9E9E

Structure of AMPA receptor GluA2 and auxiliary subunit TARP gamma-2 (LBD-TMD) in complex with anti-miR 17 oligonucleotide RGLS4326

This is a non-PDB format compatible entry.

Summary for 9E9E

• Entry DOI: 10.2210/pdb9e9e/pdb
• EMDB information: 47793
• Descriptor: Isoform Flip of Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit, O-{[(1S,3S,4R,6S,7R)-7-{[(R)-{[(1R,3R,4R,6S,7R)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-7-hydroxy-6-methyl-2,5-dioxabicyclo[2.2.1]heptan-1-yl]methoxy}(sulfanyl)phosphoryl]oxy}-3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-6-methyl-2,5-dioxabicyclo[2.2.1]heptan-1-yl]methyl} O-[(2R,3S,4R,5S)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methoxy-2-methyloxolan-3-yl] hydrogen (R)-phosphorothioate (2 entities in total)
• Functional Keywords: ampa receptor, tarp gamma-2, ion channel, anti-mir 17, oligonucleotide, signaling protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 4
• Total formula weight: 463596.41

Authors

Yen, L.Y.,Gangwar, S.P.,Yelshanskaya, M.V.,Sobolevsky, A.I. (deposition date: 2024-11-08, release date: 2026-02-11)

Primary citation

Valencia, T.,Yen, L.Y.,Berman, C.,Vincent, T.,Davis, S.,Varrone, F.,Huang, J.,Mastroianni, J.,Carlson, M.,Owen, T.,Kamel, A.,Drygin, D.,Kinberger, G.A.,Gangwar, S.P.,Yelshanskaya, M.V.,Ridley, J.,Kirby, R.,Alvarez, J.,Lakhia, R.,Patel, V.,Sobolevsky, A.I.,Lee, E.C.
The nucleobase guanine at the 3'-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity.
Nat Commun, 16:10762-10762, 2025

PubMed Abstract: Designing safe and effective oligonucleotide (ON) therapeutics requires thorough understanding of structural-activity relationship (SAR) with the intended on-target(s) as well as the unintended off-target(s). Despite encouraging pharmacodynamic activity in a Phase 1b study, development of the first-generation anti-miR-17 ON RGLS4326 for the treatment of autosomal dominant polycystic kidney disease was discontinued due to dose-limiting central nervous system (CNS)-related toxicity observed in nonclinical chronic toxicity studies. Here, we provide SAR evidence that the nucleobase guanine at the 3'-terminus of RGLS4326 drives an unexpected off-target aptamer-like direct interaction with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), thereby causing CNS toxicity. By replacing the 3'-terminal guanine with adenine, we discover the next-generation anti-miR-17 RGLS8429 that is devoid of off-target AMPAR interaction and CNS toxicity while preserving the potency against the on-target miR-17. Here, we show a way to avoid off-target CNS effects and, more importantly, data that support the clinical development of RGLS8429.

PubMed: 41315228
DOI: 10.1038/s41467-025-65799-5

Experimental method

ELECTRON MICROSCOPY (3.24 Å)