Unknown

Dataset Information

0

Sequence-based design of bioactive small molecules that target precursor microRNAs.


ABSTRACT: Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.

SUBMITTER: Velagapudi SP 

PROVIDER: S-EPMC3962094 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Sequence-based design of bioactive small molecules that target precursor microRNAs.

Velagapudi Sai Pradeep SP   Gallo Steven M SM   Disney Matthew D MD  

Nature chemical biology 20140209 4


Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogene  ...[more]

Similar Datasets

| S-EPMC5838524 | biostudies-literature
| S-EPMC4086140 | biostudies-literature
| S-EPMC4912454 | biostudies-literature
| S-EPMC5650530 | biostudies-literature
| S-EPMC6676798 | biostudies-literature
2017-09-26 | PXD007570 | Pride
2015-11-02 | E-MTAB-2948 | biostudies-arrayexpress
| S-EPMC2901564 | biostudies-literature
| S-EPMC10418101 | biostudies-literature
| S-EPMC7200645 | biostudies-literature