Abstract: The spleen clears rigid erythrocytes from the circulation. Drug-induced stiffening of Plasmodium falciparum intra-erythrocytic sexual stages (mature gametocytes) is therefore expected to block the transmission of malaria By screening 13 555 compounds with spleen-mimetic microfilters, the inventors identified 82 compounds that stiffen mature gametocytes. Eight active families were identified, including known anti-malarial, antimicrobial or anticancer agents, amongst others. Hit prioritization based on accessible safety and pharmacokinetics data in humans identified 3 leading candidates. NITD609 displayed killing and stiffening effects (IC50 of 100 and 50 nM, respectively), while TD-6450 and L-THP had a pure or predominant stiffening effect (IC50 of 600 and 5 nM, respectively). These values are lower than or close to peak plasma concentrations in humans. Clinical trials with these strong malaria transmission-blocking candidates are envisioned.