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, Sanofi Pasteur
Nina F. Gnädig, Columbia University Irving Medical Center
Charisse Flerida A. Pasaje, Massachusetts Institute of Technology
Kelly Rubiano, Columbia University Irving Medical Center
Tomas Yeo, Columbia University Irving Medical Center
Sachel Mok, Columbia University Irving Medical Center
Sylvie Klieber, Sanofi R&D, Translational Medicine & Early Development
Paul Desert, Sanofi Pasteur
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 Biology
Patrick Tumwebaze, Infectious Diseases Research Collaboration
Roland A. Cooper, Dominican University of CaliforniaFollow
Philip J. Rosenthal, University of California, San FranciscoFollow
Laura M. Sanz, Global Health Pharma Research Unit, GSK
Francisco-Javier Gamo, GlaxoSmithKline
Jayan Joseph, Syngene International Ltd.
Shivendra Singh, Syngene International Ltd.
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, Vitry-sur-Seine
Marie-José Cabanis, Sanofi R&D, Translational Medicine & Early Development
Marie Françoise Nicolas, Sanofi, Vitry-sur-Seine
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, Massachusetts Institute of Technology
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
Source
Science Translational Medicine
Publication Date
7-21-2021
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.
Rights
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publisher's Statement
This is the accepted manuscript version of the article. The final version is available from American Association for the Advancement of Science at: https://doi.org/10.1126/scitranslmed.abg6013
