How do antimalarial drugs reach their intracellular targets?

Abstract

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. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our 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. We also review 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. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention.

Keywords: antimalarials; drug absorption; drug uptake; lipid diffusion of drugs; plasmodial surface anion channel; plasmodium falciparum.

FIGURE 1

Routes used by antimalarial compounds to reach their intracellular parasite targets. (A) Plot of PSA vs. AlogP98 for antimalarial compounds, calculated using Accelrys Draw 4.2. Solid lines represent the 95 and 99% confidence ellipses for drugs with good absorption (inner and outer ellipses, respectively), as determined by (Egan et al., 2000). Notice that approved antimalarial drugs generally fall within these ellipses (green circles), indicating a high likelihood for adequate lipid-diffusion to reach intracellular targets. Compounds in the medicines for malaria (MMV) pipeline and key antimalarial toxins are shown as blue triangles and red squares, respectively. Approved drugs shown: chloroquine, mefloquine, quinine, artemisinin, dihydroartemisinin, artesunate, artemether, atovaquone, proguanil, naphthoquine, amodiaquine, piperaquine, doxycycline**, clindamycin, azithromycin**, sulfadoxine, lumefantrine^**, pyrimethamine, pyronaridine. MMV pipeline compounds: DSM265, MMV390048, NITD609, KAF156, P218^*, SJ733, PA21A092, OZ439, tafenoquine. Antimalarial toxins: fosmidomycin^*, blasticidin S^**, leupeptin^**, pentamidine. Single asterisk indicates compound is outside the 95% confidence ellipse only; Double asterisk indicates compound is outside both ellipses. (B) Schematic showing membrane barriers and transporters available for drug uptake at key membranes of the infected erythrocyte. Drugs may enter via lipid-diffusion (upper arrows) or through PSAC or a host transporter (e.g., organic anion transporter, OAT) at the erythrocyte membrane, the PVM channel at the parasitophorous vacuolar membrane (PVM), and one or more transporters (e.g., aquaglyceroporin, AQP) at the parasite plasma membrane (PPM). Drugs may act within parasite organelles such as the digestive vacuole (DV, shown containing crystalline hemozoin) or the multilamellar apicoplast (Ap), imposing additional membranous barriers; drug transporters are also present at these membranes (not shown). A parasite-generated Maurer’s cleft (MC) is shown in the host cytosol. Transporters for nutrients such as sugars, amino acids, and nucleobases are also present at some membranes (not shown); certain drugs may use these nutrient transporters for uptake.