Chemical genetics of Plasmodium falciparum

Guiguemde, W. Armand; Shelat, Anang A.; Bouck, David C.; Duffy, Sandra; Crowther, Gregory J.; Davis, Paul H.; Smithson, David C.; Connelly, Michele; Clark, Julie; Zhu, Fangyi; Jiménez-Dı́az, Marı́a Belén; Martínez, María Santos; Wilson, Emily B.; Tripathi, Abhai K.; Gut, Jiří; Sharlow, Elizabeth R.; Bathurst, Ian C.; Mazouni, Farah El; Fowble, Joseph; Forquer, Isaac; McGinley, Paula L.; Castro, Steve; Angulo-Barturen, Íñigo; Ferrer, Santiago; Rosenthal, Philip J.; DeRisi, Joseph L.; Sullivan, David J.; Lazo, John S.; Roos, David S.; Riscoe, Michael K.; Phillips, Margaret A.; Rathod, Pradipsinh K.; Voorhis, Wesley C. Van; Avery, Vicky M.; Guy, R. Kiplin

doi:10.1038/nature09099

Cited by 530 publications

(487 citation statements)

References 27 publications

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“…New drugs against malaria are urgently needed. Two recent publications describing thousands of compounds active against blood-stage malaria give us hope (22,23). However, elucidation of the compound targets is important for drug development.…”

Section: Discussionmentioning

confidence: 99%

Validation of isoleucine utilization targets in Plasmodium falciparum

Istvan

Dharia

Bopp

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

125

141

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Intraerythrocytic malaria parasites can obtain nearly their entire amino acid requirement by degrading host cell hemoglobin. The sole exception is isoleucine, which is not present in adult human hemoglobin and must be obtained exogenously. We evaluated two compounds for their potential to interfere with isoleucine utilization. Mupirocin, a clinically used antibacterial, kills Plasmodium falciparum parasites at nanomolar concentrations. Thiaisoleucine, an isoleucine analog, also has antimalarial activity. To identify targets of the two compounds, we selected parasites resistant to either mupirocin or thiaisoleucine. Mutants were analyzed by genome-wide high-density tiling microarrays, DNA sequencing, and copy number variation analysis. The genomes of three independent mupirocin-resistant parasite clones had all acquired either amplifications encompassing or SNPs within the chromosomally encoded organellar (apicoplast) isoleucyl-tRNA synthetase. Thiaisoleucine-resistant parasites had a mutation in the cytoplasmic isoleucyl-tRNA synthetase. The role of this mutation in thiaisoleucine resistance was confirmed by allelic replacement. This approach is generally useful for elucidation of new targets in P. falciparum . Our study shows that isoleucine utilization is an essential pathway that can be targeted for antimalarial drug development.

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Section: Discussionmentioning

confidence: 99%

Validation of isoleucine utilization targets in Plasmodium falciparum

Istvan

Dharia

Bopp

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

125

141

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“…Analysis of historical GSK data suggested that the main target classes affected by these compounds are malaria kinases, proteases and G-protein coupled receptors (Gamo et al, 2010). In a similar study, a library of nearly 310,000 chemicals, designed to cover a large diversity of bioactive compounds, was screened upon drug sensitive and multidrug resistant P. falciparum strains (Guiguemde et al, 2010). Amongst hits, 172 were cross-validated by three laboratories using distinct assays.…”

Section: Renew Of Phenotypic Screening Approachesmentioning

confidence: 99%

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

Grellier¹,

Deregnaucourt²,

Isabelle³

2012

Malaria Parasites

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“…9 Where should the search for leads for new antimalarial drugs start? In visionary initiatives, in 2010, St Jude's Children's Research Hospital 10 and Novartis 11 both published the structures of thousands of compounds that inhibit parasite growth, which represents a step change in the number of leads available for drug discovery programs. Also, in 2010, we at GlaxoSmithKline (GSK) published the Tres Cantos Antimalarial Set (TCAMS), 13533 compounds that are the result of screening nearly 2 million compounds from the GSK corporate collection.…”

mentioning

confidence: 99%