A cell-based high-throughput screen validates the plasmodial surface anion channel as an antimalarial target.

Molecular Pharmacology
Ajay D PillaiSanjay A Desai

Abstract

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.

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Citations

Mar 1, 2013·Open Biology·Elizabeth BilslandStephen G Oliver
Oct 13, 2011·PLoS Neglected Tropical Diseases·Elizabeth BilslandStephen G Oliver
Feb 11, 2014·Trends in Parasitology·Sanjay A Desai
Aug 21, 2013·TheScientificWorldJournal·Sanjay A Desai
Sep 23, 2014·BioMed Research International·Abdullah A B BokhariSanjay A Desai
Apr 16, 2010·Trends in Parasitology·Henry M StainesSanjeev Krishna
Mar 22, 2012·Cellular Microbiology·Sanjay A Desai
May 23, 2015·Frontiers in Pharmacology·Katherine BasoreSanjay A Desai
Nov 26, 2011·Biochimica Et Biophysica Acta·Abdulnaser AlkhalilSanjay A Desai
Nov 26, 2013·Biophysical Journal·Tobias SawetzkiDavid W M Marr
Dec 4, 2014·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ankit GuptaSanjay A Desai
Jul 3, 2016·International Journal for Parasitology·Paul R GilsonTania F de Koning-Ward
May 31, 2013·The Journal of Biological Chemistry·Paresh SharmaSanjay A Desai
Jan 27, 2015·Annual Review of Biochemistry·Natalie J SpillmanDaniel E Goldberg

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