Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. In this review, the authors evaluate the features of available antimalarials and examine whether transporters may be required for their uptake. Computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. In addition, the authors reviewed parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. The authors concluded that a better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritising drug leads for antimalarial development and may reveal new targets for therapeutic intervention.
Authors: Basore K, Cheng Y, Kushwaha AK, Nguyen ST, Desai SA. ;Full Source: Frontiers in Pharmacology. 2015 May 5;6:91. doi: 10.3389/fphar.2015.00091. eCollection 2015. ;