Small molecule-RNA targeting: starting with the fundamentals.

Chemical Communications : Chem Comm
Amanda E Hargrove

Abstract

The structural and regulatory elements in therapeutically relevant RNAs offer many opportunities for targeting by small molecules, yet fundamental understanding of what drives selectivity in small molecule:RNA recognition has been a recurrent challenge. In particular, RNAs tend to be more dynamic and offer less chemical functionality than proteins, and biologically active ligands must compete with the highly abundant and highly structured RNA of the ribosome. Indeed, the only small molecule drug targeting RNA other than the ribosome was just approved in August 2020, and our recent survey of the literature revealed fewer than 150 reported chemical probes that target non-ribosomal RNA in biological systems. This Feature outlines our efforts to improve small molecule targeting strategies and gain fundamental insights into small molecule:RNA recognition by analyzing patterns in both RNA-biased small molecule chemical space and RNA topological space privileged for differentiation. First, we synthesized libraries based on RNA binding scaffolds that allowed us to reveal general principles in small molecule:recognition and to ask precise chemical questions about drivers of affinity and selectivity. Elaboration of these scaffolds has le...Continue Reading

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Citations

May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zhichao TangJingxin Wang
May 15, 2021·Wiley Interdisciplinary Reviews. RNA·Nils Schmerer, Leon N Schulte
Jun 9, 2021·ChemMedChem·Kasper P LundquistMads H Clausen
Jul 21, 2021·Nucleic Acids Research·Zhichao TangJingxin Wang
Oct 8, 2021·Nature Communications·Sumirtha BalaratnamJohn S Schneekloth

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Methods Mentioned

BETA
antisense oligonucleotides
NMR
X-ray
FRET
pull-down
PCA

Software Mentioned

PRSSM
PRRSM

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