Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Pain, Margaret, Fuller, Alexandra W., Basore, Katherine, Pillai, Ajay D., Solomon, Tsione, Bokhari, Abdullah A. B., Desai, Sanjay A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750852/
https://www.ncbi.nlm.nih.gov/pubmed/26866812
http://dx.doi.org/10.1371/journal.pone.0149214
_version_ 1782415489103822848
author Pain, Margaret
Fuller, Alexandra W.
Basore, Katherine
Pillai, Ajay D.
Solomon, Tsione
Bokhari, Abdullah A. B.
Desai, Sanjay A.
author_facet Pain, Margaret
Fuller, Alexandra W.
Basore, Katherine
Pillai, Ajay D.
Solomon, Tsione
Bokhari, Abdullah A. B.
Desai, Sanjay A.
author_sort Pain, Margaret
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4750852
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-47508522016-02-26 Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors Pain, Margaret Fuller, Alexandra W. Basore, Katherine Pillai, Ajay D. Solomon, Tsione Bokhari, Abdullah A. B. Desai, Sanjay A. PLoS One Research Article 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. Public Library of Science 2016-02-11 /pmc/articles/PMC4750852/ /pubmed/26866812 http://dx.doi.org/10.1371/journal.pone.0149214 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Pain, Margaret
Fuller, Alexandra W.
Basore, Katherine
Pillai, Ajay D.
Solomon, Tsione
Bokhari, Abdullah A. B.
Desai, Sanjay A.
Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors
title Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors
title_full Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors
title_fullStr Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors
title_full_unstemmed Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors
title_short Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors
title_sort synergistic malaria parasite killing by two types of plasmodial surface anion channel inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750852/
https://www.ncbi.nlm.nih.gov/pubmed/26866812
http://dx.doi.org/10.1371/journal.pone.0149214
work_keys_str_mv AT painmargaret synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors
AT fulleralexandraw synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors
AT basorekatherine synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors
AT pillaiajayd synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors
AT solomontsione synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors
AT bokhariabdullahab synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors
AT desaisanjaya synergisticmalariaparasitekillingbytwotypesofplasmodialsurfaceanionchannelinhibitors