Evidence map›Paper›PMID 40977082›Full record

ArticleAngewandte Chemie (International ed. in English)2025

Synthesis, Biological Activity, and Molecular Dynamics Simulations of LNA-Charge Neutral Linkages for Enhanced Splice-Switching Antisense Oligonucleotides.

Alice Kennett, Lillian Lie, Martin Flerin, Belma Zengin Kurt, Ysobel R Baker, Alyssa C Hill, Abinaya Ramesh, Matthew J A Wood, Debashis Dhara, Afaf H El-Sagheer and 2 more

Abstract read
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In one paragraph

Article in Angewandte Chemie (International ed. in English), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Alice Kennett *Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Lillian Lie *Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Martin FlerinDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Belma Zengin KurtDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Ysobel R BakerDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Alyssa C HillDepartment of Paediatrics, Institute of Developmental and Regenerative Medicine (IDRM), University of Oxford, Oxford, OX3 7TY, UK.
Abinaya RameshDepartment of Paediatrics, Institute of Developmental and Regenerative Medicine (IDRM), University of Oxford, Oxford, OX3 7TY, UK.
Matthew J A WoodDepartment of Paediatrics, Institute of Developmental and Regenerative Medicine (IDRM), University of Oxford, Oxford, OX3 7TY, UK.
Debashis DharaDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Afaf H El-SagheerDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.ORCID 0000-0001-8706-1292
Fernanda DuarteDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.ORCID 0000-0002-6062-8209
Tom BrownDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.ORCID 0000-0002-6538-3036

Funding

Scientific and Technological Research Council of TurkeyTUBITAK 059B192200269UK Biotechnology and Biological Sciences Research Council (BBSRC) BB/W003902/1UKUK Medical Research Council (MRC) MR/X008029/1
6 · The paper itself

Abstract

Antisense oligonucleotides are promising therapeutic agents for a range of diseases, having found special clinical success for splice-switching genetic conditions such as spinal muscular atrophy and Duchenne muscular dystrophy. However, novel chemistries are still required to discover modifications which improve their druggable properties. For in vitro studies, thermal duplex stability, resistance to enzymatic degradation and gymnotic cellular activity are important, and biodistribution, toxicology and potency must be optimised for clinical progression. We investigate the combination of locked nucleic acids (LNA) and charge neutral backbones in chimeric ASOs containing 2'-O-methyl sugars and phosphorothioate backbones by evaluating their physical and biological properties. Backbones investigated are LNA-amide, LNA-carbamate, LNA-alkoxyamide, and LNA-sulfamate. Molecular dynamics simulations of these LNA-charge neutral backbones were conducted to explore the structural features which determine the experimentally observed thermal duplex stability and conformation. The LNA-sulfamate linkage is of particular interest, forming very stable duplexes with its RNA target and having comparable gymnotic activity to the previously investigated LNA-amide, while being synthetically more accessible. Together, our studies indicate that a multi-faceted approach to expanding the ASO chemical space, using a combination of computational and experimental methods, can build structure-activity relationships and discover novel promising backbones for future therapeutic use.

Indexed as

Molecular Dynamics SimulationOligonucleotidesOligonucleotides, AntisenseHumansRNA Splicinglocked nucleic acidOligonucleotidesOligonucleotides, AntisenseAntisense oligonucleotideGymnotic activityLocked nucleic acidNeutral linkageSplice‐switching

Identifiers

PMID40977082
PMCPMC12603973

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.