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© Liliana Mancio, Institut Pasteur
Primary human hepatocytes co-cultured with parenchymal cells at 6 days post-seeding. The expression of human CD81 is depicted in pink
Publication : Nature communications

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 07 Apr 2023

Carucci M, Duez J, Tarning J, García-Barbazán I, Fricot-Monsinjon A, Sissoko A, Dumas L, Gamallo P, Beher B, Amireault P, Dussiot M, Dao M, Hull MV, McNamara CW, Roussel C, Ndour PA, Sanz LM, Gamo FJ, Buffet P

Link to Pubmed [PMID] – 37029122

Link to DOI – 10.1038/s41467-023-37359-2

Nat Commun 2023 Apr; 14(1): 1951

Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome ( https://clinicaltrials.gov , ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials.