Programming inactive RNA-binding small molecules into bioactive degraders

Yuquan Tong, Yeongju Lee, Xiaohui Liu, Jessica L. Childs-Disney, Blessy M. Suresh, Raphael I. Benhamou, Chunying Yang, Weimin Li, Matthew G. Costales, Hafeez S. Haniff, Sonja Sievers, Daniel Abegg, Tristan Wegner, Tiffany O. Paulisch, Elizabeth Lekah, Maison Grefe, Gogce Crynen, Montina Meter, Tenghui Wang, Quentin M. R. Gibaut, John L. Cleveland, Alexander Adibekian, Frank Glorius (), Herbert Waldmann () and Matthew D. Disney ()
Additional contact information
Yuquan Tong: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Yeongju Lee: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Xiaohui Liu: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Jessica L. Childs-Disney: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Blessy M. Suresh: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Raphael I. Benhamou: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Chunying Yang: Moffitt Cancer Center & Research Institute
Weimin Li: Moffitt Cancer Center & Research Institute
Matthew G. Costales: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Hafeez S. Haniff: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Sonja Sievers: Max Planck Institute of Molecular Physiology
Daniel Abegg: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Tristan Wegner: University of Münster
Tiffany O. Paulisch: University of Münster
Elizabeth Lekah: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Maison Grefe: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Gogce Crynen: The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Montina Meter: The Scripps Research Institute and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Tenghui Wang: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Quentin M. R. Gibaut: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
John L. Cleveland: Moffitt Cancer Center & Research Institute
Alexander Adibekian: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
Frank Glorius: University of Münster
Herbert Waldmann: Max Planck Institute of Molecular Physiology
Matthew D. Disney: The Scripps Research Institute & The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology

Nature, 2023, vol. 618, issue 7963, 169-179

Abstract: Abstract Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

Date: 2023
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DOI: 10.1038/s41586-023-06091-8

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