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

Sci Transl Med. 2021 Jul 21;13(603):eabg6013. doi: 10.1126/scitranslmed.abg6013.

James M Murithi ¹, Cécile Pascal ², Jade Bath ¹, Xavier Boulenc ³, Nina F Gnädig ¹, Charisse Flerida A Pasaje ⁴, Kelly Rubiano ¹, Tomas Yeo ¹, Sachel Mok ¹, Sylvie Klieber ⁵, Paul Desert ³, María Belén Jiménez-Díaz ⁶, Jutta Marfurt ⁷, Mélanie Rouillier ⁸, Mohammed H Cherkaoui-Rbati ⁸, Nathalie Gobeau ⁸, Sergio Wittlin ⁹ ¹⁰, Anne-Catrin Uhlemann ¹¹, Ric N Price ⁷ ¹² ¹³, Grennady Wirjanata ⁷, Rintis Noviyanti ¹⁴, Patrick Tumwebaze ¹⁵, Roland A Cooper ¹⁶, Philip J Rosenthal ¹⁷, Laura M Sanz ¹⁸, Francisco Javier Gamo ¹⁸, Jayan Joseph ¹⁹, Shivendra Singh ¹⁹, Sridevi Bashyam ¹⁹, Jean Michel Augereau ², Elie Giraud ², Tanguy Bozec ², Thierry Vermat ², Gilles Tuffal ⁵, Jean-Michel Guillon ², Jérôme Menegotto ², Laurent Sallé ⁵, Guillaume Louit ²⁰, Marie-José Cabanis ⁵, Marie Françoise Nicolas ²⁰, Michel Doubovetzky ², Rita Merino ², Nadir Bessila ², Iñigo Angulo-Barturen ⁶, Delphine Baud ⁸, Lidiya Bebrevska ⁸, Fanny Escudié ⁸, Jacquin C Niles ⁴, Benjamin Blasco ⁸, Simon Campbell ⁸, Gilles Courtemanche ²¹, Laurent Fraisse ², Alain Pellet ², David A Fidock ²² ¹¹, Didier Leroy ²³

Affiliations

1 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA.
2 Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France.
3 Sanofi Pasteur, Marcy L'Etoile, France.
4 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
5 Sanofi R&D, Translational Medicine & Early Development, Montpellier, France.
6 The Art of Discovery, Bizkaia, Basque Country, Spain.
7 Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.
8 Medicines for Malaria Venture, Geneva, Switzerland.
9 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
10 Universität Basel, Basel, Switzerland.
11 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
12 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
13 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
14 Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
15 Infectious Diseases Research Collaboration, Kampala, Uganda.
16 Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, USA.
17 Department of Medicine, University of California, San Francisco, CA, USA.
18 Global Health Pharma Research Unit, GSK, Tres Cantos, Madrid, Spain.
19 Syngene International Ltd., Bangalore, India.
20 Sanofi, Vitry-sur-Seine, France.
21 Bioaster, Paris, France.
22 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA. df2260@cumc.columbia.edu leroyd@mmv.org.
23 Medicines for Malaria Venture, Geneva, Switzerland. df2260@cumc.columbia.edu leroyd@mmv.org.

PMID: 34290058 DOI: 10.1126/scitranslmed.abg6013

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-148178

MMV688533

antimalarial agent

Parasite

Infection

Name
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