Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening
Issued Date
2023-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85152052589
Pubmed ID
37029122
Journal Title
Nature Communications
Volume
14
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.14 No.1 (2023)
Suggested Citation
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 M.V., McNamara C.W., Roussel C., Ndour P.A., Sanz L.M., Gamo F.J., Buffet P. Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening. Nature Communications Vol.14 No.1 (2023). doi:10.1038/s41467-023-37359-2 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81319
Title
Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening
Author's Affiliation
Mahidol Oxford Tropical Medicine Research Unit
Biologie Intégrée du Globule Rouge
Hôpital Necker Enfants Malades
Centro Nacional de Microbiologia
Massachusetts Institute of Technology
Nuffield Department of Medicine
Scripps Research Institute
Institut Pasteur, Paris
Inserm
SYNSIGHT
Laboratoire d'Excellence GR-Ex
Glaxo Smith Kline
Biologie Intégrée du Globule Rouge
Hôpital Necker Enfants Malades
Centro Nacional de Microbiologia
Massachusetts Institute of Technology
Nuffield Department of Medicine
Scripps Research Institute
Institut Pasteur, Paris
Inserm
SYNSIGHT
Laboratoire d'Excellence GR-Ex
Glaxo Smith Kline
Other Contributor(s)
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.