Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.

Inhibition of protein–protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α‐Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed “proteomimetics”, which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N‐alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.

This edge article reports the multiscale modelling of spermine-functionalised dendrons designed to bind DNA and deliver it into cells. The modelling provides an insight into the mode of self-assembly of the dendrons, in particular aggregate charge density and shape, and hence suggests explanations for some of the unexpected experimental observations. In particular, the self-assembly model helps explain why the first generation dendron is more effective in binding DNA than the second generation analogue, even though the second generation system has a greater number of surface spermine ligands. Effective self assembly of the first generation dendron leads to a high charge density assembled structure – more effective than the larger number of ligands on the second generation dendron – i.e., less is more. The modelling also suggests an alternative shape of self-assembly for the system with two hydrophobic cholesterol units (rather than one) at the dendron focal point – this may help explain why this system shows much enhanced gene delivery in vitro.