Systematic biochemical and cheminformatic evaluation of the gametocytocidal activity of antimalarial lead candidates

Abstract

Malaria drug discovery initiatives are driven by concerns regarding the emergence of parasite resistance to current antimalarials and require novel compounds with the ability to target both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum. These individual stages respond differently to compounds with majority affecting asexual blood stage (ABS) parasites and a loss in activity observed against gametocytes. This study investigated the compounding factors associated with stage-specific vs. multistage activity of antiplasmodial compounds. Here, it was observed that there is a threshold for loss of activity from ABS parasites to gametocytes to effectively kill gametocytes populations with dosing based on in vitro ABS activity. Moreover, compounds with immature gametocyte activity are of utmost importance to ensure complete clearance of gametocytes and therefore block transmission. To improve the development of compounds with gametocyte activity, the mechanistic causes of these differential activities were investigated. We showed for the first time that gametocytocidal activity is driven by their distinct physicochemical properties that allow for effective uptake into gametocytes. Therefore, this study provides a comprehensive analysis as to the required profiles of potential multistage active antimalarial agents and facilitate the development of effective transmission-blocking compounds.