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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

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

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
Naveen K Kaushik, Jyotsna Sharma, Dinkar Sahal
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-256) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

NKK and JS carried out the experiments to determine the antiplasmodial potencies of different peptides, NKK performed mechanistic experiments including FACS and immunofluorescence microscopy, DS conceived of the study, participated in its design, coordination and brain storming and drafted the manuscript. All authors read and approved the final manuscript.

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,ΔF) (Fm, ΔFm IC50 >100 μM)}, the lysine-branched,dimeric versions showed far greater potency {IC50 (μM) Fd 1.5 , ΔFd 1.39}. The more helical and proteolytically stable ΔFd was studied for mechanistic details. ΔFq, a K-K2 dendrimer of ΔFm and (ΔFm)2 a linear dimer of ΔFm showed IC50 (μM) of 0.25 and 2.4 respectively. The healthy/infected red cell selectivity indices were >35 (ΔFd), >20 (ΔFm)2 and 10 (ΔFq). FITC-ΔFd showed rapid and selective accumulation in parasitized red cells. Overlaying DAPI and FITC florescence suggested that ΔFd binds DNA. Trophozoites and schizonts incubated with ΔFd (2.5 μM) 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 ΔFd against malaria.
Zusatzmaterial
Additional file 1: RPHPLC profiles of control peptides.(PDF 25 KB)
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Additional file 2: RPHPLC profiles of ΔFm and ΔFd.(PDF 51 KB)
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Additional file 3: ESMS of RPHPLC purified prochitinase, E30 and Insulin.(PDF 59 KB)
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Additional file 4: ESMS of RPHPLC purified ΔFm and ΔFd.(PDF 35 KB)
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Additional file 5: MALDI mass spectrum (Bruker Daltonics Flex analysis) of RPHPLC purified linear dimeric peptide.(PDF 107 KB)
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Additional file 6: Chromatographic and mass spectral characterization of ΔFq.(PDF 201 KB)
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Additional file 7: ESMS of RPHPLC purified Fm, Fd and D-Lys-ΔFd.(PDF 47 KB)
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Additional file 8: Microscopic differential counts of ΔFd (2.5 μM) treated trophozoites after 24 h.(PDF 122 KB)
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Additional file 9: ΔFd treated schizonts express MSP3.(PDF 206 KB)
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Additional file 10: ΔFd causes premature egress of schizonts.(PDF 138 KB)
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Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Authors’ original file for figure 7
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Authors’ original file for figure 8
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Authors’ original file for figure 9
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Literatur
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