title: Erythrocyte membrane modifying agents and the inhibition of Plasmodium falciparum growth: structure-activity relationships for betulinic acid analogues.
abstract: The natural triterpene betulinic acid and its analogues (betulinic aldehyde, lupeol, betulin, methyl betulinate and betulinic acid amide) caused concentration-dependent alterations of erythrocyte membrane shape towards stomatocytes or echinocytes according to their hydrogen bonding properties. Thus, the analogues with a functional group having a capacity of donating a hydrogen bond (COOH, CH(2)OH, CONH(2)) caused formation of echinocytes, whereas those lacking this ability (CH(3), CHO, COOCH(3)) induced formation of stomatocytes. Both kinds of erythrocyte alterations were prohibitive with respect to Plasmodium falciparum invasion and growth; all compounds were inhibitory with IC(50) values in the range 7-28 microM, and the growth inhibition correlated well with the extent of membrane curvature changes assessed by transmission electron microscopy. Erythrocytes pre-loaded with betulinic acid or its analogues and extensively washed in order to remove excess of the chemicals could not serve as hosts for P. falciparum parasites. Betulinic acid and congeners can be responsible for in vitro antiplasmodial activity of plant extracts, as shown for Zataria multiflora Boiss. (Labiatae) and Zizyphus vulgaris Lam. (Rhamnaceae). The activity is evidently due to the incorporation of the compounds into the lipid bilayer of erythrocytes, and may be caused by modifications of cholesterol-rich membrane rafts, recently shown to play an important role in parasite vacuolization. The established link between erythrocyte membrane modifications and antiplasmodial activity may provide a novel target for potential antimalarial drugs.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Hanne L
authors.initials: HL
authors.lastname: Ziegler
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.forename: Majid
authors.initials: M
authors.lastname: Sairafianpour
authors.forename: Mehrnoush
authors.initials: M
authors.lastname: Tabatabai
authors.forename: Mahboubeh D
authors.initials: MD
authors.lastname: Tehrani
authors.forename: Karim
authors.initials: K
authors.lastname: Bagherzadeh
authors.forename: Henry
authors.initials: H
authors.lastname: Hägerstrand
authors.forename: Dan
authors.initials: D
authors.lastname: Staerk
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Jaroszewski
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000187:drug effects* / Q000469:parasitology; D006801:Humans; D019686:Lamiaceae; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development*; D027823:Rhamnaceae; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D000981:Antiprotozoal Agents; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D014315:Triterpenes; D000094062:Betulinic Acid