Authors
Lei Zhang, Nemanja Djokovic, Alexander Herr, Anna Wacker, Emily Swanson Hay, Daniel Santana, Amanda E Hargrove, Harald Schwalbe, Katarina Nikolic, Frank Abendroth, Olalla Vázquez
Published in
Chemistry (Weinheim an der Bergstrasse, Germany). Pages e71371. Jul 12, 2026. Epub Jul 12, 2026.
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.
PMID:
42437438
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.
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