title: Antiplasmodial properties of acyl-lysyl oligomers in culture and animal models of malaria.
abstract: Our previous analysis of antiplasmodial properties exhibited by dodecanoyl-based oligo-acyl-lysyls (OAKs) has outlined basic attributes implicated in potent inhibition of parasite growth and underlined the critical role of excess hydrophobicity in hemotoxicity. To dissociate hemolysis from antiplasmodial effect, we screened >50 OAKs for in vitro growth inhibition of Plasmodium falciparum strains, thus revealing the minimal requirements for antiplasmodial potency in terms of sequence and composition, as confirmed by efficacy studies in vivo. The most active sequence, dodecanoyllysyl-bis(aminooctanoyllysyl)-amide (C(12)K-2α(8)), inhibited parasite growth at submicromolar concentrations (50% inhibitory concentration [IC(50)], 0.3 ± 0.1 μM) and was devoid of hemolytic activity (<0.4% hemolysis at 150 μM). Unlike the case of dodecanoyl-based analogs, which equally affect ring and trophozoite stages of the parasite developmental cycle, the ability of various octanoyl-based OAKs to distinctively affect these stages (rings were 4- to 5-fold more sensitive) suggests a distinct antiplasmodial mechanism, nonmembranolytic to host red blood cells (RBCs). Upon intraperitoneal administration to mice, C(12)K-2α(8) demonstrated sustainable high concentrations in blood (e.g., 0.1 mM at 25 mg/kg of body weight). In Plasmodium vinckei-infected mice, C(12)K-2α(8) significantly affected parasite growth (50% effective dose [ED(50)], 22 mg/kg) but also caused mortality in 2/3 mice at high doses (50 mg/kg/day × 4).
authors.affiliation: Department of Biotechnology & Food Engineering, Technion, Israel Institute of Technology, Haifa, Israel 32000.
authors.forename: Fadia
authors.initials: F
authors.lastname: Zaknoon
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.forename: Ohad
authors.initials: O
authors.lastname: Meir
authors.forename: Shahar
authors.initials: S
authors.lastname: Rotem
authors.forename: Hagai
authors.initials: H
authors.lastname: Ginsburg
authors.forename: Henri
authors.initials: H
authors.lastname: Vial
authors.forename: Amram
authors.initials: A
authors.lastname: Mor
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006461:Hemolysis / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D009842:Oligopeptides; C569665:dodecanoyllysyl-bis(aminooctanoyllysyl)amide