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

Mario Carucci, Julien Duez, Joel Tarning, Irene García-Barbazán, Aurélie Fricot-Monsinjon, Abdoulaye Sissoko, Lucie Dumas, Pablo Gamallo, Babette Beher, Pascal Amireault, Michael Dussiot, Ming Dao, Mitchell V. Hull, Case W. McNamara, Camille Roussel, Papa Alioune Ndour, Laura Maria Sanz, Francisco Javier Gamo and Pierre Buffet ()
Additional contact information
Mario Carucci: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Julien Duez: SYNSIGHT
Joel Tarning: Mahidol University
Irene García-Barbazán: Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III
Aurélie Fricot-Monsinjon: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Abdoulaye Sissoko: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Lucie Dumas: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Pablo Gamallo: Global Health Medicines R&D, GlaxoSmith Kline (GSK)
Babette Beher: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Pascal Amireault: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Michael Dussiot: Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, INSERM
Ming Dao: Massachusetts Institute of Technology
Mitchell V. Hull: Calibr, a division of The Scripps Research Institute
Case W. McNamara: Calibr, a division of The Scripps Research Institute
Camille Roussel: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Papa Alioune Ndour: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
Laura Maria Sanz: Global Health Medicines R&D, GlaxoSmith Kline (GSK)
Francisco Javier Gamo: Global Health Medicines R&D, GlaxoSmith Kline (GSK)
Pierre Buffet: Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37359-2

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