Authors

James M. Murithi, Columbia University Irving Medical Center
Cécile Pascal, Sanofi, Infectious Diseases Therapeutic Area
Jade Bath, Columbia University Irving Medical Center
Xavier Boulenc, Massachusetts Institute of Technology
Nina F. Gnädig, Columbia University Irving Medical Center
Charisse Flerida A. Pasaje, Sanofi R&D, Translational Medicine & Early DevelopmentFollow
Kelly Rubiano, Columbia University Irving Medical Center
Tomas Yeo, Columbia University Irving Medical CenterFollow
Sachel Mok, Columbia University Irving Medical Center
Sylvie Klieber, The Art of Discovery
Paul Desert, Massachusetts Institute of Technology
María Belén Jiménez-Díaz, The Art of Discovery
Jutta Marfurt, Menzies School of Health Research and Charles Darwin University
Mélanie Rouillier, Medicines for Malaria Venture
Mohammed H. Cherkaoui-Rbati, Medicines for Malaria Venture
Nathalie Gobeau, Medicines for Malaria Venture
Sergio Wittlin, Swiss Tropical and Public Health Institute
Anne-Catrin Uhlemann, Columbia University Irving Medical Center
Ric N. Price, Menzies School of Health Research and Charles Darwin University
Grennady Wirjanata, Menzies School of Health Research and Charles Darwin University
Rintis Noviyanti, Eijkman Institute for Molecular Biolog
Patrick K. Tumwebaze, Infectious Diseases Research CollaborationFollow
Roland A. Cooper, Dominican University of CaliforniaFollow
Philip J. Rosenthal, University of California, San FranciscoFollow
Laura M. Sanz, GlaxoSmithKlineFollow
Francisco-Javier Gamo, GlaxoSmithKline
Jayan Joseph, Syngene International Ltd
Shivendra Singh, Syngene International LtdFollow
Sridevi Bashyam, Syngene International Ltd
Jean Michel Augereau, Sanofi, Infectious Diseases Therapeutic Area
Elie Giraud, Sanofi, Infectious Diseases Therapeutic Area
Tanguy Bozec, Sanofi, Infectious Diseases Therapeutic Area
Thierry Vermat, Sanofi, Infectious Diseases Therapeutic Area
Gilles Tuffal, Sanofi R&D, Translational Medicine & Early Development
Jean-Michel Guillon, Sanofi, Infectious Diseases Therapeutic Area
Jérôme Menegotto, Sanofi, Infectious Diseases Therapeutic Area
Laurent Sallé, Sanofi R&D, Translational Medicine & Early Development
Guillaume Louit, Sanofi
Marie-José Cabanis, Sanofi R&D, Translational Medicine & Early Development
Marie Françoise Nicolas, Sanofi
Michel Doubovetzky, Sanofi, Infectious Diseases Therapeutic Area
Rita Merino, Sanofi, Infectious Diseases Therapeutic Area
Nadir Bessila, Sanofi, Infectious Diseases Therapeutic Area
Iñigo Angulo-Barturen, The Art of Discovery
Delphine Baud, Medicines for Malaria Venture
Lidiya Bebrevska, Medicines for Malaria Venture
Fanny Escudié, Medicines for Malaria Venture
Jacquin C. Niles, Sanofi R&D, Translational Medicine & Early Development
Benjamin Blasco, Medicines for Malaria Venture
Simon Campbell, Medicines for Malaria Venture
Gilles Courtemanche, Bioaster
Laurent Fraisse, Sanofi, Infectious Diseases Therapeutic Area
Alain Pellet, Sanofi, Infectious Diseases Therapeutic Area
David A. Fidock, Columbia University Irving Medical Center
Didier Leroy, Medicines for Malaria Venture

Department

Natural Sciences and Mathematics

Document Type

Article

Source

Science Translational Medicine

Publication Date

7-21-2021

ISSN

1946-6242

Volume

13

Issue

603

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.

PubMed ID

34290058

Rights

Copyright © 2021 The Authors

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