloids are berberine-like alkaloids present in a number of medicinal plants traditionally used for the management of malaria. These alkaloids have been confirmed to have in vitro antiplasmodial activity. However, their development as antimalarials has been marred by their poor bioavailability. Among other features expected of drugs, understanding their mechanism of antiplasmodial action can spur research into designing of orally active and pharmacokinetically robust analogues. Methods To investigate the anti-plasmodial activity of protoberberine alkaloids, Berberine and Palmatine were chosen for the present study. The mechanistic study of both alkaloids including intra-parasite localization was achieved by taking advantage of their inherent fluorescence property. Results and Discussion Herein, we show that the protoberberine alkaloids Berberine and Palmatine, interact with vacuolar P-glycoprotein homologue-1 ( Pf Pgh-1) transporter, enter the digestive vacuole and inhibit heme to hemozoin detoxification leading to death of the parasite.