ArticleMolecular therapy : the journal of the American Society of Gene Therapy2012
SHAPE-directed discovery of potent shRNA inhibitors of HIV-1.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Type III CRISPR-based RNA editing for programmable control of SARS-CoV-2 and human coronaviruses.Nucleic acids research · 2022Article
- Exosomes as natural delivery carriers for programmable therapeutic nucleic acid nanoparticles (NANPs).Advanced drug delivery reviews · 2021Review
- Antiviral efficacy of short-hairpin RNAs and artificial microRNAs targeting foot-and-mouth disease virus.PeerJ · 2021Article
- Programmable Inhibition and Detection of RNA Viruses Using Cas13.Molecular cell · 2019Article
- New windows into retroviral RNA structures.Retrovirology · 2018Review
- RNA Interference Therapies for an HIV-1 Functional Cure.Viruses · 2017Review
- Silencing of HIV-1 by AgoshRNA molecules.Gene therapy · 2017Article
- Intracellular Reassociation of RNA-DNA Hybrids that Activates RNAi in HIV-Infected Cells.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Evaluation of the Efficacy And Toxicity of RNAs Targeting HIV-1 Production for Use in Gene or Drug Therapy.Journal of visualized experiments : JoVE · 2016Article
- Characterizing RNA structures in vitro and in vivo with selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq).Methods (San Diego, Calif.) · 2016Article
- The Use of Minimal RNA Toeholds to Trigger the Activation of Multiple Functionalities.Nano letters · 2016Article
- Bolaamphiphiles as carriers for siRNA delivery: From chemical syntheses to practical applications.Journal of controlled release : official journal of the Controlled Release Society · 2015Article
- Article
- Towards Antiviral shRNAs Based on the AgoshRNA Design.PloS one · 2015Article
- Triggering RNAi with multifunctional RNA nanoparticles and their delivery.DNA and RNA nanotechnology · 2015Article
- RNA and DNA nanoparticles for triggering RNA interference.RNA & disease (Houston, Tex.) · 2015Article
- Progress and outlook in structural biology of large viral RNAs.Virus research · 2014Review
- Multifunctional RNA nanoparticles.Nano letters · 2014Article
- Insights into RNA structure and function from genome-wide studies.Nature reviews. Genetics · 2014Review
- The impact of unprotected T cells in RNAi-based gene therapy for HIV-AIDS.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The RNA interference (RNAi) pathway can be exploited using short hairpin RNAs (shRNAs) to durably inactivate pathogenic genes. Prediction of optimal target sites is notoriously inaccurate and current approaches applied to HIV-1 show weak correlations with virus inhibition. In contrast, using a high-content model for disrupting pre-existing intramolecular structure in the HIV-1 RNA, as achievable using high-resolution SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing information, we discovered strong correlations between inhibition of HIV-1 production in a quantitative cell-based assay and very simple thermodynamic features in the target RNA. Strongest inhibition occurs at RNA target sites that both have an accessible "seed region" and, unexpectedly, are structurally accessible in a newly identified downstream flanking sequence. We then used these simple rules to create a new set of shRNAs and achieved inhibition of HIV-1 production of 90% or greater for up to 82% of designed shRNAs. These shRNAs inhibit HIV-1 replication in therapy-relevant T cells and show no or low cytotoxicity. The remarkable success of this straightforward SHAPE-based approach emphasizes that RNAi is governed, in significant part, by very simple, predictable rules reflecting the underlying RNA structure and illustrates principles likely to prove broadly useful in understanding transcriptome-scale biological recognition and therapeutics involving RNA.
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Registered trials
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