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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Clardy, Jon Prudêncio, Miguel Mota, Maria M. Derbyshire, Emily R. |
| Description | Author Affiliation: Derbyshire ER ( Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.); |
| Abstract | Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite's life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 22 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antimalarials Pharmacology Liver Drug Effects Malaria Prevention & Control Plasmodium Berghei Animals Anopheles Parasitology Classification Drug Evaluation, Preclinical Hep G2 Cells Inhibitory Concentration 50 Insect Vectors Life Cycle Stages Pathology Malaria, Falciparum Mice Mice, Inbred C57BL Growth & Development Isolation & Purification Plasmodium Falciparum Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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