Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum

Aprajita Garg, Donna Wesolowski, Dulce Alonso, Kirk W. Deitsch, Choukri Ben Mamoun, Sidney Altman

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome.

Original languageEnglish (US)
Pages (from-to)11935-11940
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number38
DOIs
StatePublished - Sep 22 2015
Externally publishedYes

Fingerprint

RNA Splicing
Morpholinos
RNA Stability
Chloroquine
Protein Biosynthesis
Plasmodium falciparum
Parasites
Apicoplasts
Genome
Essential Genes
Antimalarials
Vacuoles
Life Cycle Stages
Genes
Phospholipids
Down-Regulation
Growth

Keywords

  • Gene expression
  • Intraerythrocytic development
  • Malaria
  • Peptide conjugated morpholino oligomer
  • Vivo morpholino oligomer

ASJC Scopus subject areas

  • General

Cite this

Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum. / Garg, Aprajita; Wesolowski, Donna; Alonso, Dulce; Deitsch, Kirk W.; Ben Mamoun, Choukri; Altman, Sidney.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 38, 22.09.2015, p. 11935-11940.

Research output: Contribution to journalArticle

Garg, Aprajita ; Wesolowski, Donna ; Alonso, Dulce ; Deitsch, Kirk W. ; Ben Mamoun, Choukri ; Altman, Sidney. / Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 38. pp. 11935-11940.
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