Chemical signatures and new drug targets for gametocytocidal drug development

Abstract

Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.

Characterization and screening of in vitro antimalarial and larvicidal activities of selected seaweeds from southeast coast of India against Plasmodium falciparum and Anopheles stephensi

“…In this previous study, result mentioned the experimental verification of early stage gametocytocidal activity in the development of new antimalarial activity. These studies had confirmed that effects of tryptanthrin and the derivatives NT1, T8, epoxomicin and chloroquine were investigated on the development of stage II to stage V gametocytes [22]. Although marine algae have been recognized as attractive sources of known bioactive compounds, very little research has been focused on antiprotozoal activity.…”

Discovering New Transmission-Blocking Antimalarial Compounds: Challenges and Opportunities

“…Primary hit rates (>80% inhibition at 5 μM) of 4.5-24% [20,23,27,29] were achieved when screened against stage IV/V gametocytes; this increased to 33% against stage I-III gametocytes [23,26]. Furthermore, although the rank-order of hits were similar, there was not complete overlap between MMV Malaria Box screens conducted with different assay platforms or between laboratories using the same assay platform [24,25].…”

“…The Medicines for Malaria Venture (MMV) Malaria Box of 400 compounds (selectively active against asexual parasites [22]) has been screened worldwide for activity against stage IV/V gametocytes [20,[23][24][25][26][27][28][29][30][31]. Primary hit rates (>80% inhibition at 5 μM) of 4.5-24% [20,23,27,29] were achieved when screened against stage IV/V gametocytes; this increased to 33% against stage I-III gametocytes [23,26].…”

“…Some chemical signatures for compounds targeting both asexual and gametocyte stages have been described [24] including endoperoxides, certain quinolines (including primaquine and mefloquine), anthracyclines, dihydroergotamine-type adrenergic agents and inhibitors of kinases, protein biosynthesis, the proteasome, protein modification / membrane trafficking and ion homeostasis [20,32]. Additionally, certain chemical classes (e.g.…”

“…[24]), cheminformatic clustering [20] or developing MOA deconvolution strategies [40], similar to what has been done for other infectious diseases [41,42] to retain biological activity within derivatized sets compared to the parent compounds Assays in this tier characterise the gametocytocidal effects of compounds further and provide an additional level of stringency in prioritising hits for tier 3. The inclusion of field isolates as an early filter is particularly important since it could minimize the downstream attrition rate.…”