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

TitleTargeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum.
Publication TypeJournal Article
Year of Publication2015
AuthorsGarg A, Wesolowski D, Alonso D, Deitsch KW, Ben Mamoun C, Altman S
JournalProc Natl Acad Sci U S A
Volume112
Issue38
Pagination11935-40
Date Published2015 Sep 22
ISSN1091-6490
KeywordsAnimals, Antimalarials, Artemisinins, Chloroquine, Down-Regulation, Drug Resistance, Flow Cytometry, Genes, Reporter, Hemiterpenes, Luciferases, Morpholinos, Organophosphorus Compounds, Parasites, Peptides, Plasmodium falciparum, Protein Biosynthesis, Proteolysis, RNA Splicing, RNA, Messenger, Sequence Analysis, DNA
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.

DOI10.1073/pnas.1515864112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26351679
PubMed Central IDPMC4586866
Grant ListR21 AI109486 / AI / NIAID NIH HHS / United States
AI109486 / AI / NIAID NIH HHS / United States
AI116930 / AI / NIAID NIH HHS / United States

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