Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors

Autor: Abdullah A. B. Bokhari, Alexandra W. Fuller, Tsione Solomon, Ajay Pillai, Sanjay A. Desai, Margaret Pain, Katherine Basore
Rok vydání: 2016
Předmět:
0301 basic medicine
Osmosis
Cell Membrane Permeability
Erythrocytes
Protozoan Proteins
lcsh:Medicine
Plant Science
Pharmacology
Ion Channels
0302 clinical medicine
Animal Cells
Red Blood Cells
Medicine and Health Sciences
Parasite hosting
Drug Interactions
lcsh:Science
Protozoans
Multidisciplinary
Cell Death
biology
Malarial Parasites
Bioassays and Physiological Analysis
Cell Processes
Plant Physiology
Plasmodium knowlesi
Physical Sciences
Solute Transport
Cellular Types
Research Article
Anions
High-throughput screening
Plasmodium falciparum
Materials Science
Material Properties
Research and Analysis Methods
Permeability
Antimalarials
03 medical and health sciences
Animals
Humans
Molecular Biology Techniques
Molecular Biology
Ion channel
Ions
Molecular Biology Assays and Analysis Techniques
Blood Cells
Cytolysis
lcsh:R
Organisms
Biology and Life Sciences
Biological Transport
Cell Biology
biology.organism_classification
Macaca mulatta
High Throughput Screening
Parasitic Protozoans
In vitro
Malaria
030104 developmental biology
Transport Inhibition Assay
Biophysics
lcsh:Q
030217 neurology & neurosurgery
Zdroj: PLoS ONE
PLoS ONE, Vol 11, Iss 2, p e0149214 (2016)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0149214
Popis: Malaria parasites increase their host erythrocyte's permeability to a broad range of ions and organic solutes. The plasmodial surface anion channel (PSAC) mediates this uptake and is an established drug target. Development of therapies targeting this channel is limited by several problems including interactions between known inhibitors and permeating solutes that lead to incomplete channel block. Here, we designed and executed a high-throughput screen to identify a novel class of PSAC inhibitors that overcome this solute-inhibitor interaction. These new inhibitors differ from existing blockers and have distinct effects on channel-mediated transport, supporting a model of two separate routes for solute permeation though PSAC. Combinations of inhibitors specific for the two routes had strong synergistic action against in vitro parasite propagation, whereas combinations acting on a single route produced only additive effects. The magnitude of synergism depended on external nutrient concentrations, consistent with an essential role of the channel in parasite nutrient acquisition. The identified inhibitors will enable a better understanding of the channel's structure-function and may be starting points for novel combination therapies that produce synergistic parasite killing.
Databáze: OpenAIRE
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