2026-06-14T03:32:24Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/165322024-09-27T21:14:35Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609

00925njm 22002777a 4500 dc Carucci, Mario author Duez, Julien author Tarning, Joel author Garcia-Barbazan, Irene author Fricot-Monsinjon, Aurélie author Sissoko, Abdoulaye author Dumas, Lucie author Gamallo, Pablo author Beher, Babette author Amireault, Pascal author Dussiot, Michael author Dao, Ming author Hull, Mitchell V author McNamara, Case W author Roussel, Camille author Ndour, Papa Alioune author Sanz, Laura Maria author Gamo, Francisco Javier author Buffet, Pierre author 2023-04-07 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. Nat Commun. 2023 Apr 7;14(1):1951. 10.1038/s41467-023-37359-2 2041-1723 Nature communications 37029122 http://hdl.handle.net/20.500.12105/16532 Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening