Antimalarial pantothenamide metabolites target acetyl-CoA synthesis inPlasmodium falciparum

Abstract

Malaria eradication is critically dependent on novel drugs that target resistant Plasmodium parasites and block transmission of the disease. Here we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage P. falciparum and also block onward mosquito transmission. These compounds are resistant to degradation by serum pantetheinases, show favorable pharmacokinetic properties and clear parasites in a humanized rodent infection model. Metabolomics revealed that CoA biosynthetic enzymes convert pantothenamides into drug-conjugates that interfere with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11, confirming the key roles of these enzymes in the sensitivity to pantothenamides.These new pantothenamides provide a promising class of antimalarial drugs with a unique mode of action.

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

“…It provides activated acyl groups for various metabolic pathways, such as the tricarboxylic acid cycle, fatty acid synthesis, and heme synthesis, as well as for gene regulation and post-translational modification of proteins (59). Pantothenate kinase (PanK), which catalyzes the first step in CoA synthesis, has been extensively characterized in P. falciparum (60), allowing pantothenamides (pantothenate mimetic compounds) to be catabolized into CoA antimetabolites (61) with deleterious effects for the parasite (62). Interestingly, of the five enzymes required for CoA synthesis, phosphopantetheine-cysteine ligase and phosphopantothenoylcysteine decarboxylase, which catalyze the second and third step, respectively, are dispensable in both the rodent malaria parasites Plasmodium yoelii and P. berghei (19,63).…”

1,5,7-Triazabicyclo[4.4.0]dec-5-ene: An Effective Catalyst for Amide Formation by Lactone Aminolysis

“…Considering the extensive application of d -pantolactone in medicinal chemistry and in the cosmetics industry, we selected the ring-opening of d -pantolactone with piperonylamine (Figure ) as a model reaction to explore lactone aminolysis. Various additives with potential acyl-transfer ability were tested, including aprotic nucleophiles (Figure a), protic nucleophiles (Figure b), and miscellaneous promoters, classified based on their potential mechanism of action (Figure c).…”