Use of peptide nucleic acids to manipulate gene expression in the malaria parasite Plasmodium falciparum

Netanel Kolevzon, Abed Nasereddin, Shankar Naik, Eylon Yavin, Ron Dzikowski

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

One of the major concerns in treating malaria by conventional small drug molecules is the rapid emergence of drug resistance. Specific silencing of essential genes by antisense oliogomers has been proposed as an alternative approach that may result in antimalarial activity which is not associated with drug resistance. In addition, such an approach could be an important biological tool for studying many genes' function by reverse genetics. Here we present a novel methodology of using peptide nucleic acids (PNAs) as a useful tool for gene silencing in Plasmodium falciparum. PNAs, designed as specific antisense molecules, were conjugated to a cell penetrating peptide (CPP); namely, octa-D-lysine via the C-terminus, to allow facile delivery through cell membranes. PNAs added to P. falciparum cultures were found exclusively in infected erythrocytes and were eventually localized in nuclei of the parasites at all stages of intra erythrocytic development. We show that these PNAs specifically down regulated both a stably expressed transgene as well as an endogenous essential gene, which significantly reduced parasites' viability. This study paves the way for a simple approach to silence a variety of P. falciparum genes as means of deciphering their function and potentially to develop highly specific and potent antimalarial agents.

Original languageAmerican English
Article numbere86802
JournalPLoS ONE
Volume9
Issue number1
DOIs
StatePublished - 22 Jan 2014

Bibliographical note

Funding Information:
RD is supported by the Israeli Academy for Science [660/09], the Abisch-Frenkel foundation and by the German Israeli Foundation [997/2008]. RD is also supported by the Jacob and Lena Joels Memorial Foundation Senior Lectureship for Excellence in the Life and Medical Sciences. EY acknowledges the David R. Bloom Center for Pharmacy and the Grass Center for Drug Design and Synthesis of Novel Therapeutics for financial support. We thank Dr. Adva Biton for her technical support and Ms. Shiri Eshar for critically reading the manuscript.

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