263: Bifacial γPNA triplets target rCUG repeats and displace MBNL1 in Myotonic Dystrophy type 1

Perera J et al., Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2507065123 - Gamma-PNA triplet ligands with Janus bases selectively bind expanded rCUG repeats, displace MBNL1, and show length-dependent cooperativity with partial splicing rescue. Key terms: rCUG repeats, gamma PNA, Janus bases, MBNL1 displacement, myotonic dystrophy type 1. Study Highlights:The authors designed compact three-unit bifacial nucleic acid ligands (Janus bases on a γPNA backbone) and evaluated them against rCUG repeat duplexes and DM1 patient-derived myotubes using molecular dynamics, EMSA, SPR, AFM, and cellular splicing assays. MD and EMSA/SPR show cooperative, length-dependent binding with Kd values decreasing to ~0.56 µM for rCUG98 and Hill coefficients rising to ~5, driven by enhanced hydrogen-bonding and π–π stacking between adjacent ligands. AFM revealed a 0.348 nm increase in RNA helix contour height on binding, consistent with a pothole-filling insertion mechanism that selectively recognizes hairpin duplexes over single-stranded RNA. Functionally, a cell-permeable LG2c analog reduced nuclear foci and partially restored mis-splicing of Serca1, cTNT, and IR in DM1 myotubes, though cellular uptake remains limiting. Conclusion:Short bifacial γPNA triplet ligands selectively recognize pathogenic rCUG hairpins via a pothole-filling mechanism, displace MBNL1, and can partially restore splicing in DM1 myotubes while cellular delivery requires further optimization. Music:Enjoy the music based on this article at the end of the episode. Article title:A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1 First author:Perera J Journal:Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2507065123 DOI:10.1073/pnas.2507065123 Reference:Perera J. D. R., Thadke S. A., Thrikawala S. W., Wilson W. D., Tan K. W. R., Chand N. Z. W., Phan A. T., Ly D. H., et al. A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2507065123. https://doi.org/10.1073/pnas.2507065123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/pothole-filling-rcug-gamma-pna QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing (a) design of bifacial Janus bases on a gammaPNA backbone, (b) pothole-filling mechanism and cooperative binding to rCUG repeats, (c) selectivity for long pathogenic repeats vs. short normal repeats, (d) displacement of MBNL1, (e) splicing rescue in DM1 patient-derived myotube- transcript topics: Janus bases and gammaPNA backbone design; Pothole-filling mechanism and RNA hairpin targeting; Cooperativity and length-dependent binding to rCUG repeats; Pathogenic vs normal repeat selectivity (rCUG98 vs rCUG33); MBNL1 displacement by LG2b; LG2c: cell uptake and rescue of splicing in DM1 myotubes QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi<...