Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi.
BACKGROUND:Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling...
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ftdoajarticles:oai:doaj.org/article:5dc4633f52c0420b981621e9ec74d512 2023-05-15T15:16:20+02:00 Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. Elizabeth Bilsland Daniel M Bean Eileen Devaney Stephen G Oliver 2016-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004401 https://doaj.org/article/5dc4633f52c0420b981621e9ec74d512 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4727890?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004401 https://doaj.org/article/5dc4633f52c0420b981621e9ec74d512 PLoS Neglected Tropical Diseases, Vol 10, Iss 1, p e0004401 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004401 2022-12-31T00:22:00Z BACKGROUND:Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling of the affected tissues. According to the World Health Organization, over 1.2 billion people in 58 countries are at risk of contracting lymphatic filariasis. Very few drugs are available to treat patients infected with these parasites, and these have low efficacy against the adult stages of the worms, which can live for 7-15 years in the human body. The requirement for annual treatment increases the risk of drug-resistant worms emerging, making it imperative to develop new drugs against these devastating diseases. METHODOLOGY/PRINCIPAL FINDINGS:We have developed a yeast-based, high-throughput screening system whereby essential yeast genes are replaced with their filarial or human counterparts. These strains are labeled with different fluorescent proteins to allow the simultaneous monitoring of strains with parasite or human genes in competition, and hence the identification of compounds that inhibit the parasite target without affecting its human ortholog. We constructed yeast strains expressing eight different Brugia malayi drug targets (as well as seven of their human counterparts), and performed medium-throughput drug screens for compounds that specifically inhibit the parasite enzymes. Using the Malaria Box collection (400 compounds), we identified nine filarial specific inhibitors and confirmed the antifilarial activity of five of these using in vitro assays against Brugia pahangi. CONCLUSIONS/SIGNIFICANCE:We were able to functionally complement yeast deletions with eight different Brugia malayi enzymes that represent potential drug targets. We demonstrated that our yeast-based screening platform is efficient in identifying compounds that can discriminate between human and filarial enzymes. Hence, we are ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 1 e0004401 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Elizabeth Bilsland Daniel M Bean Eileen Devaney Stephen G Oliver Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND:Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling of the affected tissues. According to the World Health Organization, over 1.2 billion people in 58 countries are at risk of contracting lymphatic filariasis. Very few drugs are available to treat patients infected with these parasites, and these have low efficacy against the adult stages of the worms, which can live for 7-15 years in the human body. The requirement for annual treatment increases the risk of drug-resistant worms emerging, making it imperative to develop new drugs against these devastating diseases. METHODOLOGY/PRINCIPAL FINDINGS:We have developed a yeast-based, high-throughput screening system whereby essential yeast genes are replaced with their filarial or human counterparts. These strains are labeled with different fluorescent proteins to allow the simultaneous monitoring of strains with parasite or human genes in competition, and hence the identification of compounds that inhibit the parasite target without affecting its human ortholog. We constructed yeast strains expressing eight different Brugia malayi drug targets (as well as seven of their human counterparts), and performed medium-throughput drug screens for compounds that specifically inhibit the parasite enzymes. Using the Malaria Box collection (400 compounds), we identified nine filarial specific inhibitors and confirmed the antifilarial activity of five of these using in vitro assays against Brugia pahangi. CONCLUSIONS/SIGNIFICANCE:We were able to functionally complement yeast deletions with eight different Brugia malayi enzymes that represent potential drug targets. We demonstrated that our yeast-based screening platform is efficient in identifying compounds that can discriminate between human and filarial enzymes. Hence, we are ... |
format |
Article in Journal/Newspaper |
author |
Elizabeth Bilsland Daniel M Bean Eileen Devaney Stephen G Oliver |
author_facet |
Elizabeth Bilsland Daniel M Bean Eileen Devaney Stephen G Oliver |
author_sort |
Elizabeth Bilsland |
title |
Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. |
title_short |
Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. |
title_full |
Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. |
title_fullStr |
Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. |
title_full_unstemmed |
Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi. |
title_sort |
yeast-based high-throughput screens to identify novel compounds active against brugia malayi. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004401 https://doaj.org/article/5dc4633f52c0420b981621e9ec74d512 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 1, p e0004401 (2016) |
op_relation |
http://europepmc.org/articles/PMC4727890?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004401 https://doaj.org/article/5dc4633f52c0420b981621e9ec74d512 |
op_doi |
https://doi.org/10.1371/journal.pntd.0004401 |
container_title |
PLOS Neglected Tropical Diseases |
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10 |
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1 |
container_start_page |
e0004401 |
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