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The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

Murithi, J. M. and Pascal, C. and Bath, J. and Boulenc, X. and Gnadig, N. F. and Pasaje, C. F. A. and Rubiano, K. and Yeo, T. and Mok, S. and Klieber, S. and Desert, P. and Jimenez-Diaz, M. B. and Marfurt, J. and Rouillier, M. and Cherkaoui-Rbati, M. H. and Gobeau, N. and Wittlin, S. and Uhlemann, A. C. and Price, R. N. and Wirjanata, G. and Noviyanti, R. and Tumwebaze, P. and Cooper, R. A. and Rosenthal, P. J. and Sanz, L. M. and Gamo, F. J. and Joseph, J. and Singh, S. and Bashyam, S. and Augereau, J. M. and Giraud, E. and Bozec, T. and Vermat, T. and Tuffal, G. and Guillon, J. M. and Menegotto, J. and Salle, L. and Louit, G. and Cabanis, M. J. and Nicolas, M. F. and Doubovetzky, M. and Merino, R. and Bessila, N. and Angulo-Barturen, I. and Baud, D. and Bebrevska, L. and Escudie, F. and Niles, J. C. and Blasco, B. and Campbell, S. and Courtemanche, G. and Fraisse, L. and Pellet, A. and Fidock, D. A. and Leroy, D.. (2021) The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Sci Transl Med, 13 (603). eabg6013.

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Official URL: https://edoc.unibas.ch/89244/

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Abstract

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1946-6242 (Electronic)1946-6234 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Dec 2022 14:26
Deposited On:20 Dec 2022 14:26

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