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A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

ABSTRACT: Antisense oligomer (ASO)-based antibiotics that target mRNAs of essential bacterial genes bear great potential in the fight against antimicrobial resistance and for precision microbiome editing. The development of such antisense antibiotics has primarily focused on using phosphoramidite morpholino (PMO) and peptide nucleic acid (PNA) backbones, largely ignoring the growing number of chemical modalities that have spurred the success of ASO-based therapy in general. Here, we compare seven chemically distinct 10mer-ASOs, all designed to target the same essential acpP mRNA upon delivery with a KFF-peptide carrier into Salmonella, comparing PNA, PMO, phosphorothioate modified-DNA (PTO), 2’-methoxylated RNA (RNA-OMe), 2’-methoxyethylated RNA (RNA-MOE), 2’-fluorinated RNA (RNA-F) and 2’-locked RNA (LNA). Our systematic analysis using a variety of in vitro and in vivo methods to evaluate ASO uptake, target pairing and bacterial killing suggests that only PNA and PMO make it into Salmonella to cause bacterial growth inhibition. However, given their high target binding and translational repression activity in vitro, ASOs based on LNA and RNA-MOE appear to be promising candidates for antisense antibiotics that will require the identification of an efficient carrier.

ORGANISM(S): Salmonella enterica subsp. enterica serovar Typhimurium

PROVIDER: GSE232819 | GEO | 2023/07/11

REPOSITORIES: GEO

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Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice

Project description:Antisense oligonucleotides (ASOs) strategies for DM1 can abolish the toxic RNA gain-of-function mechanism caused by nuclear-retained mutant DMPK transcripts containing CUG expansions (CUGexp). However, systemic use of ASOs for this muscular disease remains challenging due to poor drug distribution to skeletal muscle. To overcome this limitation, we test an arginine-rich Pip6a cell-penetrating peptide and show that Pip6a-conjugated PMO dramatically enhanced ASO delivery into striated muscles of DM1 mice following systemic administration in comparison to unconjugated PMO and other ASO strategies. Thus, low dose treatment of Pip6a-PMO-CAG targeting pathologic expansions is sufficient to reverse both splicing defects and myotonia in DM1 mice and normalizes the overall disease-transcriptome.

2019-07-27 | GSE134926 | GEO

Expression analysis of mice hepatic NMuLi cells treated LNA gapmer ASO containing nucleobase modification

Project description:Antisense oligonucleotide (ASO) has the potential to induce hybridization-dependent effects by inadvertent binding of ASOs to RNA with sequences similar to that of the target RNA. In the present study, we examined the effects of the nucleobase derivatives introduced into the gapmer ASOs on gene expression. We performed microarray analysis using NMuLi cells (mouse liver-derived cells) treated with LNA gapmer ASO containing nucleobase modification.

2022-07-12 | GSE197166 | GEO

Profiling the interactome of oligonucleotide drugs by proximity biotinylation

Project description:Drug-ID applies proximity biotinylation to identify drug-protein interactions inside living cells. The covalent conjugation of a drug molecule with a biotin ligase enables targeted biotinylation of the drug-bound proteome and its identification by SILAC-MS/MS. We investigate the interactome of two well-known small molecule drugs, JQ1 and SAHA, and applied it for the identification of the interactome of RNaseH-recruiting antisense oligonucleotides (ASO). Drug-ID allows to de novo profile the drug-protein interactome under native conditions, directly inside living cells and at the pharmacologically effective concentration of the drug using minimal amount of input material. We apply the technology to study the dose-dependent aggregation of ASOs and the effect of different wing chemistries (LNA, Fluoro, MOE) and ASO lengths on the ASO-protein interactome. Finally, we demonstrate the detection of stress-induced interactome changes (Actinomycin D treatment) in living cells. Particularly broadly applicable in the field of oligonucleotide therapeutics is the in situ variant of the approach, which uses a recombinant biotin ligase and does not require genetic manipulation of the target cell.

