Programmable translational inhibition by a molecular glue-oligonucleotide conjugate
preprint
OA: closed
Abstract
Selective inhibition of mRNA translation is a promising strategy for modulating the activity of disease-associated genes, yet achieving both high potency and specificity remains challenging. Rocaglamide A (RocA), a molecular glue, inhibits translation by clamping eIF4A onto polypurine motifs found in many transcripts, thereby limiting RocA’s specificity. Here, we developed RocASO, a chemical conjugate that links RocA to an antisense oligonucleotide (ASO) capable of base-pairing with defined mRNA sequences, thus directing RocA’s clamping mechanism to chosen targets and enhancing overall potency and specificity. We show that RocASOs are compatible with various types of ASO modalities, including gapmers that induce the degradation of target RNAs. RocASOs were designed to effectively knock down endogenous genes ( PTGES3 , HSPA1B ) and SARS-CoV-2 viral RNA, the latter conferring potent antiviral activity in cells. These findings establish RocASO as a versatile platform for programmable translational inhibition with therapeutic potential.
Full text
2,110 characters
· extracted from
oa-doi-fallback
· click to expand
Abstract
Selective inhibition of mRNA translation is a promising strategy for modulating the activity of disease-associated genes, yet achieving both high potency and specificity remains challenging. Rocaglamide A (RocA), a molecular glue, inhibits translation by clamping eIF4A onto polypurine motifs found in many transcripts, thereby limiting RocA’s specificity. Here, we developed RocASO, a chemical conjugate that links RocA to an antisense oligonucleotide (ASO) capable of base-pairing with defined mRNA sequences, thus directing RocA’s clamping mechanism to chosen targets and enhancing overall potency and specificity. We show that RocASOs are compatible with various types of ASO modalities, including gapmers that induce the degradation of target RNAs. RocASOs were designed to effectively knock down endogenous genes (PTGES3, HSPA1B) and SARS-CoV-2 viral RNA, the latter conferring potent antiviral activity in cells. These findings establish RocASO as a versatile platform for programmable translational inhibition with therapeutic potential.
Competing Interest Statement
K.M.S., S.W., and K.L., are inventors on patents related to RocASO molecules reported here. Kin of K.L. hold stock in and are employed by Pharmaron. K.M.S. has consulting agreements for the following companies, which involve monetary and/or stock compensation: AperTOR, BridGene Biosciences, Erasca, Exai, G Protein Therapeutics, Genentech, Initial Therapeutics, Kumquat Biosciences, Kura Oncology, Lyterian, Merck, Montara Therapeutics, Nested, Nextech, Revolution Medicines, Pfizer, Rezo, Totus, Type6 Therapeutics, Vevo, Wellspring Biosciences (Araxes Pharma). M.O. is a cofounder of DirectBio and on the SAB for Invisishield. The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. Nevan Krogan has a financially compensated consulting agreement with Maze Therapeutics. Nevan is the President and is on the Board of Directors of Rezo Therapeutics, and he is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and GEn1E Lifesciences.
Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.
My notes (saved in your browser only)
Ask this paper
Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works
Citation neighborhood (no data yet)
We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2025) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.
Source provenance
- europepmc
- last seen: 2026-05-20T01:45:00.602351+00:00