Tetracyclines as Inhibitors of Pre-microRNA Maturation: A Disconnection between RNA Binding and Inhibition.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
09 May 2019
09 May 2019
Historique:
received:
06
03
2019
accepted:
22
04
2019
entrez:
18
5
2019
pubmed:
18
5
2019
medline:
18
5
2019
Statut:
epublish
Résumé
In a high-throughput screening campaign, we recently discovered the rRNA-binding tetracyclines, methacycline and meclocycline, as inhibitors of Dicer-mediated processing of microRNAs. Herein, we describe our biophysical and biochemical characterization of these compounds. Interestingly, although direct, albeit weak, binding to the pre-microRNA hairpins was observed, the inhibitory activity of these compounds was not due to RNA binding. Through additional biochemical and chemical studies, we revealed that metal chelation likely plays a principle role in their mechanism of inhibition. By exploring the activity of other known RNA-binding scaffolds, we identified additional disconnections between direct RNA interaction and inhibition of Dicer processing. Thus, the results presented within provide a valuable case study in the complexities of targeting RNA with small molecules, particularly with weak binding and potentially promiscuous scaffolds.
Identifiants
pubmed: 31098005
doi: 10.1021/acsmedchemlett.9b00091
pmc: PMC6512005
doi:
Types de publication
Journal Article
Langues
eng
Pagination
816-821Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM118329
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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