Brunschweiger, Andreas, Gebert, Luca F. R., Lucic, Matije, Pradère, Ugo, Jahns, Hartmut, Hunziker, Juerg and Hall, Jonathan (2016) Site-specific conjugation of drug-like fragments to anti-miRNA oligonucleotides: pros and cons of targeting miRNAs in RISC. Angewandte Chemie International Edition, 52 (1). pp. 156-159. ISSN 1359-73451364-548X

Abstract

MicroRNAs (miRNAs) inhibit gene expression by binding mRNAs in a ribonucleoprotein (RNP) complex, miRISC. Some miRNAs, e.g. miR-122, are targets for oligonucleotide drugs (antimirs) in clinical trials. State of the art in antimir chemistry is the tightly RNA-binding bicyclic nucleic acids derivatives, but as they are not freely available researchers have sought new chemistries. Recently, the field was transformed by work confirming that antimirs inhibit miRNAs in the miRISC. We describe here a parallel synthesis of a miR-122 antimir library in which drug-like fragments were site-specifically introduced to a short 2’-O-methyl-RNA. This affected its silencing activity in cells in a position- and modification-dependent manner. We developed an assay – RNP chemical ligation PCR - and quantified the antimir presence in miRISC and showed it correlated with potency. Together, this approach represents a template for future design of a new class of short minimally-modified antimirs.

Item Type:	Article
Keywords:	medicinal chemistry · microRNA · antimir · click chemistry · fragment
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26062