TY - JOUR
T1 - Programming inactive RNA-binding small molecules into bioactive degraders
AU - Tong, Yuquan
AU - Lee, Yeongju
AU - Liu, Xiaohui
AU - Childs-Disney, Jessica L.
AU - Suresh, Blessy M.
AU - Benhamou, Raphael I.
AU - Yang, Chunying
AU - Li, Weimin
AU - Costales, Matthew G.
AU - Haniff, Hafeez S.
AU - Sievers, Sonja
AU - Abegg, Daniel
AU - Wegner, Tristan
AU - Paulisch, Tiffany O.
AU - Lekah, Elizabeth
AU - Grefe, Maison
AU - Crynen, Gogce
AU - Van Meter, Montina
AU - Wang, Tenghui
AU - Gibaut, Quentin M.R.
AU - Cleveland, John L.
AU - Adibekian, Alexander
AU - Glorius, Frank
AU - Waldmann, Herbert
AU - Disney, Matthew D.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160222236&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06091-8
DO - 10.1038/s41586-023-06091-8
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C2 - 37225982
AN - SCOPUS:85160222236
SN - 0028-0836
VL - 618
SP - 169
EP - 179
JO - Nature
JF - Nature
IS - 7963
ER -