Principal Investigator (PI)
The Foundation is providing £428,133 in support.
Ana Lisa Valenciano - Margarida Teles
GSK to share access to all generated data and provide access/use of compounds identified from the screen for further evaluation beyond the scope of this proposal. The Tres Cantos unit will provide in kind assay consumables and resources equivalent to two full-time personnel who will assist with gametocyte production, mosquito rearing and infections, dissections, imaging, data analysis, and support.
This project offers a major advance in antimalarial drug discovery by targeting pre-erythrocytic stages to block malaria infection. We have developed an innovative P. falciparum in vitro liver assay to evaluate drug toxicity and inhibitory efficacy of critical early phase of malaria infection in human hepatocytes. Consequently, this project can efficiently evaluate drug inhibition of the complete liver stage of the malaria life cycle. Central to this new screening strategy is a G384 microplate culture system using primary human hepatocytes (PHHs)(1) with modified P. falciparum sporozoite isolation procedures (2, 3). To enhance identification of the best lead compounds we will use quantitative functional assays of sporozoite entry into and egress from human hepatocytes along with transmission-blocking assays for mosquito infections. In developing our assays, we identified key microenvironmental triggers of infectivity that downstream can be used to elucidate target specificity and mechanisms of action. Altogether we provide a comprehensive new screening strategy for antimalaria drugs to block infection.