Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum

Yoann Augagneur, Donna Wesolowski, Hyun Seop Tae, Sidney Altman, Choukri Ben Mamoun

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Unique peptide-morpholino oligomer (PMO) conjugates have been designed to bind and promote the cleavage of specific mRNA as a tool to inhibit gene function and parasite growth. The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. The potency, selectivity, and predicted safety of PMO conjugates make this approach attractive for the development of a unique class of target-specific antimalarials and for largescale functional analysis of the malarial genome.

Original languageEnglish (US)
Pages (from-to)6235-6240
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number16
DOIs
StatePublished - Apr 17 2012
Externally publishedYes

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Keywords

  • Nuclease resistance
  • RNase P

ASJC Scopus subject areas

  • General

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