2026-04-27T05:20:06Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/165322024-09-27T21:14:35Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609
Repisalud
author
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
funder
Bill & Melinda Gates Foundation
funder
Tres Cantos Open Lab Foundation
funder
National Institutes of Health (Estados Unidos)
2023-09-29T09:13:33Z
2023-09-29T09:13:33Z
2023-04-07
Nat Commun. 2023 Apr 7;14(1):1951.
http://hdl.handle.net/20.500.12105/16532
37029122
10.1038/s41467-023-37359-2
2041-1723
Nature communications
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.
eng
Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening
research article
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SafeDrugsHighPotential_2023.pdf
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SafeDrugsHighPotential_2023.pdf.txt
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