Screening the Pathogen Box for Molecules Active against Plasmodium Sexual Stages Using a New Nanoluciferase-Based Transgenic Line of P. berghei Identifies Transmission-Blocking Compounds.

Therapeutic Approaches

Abstract

Malaria remains an important parasitic disease with a large morbidity and mortality burden. Plasmodium transmission-blocking (TB) compounds are essential for achieving malaria elimination efforts. Recent efforts to develop high-throughput screening (HTS) methods to identify compounds that inhibit or kill gametocytes, the Plasmodium sexual stage infectious to mosquitoes, have yielded insight into new TB compounds. However, the activities of these compounds against gametes, formed in the first minutes of mosquito infection, are typically not assessed, unless screened in a standard membrane feeding assay, a labor-intensive assay. We demonstrate here the generation of a Plasmodium model for drug screens against gametes and fertilization. The new P. berghei line, named Ookluc, was genetically and pharmacologically validated and scalable for HTS. Screening the Pathogen Box from the Medicines for Malaria Venture using the new model identified promising TB compounds. The use of Ookluc in different libraries of compounds may aid in the identification of transmission-blocking drugs not assessed in screens against asexual stages or gametocytes.

Authors

Calit, Juliana; Dobrescu, Irina; Gaitán, Xiomara A; Borges, Miriam H; Ramos, Marisé S; Eastman, Richard; Bargieri, Daniel Y;

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