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Peer-reviewedCC BY 4.0Chemistry (Weinheim an Der Bergstrasse, Germany)

Rapid Access to Photoswitchable RNA Binders: Fluorination Enhances Protein Rescue by Exon Inclusion

  • Lei Zhang1
  • Nemanja Djokovic2
  • Alexander Herr3
  • Anna Wacker3,4
  • Emily Swanson Hay5
  • Daniel Santana5
  • Amanda E. Hargrove5
  • Harald Schwalbe3
  • Katarina Nikolic2
  • Frank Abendroth1
  • Olalla Vázquez1,6
6 affiliations
  1. 1Chemistry Department Marburg University Marburg Germany
  2. 2Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Belgrade Belgrade Serbia
  3. 3Institute For Organic Chemistry and Chemical Biology Center for Biomolecular Magnetic Resonance (BMRZ) Goethe University Frankfurt Frankfurt Germany
  4. 4Max Planck Institute for Terrestrial Microbiology Marburg Germany
  5. 5Department of Chemical and Physical Science University of Toronto Toronto Ontario Canada
  6. 6Center For Synthetic Microbiology (SYNMIKRO) Marburg Germany
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Abstract

Targeting RNA is a rich, yet largely untackled opportunity for controlling biological functions, with high potential for therapeutic intervention. However, it remains inherently challenging. Beyond RNA structural diversity, functional RNA motifs are frequently context‐dependent and transient, complicating the rational design of selective small‐molecule binders. We here develop novel photoswitchable ligands to target RNA. They offer highly desirable, precise intervention by enabling light‐controlled regulation of both direct RNA interactions and downstream events. Unfortunately, access to such photoswitchable RNA molecular tools is scarce, requiring complex and lengthy synthesis routes. We present a readily adaptable platform for the straightforward synthesis of photoswitchable RNA binders capable of targeting pre‐mRNA and restoring functional survival motor neuron (SMN) protein levels by rescuing exon inclusion. Evaluation of our compounds demonstrated that both fluorination and heteroaryl groups (e.g., benzo‐ and thioxozaole) enhance binding affinity to the targeted dsRNA with in‐cellulo activity. Importantly, molecular recognition and structure–activity relationships were rationalized through a combination of computational studies and NMR spectroscopy.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026rapid,
  title = {{Rapid Access to Photoswitchable RNA Binders: Fluorination Enhances Protein Rescue by Exon Inclusion}},
  author = {Lei Zhang and Nemanja Djokovic and Alexander Herr and Anna Wacker and Emily Swanson Hay and Daniel Santana and Amanda E. Hargrove and Harald Schwalbe and Katarina Nikolic and Frank Abendroth and Olalla Vázquez},
  journal = {Chemistry (Weinheim an Der Bergstrasse, Germany)},
  year = {2026},
  month = jul,
  doi = {10.1002/chem.71371},
  url = {https://doi.org/10.1002/chem.71371},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Rapid Access to Photoswitchable RNA Binders: Fluorination Enhances Protein Rescue by Exon Inclusion
AU  - Lei Zhang
AU  - Nemanja Djokovic
AU  - Alexander Herr
AU  - Anna Wacker
AU  - Emily Swanson Hay
AU  - Daniel Santana
AU  - Amanda E. Hargrove
AU  - Harald Schwalbe
AU  - Katarina Nikolic
AU  - Frank Abendroth
AU  - Olalla Vázquez
PY  - 2026
DA  - 2026/07/12
JO  - Chemistry (Weinheim an Der Bergstrasse, Germany)
DO  - 10.1002/chem.71371
UR  - https://doi.org/10.1002/chem.71371
AB  - Targeting RNA is a rich, yet largely untackled opportunity for controlling biological functions, with high potential for therapeutic intervention. However, it remains inherently challenging. Beyond RNA structural diversity, functional RNA motifs are frequently context‐dependent and transient, complicating the rational design of selective small‐molecule binders. We here develop novel photoswitchable ligands to target RNA. They offer highly desirable, precise intervention by enabling light‐controlled regulation of both direct RNA interactions and downstream events. Unfortunately, access to such photoswitchable RNA molecular tools is scarce, requiring complex and lengthy synthesis routes. We present a readily adaptable platform for the straightforward synthesis of photoswitchable RNA binders capable of targeting pre‐mRNA and restoring functional survival motor neuron (SMN) protein levels by rescuing exon inclusion. Evaluation of our compounds demonstrated that both fluorination and heteroaryl groups (e.g., benzo‐ and thioxozaole) enhance binding affinity to the targeted dsRNA with in‐cellulo activity. Importantly, molecular recognition and structure–activity relationships were rationalized through a combination of computational studies and NMR spectroscopy.
SN  - 0947-6539
SN  - 1521-3765
ER  -