A cell-based high-throughput screen validates the plasmodial surface anion channel as an antimalarial target.
The plasmodial surface anion channel (PSAC) is an unusual small-conductance ion channel induced on erythrocytes infected with plasmodia, including parasites responsible for human malaria. Although broadly available inhibitors produce microscopic clearance of parasite cultures at high concentrations and suggest that PSAC is an antimalarial target, they have low affinity for the channel and may interfere with other parasite activities. To address these concerns, we developed a miniaturized assay for PSAC activity and carried out a high-throughput inhibitor screen. Approximately 70,000 compounds from synthetic and natural product libraries were screened, revealing inhibitors from multiple structural classes including two novel and potent heterocyclic scaffolds. Single-channel patch-clamp studies indicated that these compounds act directly on PSAC, further implicating a proposed role in transport of diverse solutes. A statistically significant correlation between channel inhibition and in vitro parasite killing by a family of compounds provided chemical validation of PSAC as a drug target. These new inhibitors should be important research tools and may be starting points for much-needed antimalarial drugs.
Pillai
Ajay D
AD
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852-8132, USA.
Pain
Margaret
M
Solomon
Tsione
T
Bokhari
Abdullah A B
AA
Desai
Sanjay A
SA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology / Q000379:methods; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008288:Malaria / Q000188:drug therapy / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D013012:Sorbitol / Q000378:metabolism
D000962:Antimalarials; D007473:Ion Channels; D011804:Quinolines; C505335:surface anion channel protein, Plasmodium falciparum; D013012:Sorbitol