title: Sphingolipid analogues inhibit development of malaria parasites.
abstract: Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo.
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Esmeralda V S
authors.initials: EV
authors.lastname: Meyer
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Holt
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Girard
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ballie
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Anatoliy S
authors.initials: AS
authors.lastname: Bushnev
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University , Atlanta, Georgia 30329, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: Lapp
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Menaldino
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: G Prabhakar
authors.initials: GP
authors.lastname: Reddy
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Evers
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Culver
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States ; Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University , Atlanta, Georgia 30329, United States ; Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Mary R
authors.initials: MR
authors.lastname: Galinski
authors.affiliation: Emory Institute for Drug Discovery (EIDD) , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
keywords: Enigmols; Plasmodium; antimalarials; drugs; malaria; sphingolipids