title: Antagonists of the miRNA-Argonaute 2 Protein Complex: Anti-miR-AGOs.
abstract: microRNAs (miRNAs) have been identified as high-value drug targets. A widely applied strategy in miRNA inhibition is the use of antisense agents. However, it has been shown that oligonucleotides are poorly cell permeable because of their complex chemical structure and due to their negatively charged backbone. Consequently, the general application of oligonucleotides in therapy is limited. Since miRNAs' functions are executed exclusively by the Argonaute 2 protein, we therefore describe a protocol for the design of a novel miRNA inhibitor class: antagonists of the miRNA-Argonaute 2 protein complex, so-called anti-miR-AGOs, that not only block the crucial binding site of the target miRNA but also bind to the protein's active site. Due to their lower molecular weight and, thus, more drug-like chemical structure, the novel inhibitor class may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use.
authors.affiliation: BEROCEUTICA GmbH, c/o Universität Potsdam, August-Bebel-Strasse 89, 14482, Potsdam, Germany. marco.schmidt@beroceutica.com.
authors.forename: Marco F
authors.initials: MF
authors.lastname: Schmidt
authors.affiliation: Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, CB2 1EZ, Cambridge, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Korb
authors.affiliation: University Chemical Laboratory, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
mesh_terms: D000070416:Antagomirs / Q000737:chemistry / Q000627:therapeutic use; D060565:Argonaute Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D001665:Binding Sites; D006801:Humans; D046911:Macromolecular Substances / Q000037:antagonists & inhibitors / Q000737:chemistry; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008967:Molecular Biology / Q000379:methods*; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000627:therapeutic use; D011485:Protein Binding; D012333:RNA, Messenger / Q000037:antagonists & inhibitors
chemical_list: C466422:AGO2 protein, human; D000070416:Antagomirs; D060565:Argonaute Proteins; D046911:Macromolecular Substances; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger
keywords: Drug design; miRNA inhibitors; miRNA seed region; miRNA-Argonaute 2 protein complex; microRNA