Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen

Abstract

Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance

“…The activation of male but not female gametes was susceptible to inhibition of Pf20S β5, with EC 50 s of 140 nM–240 nM ( Fig. 4 C and SI Appendix , Table S5 ) ( 29 ). The inability of male gametes to undergo activation would preclude the generation of infectious sporozoites and block malaria transmission.…”

Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity

“…PKG also plays an essential role in gametogenesis, regulating male gamete exflagellation and the rounding up of female gametocytes ( McRobert et al., 2008 ). MMV030084 and some of its analogs have previously been identified as inhibitors of female gamete formation ( Miguel-Blanco et al., 2017 ). In our assays, MMV030084 potently inhibited male exflagellation ( Figure 1 F), but showed ambiguous results regarding female gametocyte rounding up ( Figure S2 ).…”

A biosynthetic platform for antimalarial drug discovery

“…S3). Any compound identified using this assay with an IC50 of less than 2.0 µM is considered for further compound development 26 . Combined, these data suggest violacein is a potential drug that could be developed to antagonize resistance in the field and target both asexual and sexual stage parasites.…”