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Chemical genetics of Plasmodium falciparum
Open accessAbstract
Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.
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Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139
Artemisinin Resistance in Plasmodium falciparum Malaria
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808859 · Cited by 3,424
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Spiroindolones, a Potent Compound Class for the Treatment of Malaria
Rottmann, M., McNamara, C., Yeung, B. K. S., Lee, M. C. S., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., et al. (2010) · Science · doi:10.1126/science.1193225 · Cited by 1,206
Screening out irrelevant cell-based models of disease
Horvath, P., Aulner, N., Bickle, M., Davies, A. M., Nery, E. D., Ebner, D., Montoya, M. C., Östling, P., Pietiäinen, V., Price, L. S., et al. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.175 · Cited by 525
Van Voorhis, W. C., Adams, J. H., Adelfio, R., Ahyong, V., Akabas, M. H., Alano, P., Alday, A., Alemán Resto, Y., Alsibaee, A., Alzualde, A., et al. (2016) · PLOS Pathogens · doi:10.1371/journal.ppat.1005763 · Cited by 435
Self-citationPriming the antimalarial pipeline
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Metadata
- Authors
- Guiguemde, W. A., Shelat, A. A., Bouck, D., Duffy, S., Crowther, G. J., Davis, P. H., Smithson, D. C., Connelly, M., Clark, J., Zhu, F., Jiménez-Díaz, M. B., Martinez, M. S., Wilson, E. B., Tripathi, A. K., Gut, J., Sharlow, E. R., Bathurst, I., Mazouni, F. E., Fowble, J. W., Forquer, I., McGinley, P. L., Castro, S., Angulo-Barturen, I., Ferrer, S., Rosenthal, P. J., DeRisi, J. L., Sullivan, D. J., Lazo, J. S., Roos, D. S., Riscoe, M. K., Phillips, M. A., Rathod, P. K., Van Voorhis, W. C., Avery, V. M., & Guy, R. K.
- Venue
- Nature
- Published
- 2010-05-20
- Volume
- 465
- Issue
- 7296
- Pages
- 311-315
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1993795323
- Cited by
- 566
- References
- 2
- FWCI
- 65.30
- Type
- journal article
- Language
- en
- Open access
- bronze
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- CoChat. (2026). Citation check: Chemical genetics of Plasmodium falciparum. https://app.cochat.ai/papers/10.1038/nature09099
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- Guiguemde, W. A., Shelat, A. A., Bouck, D., Duffy, S., Crowther, G. J., Davis, P. H., Smithson, D. C., Connelly, M., Clark, J., Zhu, F., Jiménez-Díaz, M. B., Martinez, M. S., Wilson, E. B., Tripathi, A. K., Gut, J., Sharlow, E. R., Bathurst, I., Mazouni, F. E., Fowble, J. W., . . . Guy, R. K. (2010). Chemical genetics of Plasmodium falciparum. Nature. https://doi.org/10.1038/nature09099
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.