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

Autor:	Murithi JM; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Pascal C; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Bath J; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Boulenc X; Sanofi Pasteur, Marcy L'Etoile, France., Gnädig NF; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Pasaje CFA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Rubiano K; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Yeo T; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Mok S; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Klieber S; Sanofi R&D, Translational Medicine & Early Development, Montpellier, France., Desert P; Sanofi Pasteur, Marcy L'Etoile, France., Jiménez-Díaz MB; The Art of Discovery, Bizkaia, Basque Country, Spain., Marfurt J; Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia., Rouillier M; Medicines for Malaria Venture, Geneva, Switzerland., Cherkaoui-Rbati MH; Medicines for Malaria Venture, Geneva, Switzerland., Gobeau N; Medicines for Malaria Venture, Geneva, Switzerland., Wittlin S; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.; Universität Basel, Basel, Switzerland., Uhlemann AC; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Price RN; Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand., Wirjanata G; Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia., Noviyanti R; Eijkman Institute for Molecular Biology, Jakarta, Indonesia., Tumwebaze P; Infectious Diseases Research Collaboration, Kampala, Uganda., Cooper RA; Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, USA., Rosenthal PJ; Department of Medicine, University of California, San Francisco, CA, USA., Sanz LM; Global Health Pharma Research Unit, GSK, Tres Cantos, Madrid, Spain., Gamo FJ; Global Health Pharma Research Unit, GSK, Tres Cantos, Madrid, Spain., Joseph J; Syngene International Ltd., Bangalore, India., Singh S; Syngene International Ltd., Bangalore, India., Bashyam S; Syngene International Ltd., Bangalore, India., Augereau JM; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Giraud E; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Bozec T; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Vermat T; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Tuffal G; Sanofi R&D, Translational Medicine & Early Development, Montpellier, France., Guillon JM; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Menegotto J; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Sallé L; Sanofi R&D, Translational Medicine & Early Development, Montpellier, France., Louit G; Sanofi, Vitry-sur-Seine, France., Cabanis MJ; Sanofi R&D, Translational Medicine & Early Development, Montpellier, France., Nicolas MF; Sanofi, Vitry-sur-Seine, France., Doubovetzky M; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Merino R; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Bessila N; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Angulo-Barturen I; The Art of Discovery, Bizkaia, Basque Country, Spain., Baud D; Medicines for Malaria Venture, Geneva, Switzerland., Bebrevska L; Medicines for Malaria Venture, Geneva, Switzerland., Escudié F; Medicines for Malaria Venture, Geneva, Switzerland., Niles JC; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Blasco B; Medicines for Malaria Venture, Geneva, Switzerland., Campbell S; Medicines for Malaria Venture, Geneva, Switzerland., Courtemanche G; Bioaster, Paris, France., Fraisse L; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Pellet A; Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France., Fidock DA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA. df2260@cumc.columbia.edu leroyd@mmv.org.; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Leroy D; Medicines for Malaria Venture, Geneva, Switzerland. df2260@cumc.columbia.edu leroyd@mmv.org.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2021 Jul 21; Vol. 13 (603).
DOI:	10.1126/scitranslmed.abg6013
Abstrakt:	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. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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