| Autor: |
Wesley C. Van Voorhis, John S. Lazo, Paula L. McGinley, Michele Connelly, Abhai K. Tripathi, Margaret A. Phillips, Isaac P. Forquer, Gregory J. Crowther, R. Kiplin Guy, Sandra Duffy, María Belén Jiménez-Díaz, David Bouck, Paul H. Davis, María Santos Martínez, Vicky M. Avery, Julie Clark, Elizabeth R. Sharlow, Farah El Mazouni, Joseph W. Fowble, Michael K. Riscoe, Steve Castro, Anang A. Shelat, Iñigo Angulo-Barturen, David S. Roos, David J. Sullivan, Ian Bathurst, Emily Wilson, W. Armand Guiguemde, Fangyi Zhu, Jiri Gut, Santiago Ferrer, Pradipsinh K. Rathod, David C. Smithson, Philip J. Rosenthal, Joseph L. DeRisi |
| Jazyk: |
angličtina |
| Rok vydání: |
2010 |
| Předmět: |
|
| Zdroj: |
Nature
Nature, vol 465, iss 7296 |
| ISSN: |
1476-4687
0028-0836 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
