Chemical genetics of Plasmodium falciparum
Abstrak
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.
Penulis (35)
W. A. Guiguemde
A. Shelat
David C. Bouck
Sandra Duffy
Gregory J. Crowther
P. Davis
David C. Smithson
M. Connelly
Julie Clark
Fangyi Zhu
M. Jiménez-Díaz
M. Martínez
Emily B. Wilson
A. Tripathi
J. Gut
E. Sharlow
I. Bathurst
Farah El Mazouni
Joseph W. Fowble
Isaac P. Forquer
P. L. McGinley
Steve Castro
Iñigo Angulo-Barturen
S. Ferrer
P. Rosenthal
J. Derisi
D. Sullivan
J. Lazo
D. Roos
M. Riscoe
M. Phillips
P. Rathod
W. V. Van Voorhis
V. Avery
R. Guy
Akses Cepat
- Tahun Terbit
- 2010
- Bahasa
- en
- Total Sitasi
- 550×
- Sumber Database
- Semantic Scholar
- DOI
- 10.1038/nature09099
- Akses
- Open Access ✓