Publication: The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance
Issued Date
2021-07-21
Resource Type
ISSN
19466242
19466234
19466234
Other identifier(s)
2-s2.0-85112546003
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Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Science Translational Medicine. Vol.13, No.603 (2021)
Suggested Citation
James M. Murithi, Cécile Pascal, Jade Bath, Xavier Boulenc, Nina F. Gnädig, Charisse Flerida A. Pasaje, Kelly Rubiano, Tomas Yeo, Sachel Mok, Sylvie Klieber, Paul Desert, María Belén Jiménez-Díaz, Jutta Marfurt, Mélanie Rouillier, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Sergio Wittlin, Anne Catrin Uhlemann, Ric N. Price, Grennady Wirjanata, Rintis Noviyanti, Patrick Tumwebaze, Roland A. Cooper, Philip J. Rosenthal, Laura M. Sanz, Francisco Javier Gamo, Jayan Joseph, Shivendra Singh, Sridevi Bashyam, Jean Michel Augereau, Elie Giraud, Tanguy Bozec, Thierry Vermat, Gilles Tuffal, Jean Michel Guillon, Jérôme Menegotto, Laurent Sallé, Guillaume Louit, Marie José Cabanis, Marie Françoise Nicolas, Michel Doubovetzky, Rita Merino, Nadir Bessila, Iñigo Angulo-Barturen, Delphine Baud, Lidiya Bebrevska, Fanny Escudié, Jacquin C. Niles, Benjamin Blasco, Simon Campbell, Gilles Courtemanche, Laurent Fraisse, Alain Pellet, David A. Fidock, Didier Leroy The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Science Translational Medicine. Vol.13, No.603 (2021). doi:10.1126/scitranslmed.abg6013 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/78027
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Title
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance
Author(s)
James M. Murithi
Cécile Pascal
Jade Bath
Xavier Boulenc
Nina F. Gnädig
Charisse Flerida A. Pasaje
Kelly Rubiano
Tomas Yeo
Sachel Mok
Sylvie Klieber
Paul Desert
María Belén Jiménez-Díaz
Jutta Marfurt
Mélanie Rouillier
Mohammed H. Cherkaoui-Rbati
Nathalie Gobeau
Sergio Wittlin
Anne Catrin Uhlemann
Ric N. Price
Grennady Wirjanata
Rintis Noviyanti
Patrick Tumwebaze
Roland A. Cooper
Philip J. Rosenthal
Laura M. Sanz
Francisco Javier Gamo
Jayan Joseph
Shivendra Singh
Sridevi Bashyam
Jean Michel Augereau
Elie Giraud
Tanguy Bozec
Thierry Vermat
Gilles Tuffal
Jean Michel Guillon
Jérôme Menegotto
Laurent Sallé
Guillaume Louit
Marie José Cabanis
Marie Françoise Nicolas
Michel Doubovetzky
Rita Merino
Nadir Bessila
Iñigo Angulo-Barturen
Delphine Baud
Lidiya Bebrevska
Fanny Escudié
Jacquin C. Niles
Benjamin Blasco
Simon Campbell
Gilles Courtemanche
Laurent Fraisse
Alain Pellet
David A. Fidock
Didier Leroy
Cécile Pascal
Jade Bath
Xavier Boulenc
Nina F. Gnädig
Charisse Flerida A. Pasaje
Kelly Rubiano
Tomas Yeo
Sachel Mok
Sylvie Klieber
Paul Desert
María Belén Jiménez-Díaz
Jutta Marfurt
Mélanie Rouillier
Mohammed H. Cherkaoui-Rbati
Nathalie Gobeau
Sergio Wittlin
Anne Catrin Uhlemann
Ric N. Price
Grennady Wirjanata
Rintis Noviyanti
Patrick Tumwebaze
Roland A. Cooper
Philip J. Rosenthal
Laura M. Sanz
Francisco Javier Gamo
Jayan Joseph
Shivendra Singh
Sridevi Bashyam
Jean Michel Augereau
Elie Giraud
Tanguy Bozec
Thierry Vermat
Gilles Tuffal
Jean Michel Guillon
Jérôme Menegotto
Laurent Sallé
Guillaume Louit
Marie José Cabanis
Marie Françoise Nicolas
Michel Doubovetzky
Rita Merino
Nadir Bessila
Iñigo Angulo-Barturen
Delphine Baud
Lidiya Bebrevska
Fanny Escudié
Jacquin C. Niles
Benjamin Blasco
Simon Campbell
Gilles Courtemanche
Laurent Fraisse
Alain Pellet
David A. Fidock
Didier Leroy
Other Contributor(s)
Faculty of Tropical Medicine, Mahidol University
Syngene International Ltd
Infectious Diseases Research Collaboration
Bioaster, France
Dominican University of California
Eijkman Institute for Molecular Biology
Sanofi Pasteur SA
Columbia University Irving Medical Center
Menzies School of Health Research
University of California, San Francisco
Universitat Basel
Swiss Tropical and Public Health Institute (Swiss TPH)
Massachusetts Institute of Technology
Sanofi S.A.
Nuffield Department of Medicine
The Art of Discovery
Tres Cantos
Syngene International Ltd
Infectious Diseases Research Collaboration
Bioaster, France
Dominican University of California
Eijkman Institute for Molecular Biology
Sanofi Pasteur SA
Columbia University Irving Medical Center
Menzies School of Health Research
University of California, San Francisco
Universitat Basel
Swiss Tropical and Public Health Institute (Swiss TPH)
Massachusetts Institute of Technology
Sanofi S.A.
Nuffield Department of Medicine
The Art of Discovery
Tres Cantos
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.