2024-01-09 | PXD045992 | Pride

Expression analysis of Huh-7 cells treated with LNA gapmer targeting glucocorticoid receptor (GR) RNA

Project description:Antisense oligonucleotide (ASO) has the potential to induce off-target effects due by inadvertent binding of ASOs to unintended RNAs that have a sequence similar to the target RNA. In the present study, we focused on the effects of oligonucleotide extension of gapmer ASOs on off-target effects. We performed microarray analysis using Huh-7 cells (human liver-derived cells) treated with a 14-mer LNA gapmer ASO and the extended 18-mer derivatives with the same core 14-mer region.

2021-12-15 | GSE188684 | GEO

An inhaled therapeutic targeting a conserved RNA structure in SARS-CoV-2

Project description:The Covid-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and which may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the Covid-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identified an LNA ASO binding to the 5’ leader sequence of SARS-CoV-2 ORF1a/b and which disrupts a highly conserved stem-loop structure, with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the K18-hACE2 humanized Covid-19 mouse model potently (98-99%) suppressed viral replication in the lungs of infected mice, revealing strong prophylactic and treatment effects. We found that the LNA ASO is highly efficacious in countering all SARS-CoV-2 variants of concern (VOC) tested in vitro and in vivo, including B.1.427 (CA), B.1.1.7 (UK), and B.1.351 (SA) variants. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences. Hence, virus-targeting LNA ASOs represent a promising therapeutic approach to reduce the transmission of SARS-CoV-2, especially in areas where vaccine distribution is a challenge, and it may be stockpiled for future coronavirus pandemics.

2022-06-30 | GSE174382 | GEO

IER3-AS1 interacting proteins by AP-MS

Project description:Characterisation IER3-AS1 interacting proteins using chromatin oligo-affinity precipitation (ChOP) followed by mass spectrometry. The HeLa cell lysates was incubated with biotinylated antisense oligonucleotides (ASO), targeting an experimental target antisense long noncoding RNA IER3-AS1 or a control RNA LacZ. LacZ and IER3-AS1 interacting proteomes were pulldown using Streptavidin beads. The eluted protein samples from both LacZ control ASOs and IER3-AS1 ASOs subjected to mass-spectrometry analyses to identify IER3-AS1 interacting proteins.

2022-10-15 | PXD035704 | Pride

HIPSTR lncRNA knockdown in H1BP cells

Project description:HIPSTR is a conserved lncRNA that is transcribed antisense to TFAP2A gene. Unlike previously reported antisense lncRNAs, HIPSTR expression does not correlate with the expression of its antisense counterpart. HIPSTR depletion in HEK293 and H1BP cells predominantly affects genes involved in early organismal development and cell differentiation. H1BP cells were transfected with antisense oligonucleotides (ASOs) targeting HIPSTR (ASO #0, ASO #1 or ASO #2) or control scrambled ASO (ASO CTL); transfections with each targeting ASO were done in duplicate, transfections with control ASO were done in triplicate.

2016-09-08 | E-GEOD-77936 | biostudies-arrayexpress

HIPSTR lncRNA knockdown in HEK293 cells

Project description:HIPSTR is a conserved lncRNA that is transcribed antisense to TFAP2A gene. Unlike previously reported antisense lncRNAs, HIPSTR expression does not correlate with the expression of its antisense counterpart. HIPSTR depletion in HEK293 and H1BP cells predominantly affects genes involved in early organismal development and cell differentiation. HEK293 cells were transfected with antisense oligonucleotides (ASOs) targeting HIPSTR (ASO #1 or ASO #2) or control scrambled ASO (ASO CTL); transfection with each ASO was done in triplicate.

2016-09-08 | E-GEOD-77935 | biostudies-arrayexpress

Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies III

Project description:Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF. Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

2022-08-07 | GSE209747 | GEO

Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies I

2022-08-04 | GSE204930 | GEO

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