Identification of Plasmodium falciparum specific translation inhibitors from the MMV Malaria Box using a high throughput in vitro translation screen
- Malar J. 2016 Mar 17:15:173. doi: 10.1186/s12936-016-1231-8.
- 1. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
- 2. Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
- 3. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. [email protected].
- 4. Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].
Background: A major goal in the search for new anti-malarial compounds is to identify new mechanisms of action or new molecular targets. While cell-based, growth inhibition-based screening have enjoyed tremendous success, an alternative approach is to specifically assay a given pathway or essential cellular process.
Methods: Here, this work describes the development of a plate-based, in vitro luciferase assay to probe for inhibitors specific to protein synthesis in Plasmodium falciparum through the use of an in vitro translation system derived from the Parasite.
Results: Using the Medicines for Malaria Venture's Malaria Box as a pilot, 400 bioactive compounds with minimal human cytotoxicity profiles were screened, identifying eight compounds that displayed greater potency against the P. falciparum translation machinery relative to a mammalian translation system. Dose-response curves were determined in both translation systems to further characterize the top hit compound (MMV008270).
Conclusions: This assay will be useful not only in future anti-malarial screening efforts but also in the investigation of P. falciparum protein synthesis and essential processes in P. falciparum biology.