title: 2'-O-[2-(methylthio)ethyl]-modified oligonucleotide: an analogue of 2'-O-[2-(methoxy)-ethyl]-modified oligonucleotide with improved protein binding properties and high binding affinity to target RNA.
abstract: A novel 2'-modification, 2'-O-[2-(methylthio)ethyl] or 2'-O-MTE, has been incorporated into oligonucleotides and evaluated for properties relevant to antisense activity. The results were compared with the previously characterized 2'-O-[2-(methoxy)ethyl] 2'-O-MOE modification. As expected, the 2'-O-MTE modified oligonucleotides exhibited improved binding to human serum albumin compared to the 2'-O-MOE modified oligonucleotides. The 2'-O-MTE oligonucleotides maintained high binding affinity to target RNA. Nuclease digestion of 2'-O-MTE oligonucleotides showed that they have limited resistance to exonuclease degradation. We analyzed the crystal structure of a decamer DNA duplex containing the 2'-O-MTE modifcation. Analysis of the crystal structure provides insight into the improved RNA binding affinity, protein binding affinity and limited resistance of 2'-O-MTE modified oligonucleotides to exonuclease degradation.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, 2292 Faraday Ave, Carlsbad, CA 92008, USA.
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kawasaki
authors.forename: Allister S
authors.initials: AS
authors.lastname: Fraser
authors.forename: Elena A
authors.initials: EA
authors.lastname: Lesnik
authors.forename: Namir
authors.initials: N
authors.lastname: Sioufi
authors.forename: Janet M
authors.initials: JM
authors.lastname: Leeds
authors.forename: Marianna
authors.initials: M
authors.lastname: Teplova
authors.forename: Martin
authors.initials: M
authors.lastname: Egli
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry; D009705:Nucleosides / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D020319:Oligodeoxyribonucleotides, Antisense / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry; D011485:Protein Binding; D012313:RNA / Q000737:chemistry*; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: C467846:2'-O-(2-(methylthio)ethyl) RNA; C442700:2-O-(4,4'-dimethoxytrityl)ethylsulfonylethan-2'-yl-phosphate; D009692:Nucleic Acid Heteroduplexes; D009705:Nucleosides; D009838:Oligodeoxyribonucleotides; D020319:Oligodeoxyribonucleotides, Antisense; D009943:Organophosphorus Compounds; C052202:2'-O-methyluridine; D012313:RNA; D014529:Uridine