Block Transmission Techniques

2012 ◽  
pp. 39-108
Keyword(s):  
Block Transmission

scholarly journals Antimalarial pantothenamide metabolites target acetyl-CoA synthesis inPlasmodium falciparum

2018 ◽  
Author(s):  
Joost Schalkwijk ◽  
Erik L. Allman ◽  
Patrick A.M. Jansen ◽  
Laura E. de Vries ◽  
Suzanne Jackowski ◽  
...  
Keyword(s):  
Infection Model ◽  
Acetyl Coa ◽  
Human Malaria Parasite ◽  
Block Transmission ◽  
Drug Conjugates ◽  
Novel Drugs ◽  
Pharmacokinetic Properties ◽  
Acetyl Coa Synthesis ◽  
Malaria Eradication

AbstractMalaria eradication is critically dependent on novel drugs that target resistantPlasmodiumparasites and block transmission of the disease. Here we report the discovery of potent pantothenamide bioisosteres that are active against blood-stageP. falciparumand 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 vitrogenerated 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.One sentence summaryPantothenamides form antimetabolites that interfere with acetyl-CoA metabolism in the human malaria parasitePlasmodium falciparum

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