title: A pantetheinase-resistant pantothenamide with potent, on-target, and selective antiplasmodial activity.
abstract: Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC50], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC50, 52 ± 6 nM), target specificity, and low toxicity.
authors.affiliation: Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Cristiano J
authors.initials: CJ
authors.lastname: Macuamule
authors.affiliation: Research School of Biology, College of Medicine, Biology, and Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Erick T
authors.initials: ET
authors.lastname: Tjhin
authors.affiliation: Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Collins E
authors.initials: CE
authors.lastname: Jana
authors.affiliation: Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Leanne
authors.initials: L
authors.lastname: Barnard
authors.affiliation: Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Lizbé
authors.initials: L
authors.lastname: Koekemoer
authors.affiliation: Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Marianne
authors.initials: M
authors.lastname: de Villiers
authors.affiliation: Research School of Biology, College of Medicine, Biology, and Environment, The Australian National University, Canberra, ACT, Australia Medical School, College of Medicine, Biology, and Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Saliba
authors.affiliation: Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa estrauss@sun.ac.za.
authors.forename: Erick
authors.identifier: http://orcid.org/0000-0002-9898-8226
authors.initials: E
authors.lastname: Strauss
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D058851:GPI-Linked Proteins; D002738:Chloroquine; D000581:Amidohydrolases; C022314:pantetheinase
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