title: MicroRNA-specific argonaute 2 protein inhibitors.
abstract: As microRNA silencing processes are mediated by the protein Argonaute 2 and for target RNA binding only a short sequence at the microRNA's 5' end (seed region) is crucial, we report a novel inhibitor class: the microRNA-specific Argonaute 2 protein inhibitors that not only block this short recognition sequence but also bind to the protein's active site. We developed a model for rational drug design, enabling the identification of Argonaute 2 active site binders and their linkage with a peptide nucleic acid sequence (PNA), which addresses the microRNA of interest. The designed inhibitors targeting microRNA-122, a hepatitis C virus drug target, had an IC50 of 100 nM, 10-fold more active than the simple PNA sequence (IC50 of 1 μM), giving evidence that the strategy has potential. Due to their lower molecular weight, these inhibitors may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use.
authors.affiliation: University Chemical Laboratory, University of Cambridge , Lensfield Road, CB2 1EW Cambridge, United Kingdom.
authors.forename: Marco F
authors.initials: MF
authors.lastname: Schmidt
authors.forename: Oliver
authors.initials: O
authors.lastname: Korb
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
mesh_terms: D060565:Argonaute Proteins / Q000037:antagonists & inhibitors*; D001483:Base Sequence; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D020135:Peptide Nucleic Acids / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs; D020135:Peptide Nucleic Acids