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

Nat Commun. 2023 Apr 7;14(1):1951. doi: 10.1038/s41467-023-37359-2.

Mario Carucci ^# ¹, Julien Duez ^# ², Joel Tarning ³ ⁴, Irene García-Barbazán ⁵, Aurélie Fricot-Monsinjon ¹, Abdoulaye Sissoko ¹, Lucie Dumas ¹, Pablo Gamallo ⁶, Babette Beher ¹, Pascal Amireault ¹ ⁷, Michael Dussiot ⁷ ⁸, Ming Dao ⁹, Mitchell V Hull ¹⁰, Case W McNamara ¹⁰, Camille Roussel ¹ ⁸ ¹¹, Papa Alioune Ndour ¹, Laura Maria Sanz ⁶, Francisco Javier Gamo ⁶, Pierre Buffet ¹² ¹³ ¹⁴

Affiliations

1 Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge, 75015, Paris, France.
2 SYNSIGHT, 91000, Evry-Courcouronnes, France.
3 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 10400, Bangkok, Thailand.
4 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
5 Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, 28222, Madrid, Spain.
6 Global Health Medicines R&D, GlaxoSmith Kline (GSK), 28760, Tres Cantos, Spain.
7 Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, INSERM, 75014, Paris, France.
8 Laboratoire d'Excellence GR-Ex, Paris, France.
9 Department of Materials Science and Engineering, Massachusetts Institute of Technology, MA, 02139, Cambridge, USA.
10 Calibr, a division of The Scripps Research Institute, La Jolla, CA, 92037, USA.
11 Laboratoire d'Hématologie générale, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015, Paris, France.
12 Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge, 75015, Paris, France. [email protected].
13 Department of Infectious & Tropical Disease, AP-HP, Necker Hospital, 75015, Paris, France. [email protected].
14 Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur, 75015, Paris, France. [email protected].
# Contributed equally.

PMID: 37029122 DOI: 10.1038/s41467-023-37359-2

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-117620

TD-6450

HCV Inhibitor

HCV

Infection

Name
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