Article: | MedLuna.com

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Jun 23

PMID 35737519

Authors

Yuquan Tong

Quentin M R Gibaut

Warren Rouse

Jessica L Childs-Disney

Blessy M Suresh

Daniel Abegg

Shruti Choudhary

Yoshihiro Akahori

Alexander Adibekian

Walter N Moss

Matthew D Disney

Affiliations

Soon will be listed here.

Abstract

The interactions between cellular RNAs in MDA-MB-231 triple negative breast cancer cells and a panel of small molecules appended with a diazirine cross-linking moiety and an alkyne tag were probed transcriptome-wide in live cells. The alkyne tag allows for facile pull-down of cellular RNAs bound by each small molecule, and the enrichment of each RNA target defines the compound's molecular footprint. Among the 34 chemically diverse small molecules studied, six bound and enriched cellular RNAs. The most highly enriched interaction occurs between the novel RNA-binding compound F1 and a structured region in the 5' untranslated region of quiescin sulfhydryl oxidase 1 isoform a (), not present in isoform b. Additional studies show that F1 specifically bound RNA over DNA and protein; that is, we studied the entire DNA, RNA, and protein interactome. This interaction was used to design a ribonuclease targeting chimera (RIBOTAC) to locally recruit Ribonuclease L to degrade mRNA in an isoform-specific manner, as , but not , mRNA and protein levels were reduced. The RIBOTAC alleviated -mediated phenotypes in cancer cells. This approach can be broadly applied to discover ligands that bind RNA in cells, which could be bioactive themselves or augmented with functionality such as targeted degradation.

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