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

• Published in: Nature communications Vol. 14; no. 1; pp. 1951 - 16
• Main Authors: Carucci, Mario, Duez, Julien, Tarning, Joel, García-Barbazán, Irene, Fricot-Monsinjon, Aurélie, Sissoko, Abdoulaye, Dumas, Lucie, Gamallo, Pablo, Beher, Babette, Amireault, Pascal, Dussiot, Michael, Dao, Ming, Hull, Mitchell V., McNamara, Case W., Roussel, Camille, Ndour, Papa Alioune, Sanz, Laura Maria, Gamo, Francisco Javier, Buffet, Pierre
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 14; 14/19; 14/34; 14/63; 49; 49/47; 631/154/1435/2163; 631/326/417/1716; Antimalarials - pharmacology; Blocking; Clinical trials; Deformability; Disease transmission; Drugs; Erythrocytes; Erythrocytes - parasitology; Formability; Hepatitis C; Humanities and Social Sciences; Humans; Inhibitors; Malaria; Malaria, Falciparum - parasitology; multidisciplinary; Oral administration; Parasites; Pharmacokinetics; Plasmodium falciparum; Safety; Science; Science (multidisciplinary); Screening; Spleen; Stiffening; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37359-2

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. Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum -infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.