The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to <i>Plasmodium falciparum</i> parasite resistance
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 Désert, Marı́a Belén Jiménez-Dı́az, Jutta Marfurt, Mélanie Rouillier, Mohammed H. Cherkaoui‐Rbati, Nathalie Gobeau, Sergio Wittlin, Anne‐Catrin Uhlemann, Ric N. Price, Grennady Wirjanata, Rintis Noviyanti, Patrick K. Tumwebaze, Roland A. Cooper, Philip J. Rosenthal, Laura M. Sanz, Francisco‐Javier Gamo, Jayan T. Joseph, Shivendra V. Singh, Sridevi Bashyam, Jean‐Michel Augereau, Elie Giraud, Tanguy Bozec, Vermat Thierry, Gilles Tuffal, Jean-Michel Guillon, J. Ménégotto, Laurent Sallé, Guillaume Louit, Marie‐José Cabanis, Marie Françoise Nicolas, Michel Doubovetzky, Rita Merino, Nadir Bessila, Íñigo Angulo‐Barturen, Delphine Baud, Lidiya Bebrevska, Fanny Escudié, Jacquin C. Niles, Benjamin Blasco, Simon F. Campbell, Gilles Courtemanche, Laurent Fraisse, Alain Pellet, David A. Fidock, Didier Leroy
Abstract
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.