A druggable target for rescuing microRNA defects.
Bioorg Med Chem Lett
; 26(20): 4942-4946, 2016 10 15.
Article
em En
| MEDLINE
| ID: mdl-27641467
ABSTRACT
Despite immense promise, development of microRNA (miRNA) therapeutics remains limited by pharmacodynamic challenges that have hindered progress of related oligonucleotide-based technologies. Recent discovery of enzymes that mediate miRNA metabolism represent potential pharmacological targets for directing miRNA function, circumventing barriers associated with oligonucleotides. We previously identified the Translin/Trax (TN/TX) ribonuclease complex as a pre-miRNA degrading enzyme that competes with pre-miRNA processing by Dicer. Here, we establish a high-throughput TN/TX assay and screened 2320 drug and natural product compounds for inhibitors of TN/TX. Secondary analyses demonstrate small molecule mediated inhibition of pre-miRNA degradation by TN/TX and enhanced miRNA processing by Dicer. This application of traditional enzyme-inhibitor pharmacology to the miRNA pathway establishes a druggable target for rescuing global miRNA defects, providing an important complement to current approaches towards miRNA therapeutics. More broadly, demonstrating feasibility of pharmacological targeting of the 'ribonucleome' is particularly important given emerging classes of regulatory RNA and growing understanding of their importance in health and disease.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Precursores de RNA
/
MicroRNAs
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article