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.
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.
Prakash
Thazha P
TP
Department of Medicinal Chemistry, Isis Pharmaceuticals, 2292 Faraday Ave, Carlsbad, CA 92008, USA.
Manoharan
Muthiah
M
Kawasaki
Andrew M
AM
Fraser
Allister S
AS
Lesnik
Elena A
EA
Sioufi
Namir
N
Leeds
Janet M
JM
Teplova
Marianna
M
Egli
Martin
M
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*
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