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

21 Jul 2021

Murithi JM, Pascal C, Bath J, Boulenc X, Gnädig NF, Pasaje CFA, Rubiano K, Yeo T, Mok S, Klieber S, Desert P, Jiménez-Díaz MB, Marfurt J, Rouillier M, Cherkaoui-Rbati MH, Gobeau N, Wittlin S, Uhlemann AC, Price RN, Wirjanata G, Noviyanti R, Tumwebaze P, Cooper RA, Rosenthal PJ, Sanz LM, Gamo FJ, Joseph J, Singh S, Bashyam S, Augereau JM, Giraud E, Bozec T, Vermat T, Tuffal G, Guillon JM, Menegotto J, Sallé L, Louit G, Cabanis MJ, Nicolas MF, Doubovetzky M, Merino R, Bessila N, Angulo-Barturen I, Baud D, Bebrevska L, Escudié F, Niles JC, Blasco B, Campbell S, Courtemanche G, Fraisse L, Pellet A, Fidock DA, Leroy D

Science Translational Medicine
PMID: 34290058

Doi:10.1126/scitranslmed.abg6013

Photo: gerasimov_foto_174/Shutterstock.com

The emergence and spread of 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 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.

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