Progress toward the development of the small molecule equivalent of small interfering RNA

Matthew D. Disney*, Blessy M. Suresh, Raphael I. Benhamou, Jessica L. Childs-Disney

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

12 Scopus citations

Abstract

Given that many small molecules could bind to structured regions at sites that will not affect function, approaches that trigger degradation of RNA could provide a general way to affect biology. Indeed, targeted RNA degradation is an effective strategy to selectively and potently modulate biology. We describe several approaches to endow small molecules with the power to cleave RNAs. Central to these strategies is Inforna, which designs small molecules targeting RNA from human genome sequence. Inforna deduces the uniqueness of a druggable pocket, enables generation of hypotheses about functionality of the pocket, and defines on- and off-targets to drive compound optimization. RNA-binding compounds are then converted into cleavers that degrade the target directly or recruit an endogenous nuclease to do so. Cleaving compounds have significantly contributed to understanding and manipulating biological functions. Yet, there is much to be learned about how to affect human RNA biology with small molecules.

Original languageAmerican English
Pages (from-to)63-71
Number of pages9
JournalCurrent Opinion in Chemical Biology
Volume56
DOIs
StatePublished - Jun 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Ltd

Keywords

  • Antisense oligonucleotides
  • Non-coding RNA
  • Nucleic acids
  • RNA
  • Ribonuclease targeting chimeras (RIBOTACs)
  • Targeted degradation
  • siRNA

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