“The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance”
Dr Gilles Courtemanche, BIOASTER Antimicrobials Program Head is co-author of a scientific publication “MMV688533, a preclinical candidate to cure malaria” @ScienceTM Science Translational Medicine 21 Jul 2021: Vol. 13, Issue 603, eabg6013 https://stm.sciencemag.org/content/13/603/eabg6013
#malaria @MedsforMalaria @BIOASTER
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 high-throughput 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 SCID 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.
Teaser: We report an acylguanidine preclinical candidate with pharmacological features compatible with single low-dose malaria cure.