Mining predicted essential genes of Brugia malayi for nematode drug targets.

We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk o...

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Autores principales:	Sanjay Kumar, Kshitiz Chaudhary, Jeremy M Foster, Jacopo F Novelli, Yinhua Zhang, Shiliang Wang, David Spiro, Elodie Ghedin, Clotilde K S Carlow
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1ecfd8f6c9a14b828ce7f8c686abce52
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spelling	oai:doaj.org-article:1ecfd8f6c9a14b828ce7f8c686abce522021-11-25T06:10:27ZMining predicted essential genes of Brugia malayi for nematode drug targets.1932-620310.1371/journal.pone.0001189https://doaj.org/article/1ecfd8f6c9a14b828ce7f8c686abce522007-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0001189https://doaj.org/toc/1932-6203We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression.Sanjay KumarKshitiz ChaudharyJeremy M FosterJacopo F NovelliYinhua ZhangShiliang WangDavid SpiroElodie GhedinClotilde K S CarlowPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 2, Iss 11, p e1189 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sanjay Kumar Kshitiz Chaudhary Jeremy M Foster Jacopo F Novelli Yinhua Zhang Shiliang Wang David Spiro Elodie Ghedin Clotilde K S Carlow Mining predicted essential genes of Brugia malayi for nematode drug targets.
description	We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression.
format	article
author	Sanjay Kumar Kshitiz Chaudhary Jeremy M Foster Jacopo F Novelli Yinhua Zhang Shiliang Wang David Spiro Elodie Ghedin Clotilde K S Carlow
author_facet	Sanjay Kumar Kshitiz Chaudhary Jeremy M Foster Jacopo F Novelli Yinhua Zhang Shiliang Wang David Spiro Elodie Ghedin Clotilde K S Carlow
author_sort	Sanjay Kumar
title	Mining predicted essential genes of Brugia malayi for nematode drug targets.
title_short	Mining predicted essential genes of Brugia malayi for nematode drug targets.
title_full	Mining predicted essential genes of Brugia malayi for nematode drug targets.
title_fullStr	Mining predicted essential genes of Brugia malayi for nematode drug targets.
title_full_unstemmed	Mining predicted essential genes of Brugia malayi for nematode drug targets.
title_sort	mining predicted essential genes of brugia malayi for nematode drug targets.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/1ecfd8f6c9a14b828ce7f8c686abce52
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Mining predicted essential genes of Brugia malayi for nematode drug targets.

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