Anti-plasmodial action of de novo-designed, cationic, lysine-branched, amphipathic, helical peptides.

ABSTRACT:

Background

A lack of vaccine and rampant drug resistance demands new anti-malarials.

Methods

In vitro blood stage anti-plasmodial properties of several de novo-designed, chemically synthesized, cationic, amphipathic, helical, antibiotic peptides were examined against Plasmodium falciparum using SYBR Green assay. Mechanistic details of anti-plasmodial action were examined by optical/fluorescence microscopy and FACS analysis.

Results

Unlike the monomeric decapeptides {(Ac-GXRKXHKXWA-NH2) (X?=?F,?F) (Fm, ?Fm IC50 >100 ?M)}, the lysine-branched,dimeric versions showed far greater potency {IC50 (?M) Fd 1.5 , ?Fd 1.39}. The more helical and proteolytically stable ?Fd was studied for mechanistic details. ?Fq, a K-K2 dendrimer of ?Fm and (?Fm)2 a linear dimer of ?Fm showed IC50 (?M) of 0.25 and 2.4 respectively. The healthy/infected red cell selectivity indices were >35 (?Fd), >20 (?Fm)2 and 10 (?Fq). FITC-?Fd showed rapid and selective accumulation in parasitized red cells. Overlaying DAPI and FITC florescence suggested that ?Fd binds DNA. Trophozoites and schizonts incubated with ?Fd (2.5??M) egressed anomalously and Band-3 immunostaining revealed them not to be associated with RBC membrane. Prematurely egressed merozoites from peptide-treated cultures were found to be invasion incompetent.

Conclusion

Good selectivity (>35), good resistance index (1.1) and low cytotoxicity indicate the promise of ?Fd against malaria.

SUBMITTER: Kaushik NK 

PROVIDER: S-EPMC3502156 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature