Mining predicted essential genes of Brugia malayi for nematode drug targets

Sanjay Kumar, Kshitiz Chaudhary, Jeremy M. Foster, Jacopo F. Novelli, Yinhua Zhang, Shiliang Wang, David Spiro, Elodie Ghedin, Clotilde K S Carlow

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere1189
JournalPLoS One
Volume2
Issue number11
DOIs
StatePublished - Nov 14 2007

Fingerprint

Brugia malayi
Essential Genes
Genes
Nematoda
Caenorhabditis elegans
filariasis
drugs
genome
Genome
Pharmaceutical Preparations
genomics
Filarial Elephantiasis
drug therapy
Drug therapy
RNA Interference
nematode biology
onchocerciasis
animal parasitic nematodes
prioritization
new drugs

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kumar, S., Chaudhary, K., Foster, J. M., Novelli, J. F., Zhang, Y., Wang, S., ... Carlow, C. K. S. (2007). Mining predicted essential genes of Brugia malayi for nematode drug targets. PLoS One, 2(11), [e1189]. https://doi.org/10.1371/journal.pone.0001189

Mining predicted essential genes of Brugia malayi for nematode drug targets. / Kumar, Sanjay; Chaudhary, Kshitiz; Foster, Jeremy M.; Novelli, Jacopo F.; Zhang, Yinhua; Wang, Shiliang; Spiro, David; Ghedin, Elodie; Carlow, Clotilde K S.

In: PLoS One, Vol. 2, No. 11, e1189, 14.11.2007.

Research output: Contribution to journalArticle

Kumar, S, Chaudhary, K, Foster, JM, Novelli, JF, Zhang, Y, Wang, S, Spiro, D, Ghedin, E & Carlow, CKS 2007, 'Mining predicted essential genes of Brugia malayi for nematode drug targets', PLoS One, vol. 2, no. 11, e1189. https://doi.org/10.1371/journal.pone.0001189
Kumar S, Chaudhary K, Foster JM, Novelli JF, Zhang Y, Wang S et al. Mining predicted essential genes of Brugia malayi for nematode drug targets. PLoS One. 2007 Nov 14;2(11). e1189. https://doi.org/10.1371/journal.pone.0001189
Kumar, Sanjay ; Chaudhary, Kshitiz ; Foster, Jeremy M. ; Novelli, Jacopo F. ; Zhang, Yinhua ; Wang, Shiliang ; Spiro, David ; Ghedin, Elodie ; Carlow, Clotilde K S. / Mining predicted essential genes of Brugia malayi for nematode drug targets. In: PLoS One. 2007 ; Vol. 2, No. 11.
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