title: Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials.
abstract: Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Love
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Millholland
authors.forename: Satish
authors.initials: S
authors.lastname: Mishra
authors.forename: Swapnil
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Katie B
authors.initials: KB
authors.lastname: Freeman
authors.forename: Wenxi
authors.initials: W
authors.lastname: Pan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Kavash
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: Hyunil
authors.initials: H
authors.lastname: Jo
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Daly
authors.forename: Dewight R
authors.initials: DR
authors.lastname: Williams
authors.forename: M Anna
authors.initials: MA
authors.lastname: Kowalska
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Bergman
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.forename: Richard W
authors.initials: RW
authors.lastname: Scott
authors.forename: Doron C
authors.initials: DC
authors.lastname: Greenbaum
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000302:isolation & purification* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D059208:Parasite Load; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects*; D010978:Platelet Factor 4 / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D010978:Platelet Factor 4