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Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum
BACKGROUND: A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. The platform identifies hits on the basis of in vitro grow...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863362/ https://www.ncbi.nlm.nih.gov/pubmed/27165106 http://dx.doi.org/10.1186/s12936-016-1313-7 |
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author | Zhang, Jin Bowling, John J. Smithson, David Clark, Julie Jacob, Melissa R. Khan, Shabana I. Tekwani, Babu L. Connelly, Michele Samoylenko, Vladimir Ibrahim, Mohamed A. Zaki, Mohamed A. Wang, Mei Hester, John P. Tu, Ying Jeffries, Cynthia Twarog, Nathaniel Shelat, Anang A. Walker, Larry A. Muhammad, Ilias Guy, R. Kiplin |
author_facet | Zhang, Jin Bowling, John J. Smithson, David Clark, Julie Jacob, Melissa R. Khan, Shabana I. Tekwani, Babu L. Connelly, Michele Samoylenko, Vladimir Ibrahim, Mohamed A. Zaki, Mohamed A. Wang, Mei Hester, John P. Tu, Ying Jeffries, Cynthia Twarog, Nathaniel Shelat, Anang A. Walker, Larry A. Muhammad, Ilias Guy, R. Kiplin |
author_sort | Zhang, Jin |
collection | PubMed |
description | BACKGROUND: A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. The platform identifies hits on the basis of in vitro growth inhibition of Plasmodium falciparum and counter-screens for cytotoxicity to human foreskin fibroblast or embryonic kidney cell lines. The physical library was supplemented by early-stage collection of analytical data for each fraction to aid rapid identification of the active components within each screening hit. RESULTS: A total of 16,177 fractions from 1300 plants were screened, identifying several P. falciparum inhibitory fractions from 35 plants. Although individual fractions were screened for bioactivity to ensure adequate signal in the analytical characterizations, fractions containing less than 2.0 mg of dry weight were combined to produce combined fractions (COMBIs). Fractions of active COMBIs had EC(50) values of 0.21–50.28 and 0.08–20.04 µg/mL against chloroquine-sensitive and -resistant strains, respectively. In Berberis thunbergii, eight known alkaloids were dereplicated quickly from its COMBIs, but berberine was the most-active constituent against P. falciparum. The triterpenoids α-betulinic acid and β-betulinic acid of Eugenia rigida were also isolated as hits. Validation of the anti-malarial discovery platform was confirmed by these scaled isolations from B. thunbergii and E. rigida. CONCLUSIONS: These results demonstrate the value of curating and exploring a library of natural products for small molecule drug discovery. Attention given to the diversity of plant species represented in the library, focus on practical analytical data collection, and the use of counter-screens all facilitate the identification of anti-malarial compounds for lead development or new tools for chemical biology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-016-1313-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4863362 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-48633622016-05-12 Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum Zhang, Jin Bowling, John J. Smithson, David Clark, Julie Jacob, Melissa R. Khan, Shabana I. Tekwani, Babu L. Connelly, Michele Samoylenko, Vladimir Ibrahim, Mohamed A. Zaki, Mohamed A. Wang, Mei Hester, John P. Tu, Ying Jeffries, Cynthia Twarog, Nathaniel Shelat, Anang A. Walker, Larry A. Muhammad, Ilias Guy, R. Kiplin Malar J Research BACKGROUND: A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. The platform identifies hits on the basis of in vitro growth inhibition of Plasmodium falciparum and counter-screens for cytotoxicity to human foreskin fibroblast or embryonic kidney cell lines. The physical library was supplemented by early-stage collection of analytical data for each fraction to aid rapid identification of the active components within each screening hit. RESULTS: A total of 16,177 fractions from 1300 plants were screened, identifying several P. falciparum inhibitory fractions from 35 plants. Although individual fractions were screened for bioactivity to ensure adequate signal in the analytical characterizations, fractions containing less than 2.0 mg of dry weight were combined to produce combined fractions (COMBIs). Fractions of active COMBIs had EC(50) values of 0.21–50.28 and 0.08–20.04 µg/mL against chloroquine-sensitive and -resistant strains, respectively. In Berberis thunbergii, eight known alkaloids were dereplicated quickly from its COMBIs, but berberine was the most-active constituent against P. falciparum. The triterpenoids α-betulinic acid and β-betulinic acid of Eugenia rigida were also isolated as hits. Validation of the anti-malarial discovery platform was confirmed by these scaled isolations from B. thunbergii and E. rigida. CONCLUSIONS: These results demonstrate the value of curating and exploring a library of natural products for small molecule drug discovery. Attention given to the diversity of plant species represented in the library, focus on practical analytical data collection, and the use of counter-screens all facilitate the identification of anti-malarial compounds for lead development or new tools for chemical biology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-016-1313-7) contains supplementary material, which is available to authorized users. BioMed Central 2016-05-10 /pmc/articles/PMC4863362/ /pubmed/27165106 http://dx.doi.org/10.1186/s12936-016-1313-7 Text en © Zhang et al. 2016 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 Zhang, Jin Bowling, John J. Smithson, David Clark, Julie Jacob, Melissa R. Khan, Shabana I. Tekwani, Babu L. Connelly, Michele Samoylenko, Vladimir Ibrahim, Mohamed A. Zaki, Mohamed A. Wang, Mei Hester, John P. Tu, Ying Jeffries, Cynthia Twarog, Nathaniel Shelat, Anang A. Walker, Larry A. Muhammad, Ilias Guy, R. Kiplin Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum |
title | Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum |
title_full | Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum |
title_fullStr | Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum |
title_full_unstemmed | Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum |
title_short | Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum |
title_sort | diversity-oriented natural product platform identifies plant constituents targeting plasmodium falciparum |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863362/ https://www.ncbi.nlm.nih.gov/pubmed/27165106 http://dx.doi.org/10.1186/s12936-016-1313-7 |
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