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Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex
BACKGROUND: Emerging resistance of the malaria parasite Plasmodium to current therapies underscores the critical importance of exploring novel strategies for disease eradication. Plasmodium species are obligate intracellular protozoan parasites. They rely on an unusual form of substrate-dependent mo...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545932/ https://www.ncbi.nlm.nih.gov/pubmed/26289816 http://dx.doi.org/10.1186/s12936-015-0834-9 |
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author | Nemetski, Sondra Maureen Cardozo, Timothy J Bosch, Gundula Weltzer, Ryan O’Malley, Kevin Ejigiri, Ijeoma Kumar, Kota Arun Buscaglia, Carlos A Nussenzweig, Victor Sinnis, Photini Levitskaya, Jelena Bosch, Jürgen |
author_facet | Nemetski, Sondra Maureen Cardozo, Timothy J Bosch, Gundula Weltzer, Ryan O’Malley, Kevin Ejigiri, Ijeoma Kumar, Kota Arun Buscaglia, Carlos A Nussenzweig, Victor Sinnis, Photini Levitskaya, Jelena Bosch, Jürgen |
author_sort | Nemetski, Sondra Maureen |
collection | PubMed |
description | BACKGROUND: Emerging resistance of the malaria parasite Plasmodium to current therapies underscores the critical importance of exploring novel strategies for disease eradication. Plasmodium species are obligate intracellular protozoan parasites. They rely on an unusual form of substrate-dependent motility for their migration on and across host-cell membranes and for host cell invasion. This peculiar motility mechanism is driven by the ‘glideosome’, an actin–myosin associated, macromolecular complex anchored to the inner membrane complex of the parasite. Myosin A, actin, aldolase, and thrombospondin-related anonymous protein (TRAP) constitute the molecular core of the glideosome in the sporozoite, the mosquito stage that brings the infection into mammals. METHODS: Virtual library screening of a large compound library against the PfAldolase–TRAP complex was used to identify candidate compounds that stabilize and prevent the disassembly of the glideosome. The mechanism of these compounds was confirmed by biochemical, biophysical and parasitological methods. RESULTS: A novel inhibitory effect on the parasite was achieved by stabilizing a protein–protein interaction within the glideosome components. Compound 24 disrupts the gliding and invasive capabilities of Plasmodium parasites in in vitro parasite assays. A high-resolution, ternary X-ray crystal structure of PfAldolase–TRAP in complex with compound 24 confirms the mode of interaction and serves as a platform for future ligand optimization. CONCLUSION: This proof-of-concept study presents a novel approach to anti-malarial drug discovery and design. By strengthening a protein–protein interaction within the parasite, an avenue towards inhibiting a previously “undruggable” target is revealed and the motility motor responsible for successful invasion of host cells is rendered inactive. This study provides new insights into the malaria parasite cell invasion machinery and convincingly demonstrates that liver cell invasion is dramatically reduced by 95 % in the presence of the small molecule stabilizer compound 24. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-015-0834-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4545932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45459322015-08-23 Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex Nemetski, Sondra Maureen Cardozo, Timothy J Bosch, Gundula Weltzer, Ryan O’Malley, Kevin Ejigiri, Ijeoma Kumar, Kota Arun Buscaglia, Carlos A Nussenzweig, Victor Sinnis, Photini Levitskaya, Jelena Bosch, Jürgen Malar J Research BACKGROUND: Emerging resistance of the malaria parasite Plasmodium to current therapies underscores the critical importance of exploring novel strategies for disease eradication. Plasmodium species are obligate intracellular protozoan parasites. They rely on an unusual form of substrate-dependent motility for their migration on and across host-cell membranes and for host cell invasion. This peculiar motility mechanism is driven by the ‘glideosome’, an actin–myosin associated, macromolecular complex anchored to the inner membrane complex of the parasite. Myosin A, actin, aldolase, and thrombospondin-related anonymous protein (TRAP) constitute the molecular core of the glideosome in the sporozoite, the mosquito stage that brings the infection into mammals. METHODS: Virtual library screening of a large compound library against the PfAldolase–TRAP complex was used to identify candidate compounds that stabilize and prevent the disassembly of the glideosome. The mechanism of these compounds was confirmed by biochemical, biophysical and parasitological methods. RESULTS: A novel inhibitory effect on the parasite was achieved by stabilizing a protein–protein interaction within the glideosome components. Compound 24 disrupts the gliding and invasive capabilities of Plasmodium parasites in in vitro parasite assays. A high-resolution, ternary X-ray crystal structure of PfAldolase–TRAP in complex with compound 24 confirms the mode of interaction and serves as a platform for future ligand optimization. CONCLUSION: This proof-of-concept study presents a novel approach to anti-malarial drug discovery and design. By strengthening a protein–protein interaction within the parasite, an avenue towards inhibiting a previously “undruggable” target is revealed and the motility motor responsible for successful invasion of host cells is rendered inactive. This study provides new insights into the malaria parasite cell invasion machinery and convincingly demonstrates that liver cell invasion is dramatically reduced by 95 % in the presence of the small molecule stabilizer compound 24. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-015-0834-9) contains supplementary material, which is available to authorized users. BioMed Central 2015-08-20 /pmc/articles/PMC4545932/ /pubmed/26289816 http://dx.doi.org/10.1186/s12936-015-0834-9 Text en © Nemetski et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Nemetski, Sondra Maureen Cardozo, Timothy J Bosch, Gundula Weltzer, Ryan O’Malley, Kevin Ejigiri, Ijeoma Kumar, Kota Arun Buscaglia, Carlos A Nussenzweig, Victor Sinnis, Photini Levitskaya, Jelena Bosch, Jürgen Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex |
title | Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex |
title_full | Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex |
title_fullStr | Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex |
title_full_unstemmed | Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex |
title_short | Inhibition by stabilization: targeting the Plasmodium falciparum aldolase–TRAP complex |
title_sort | inhibition by stabilization: targeting the plasmodium falciparum aldolase–trap complex |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545932/ https://www.ncbi.nlm.nih.gov/pubmed/26289816 http://dx.doi.org/10.1186/s12936-015-0834-9 |
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