Configuration of the 5'-methyl group modulates the biophysical and biological properties of locked nucleic acid (LNA) oligonucleotides.
As part of a program aimed at exploring the structure- activity relationships of 2',4'-bridged nucleic acid (BNA) containing antisense oligonucleotides (ASOs), we report the synthesis and biophysical and biological properties of R- and S-5'-Me LNA modified oligonucleotides. We show that introduction of a methyl group in the (S) configuration at the 5'-position is compatible with the high affinity recognition of complementary nucleic acids observed with LNA. In contrast, introduction of a methyl group in the (R) configuration reversed the stabilization effect of LNA. NMR studies indicated that the R-5'-Me group changes the orientation around torsion angle γ from the +sc to the ap range at the nucleoside level, and this may in part be responsible for the poor hybridization behavior exhibited by this modification. In animal experiments, S-5'-Me-LNA modified gapmer antisense olignucleotides showed slightly reduced potency relative to the sequence matched LNA ASOs while improving the therapeutic profile.
Department of Medicinal Chemistry.
Punit P
PP
Seth
Charles R
CR
Allerson
Andrew
A
Siwkowski
Guillermo
G
Vasquez
Andres
A
Berdeja
Michael T
MT
Migawa
Hans
H
Gaus
Thazha P
TP
Prakash
Balkrishen
B
Bhat
Eric E
EE
Swayze
D001703:Biophysics; D019906:Nuclear Magnetic Resonance, Biomolecular; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009841:Oligonucleotides; C477371:locked nucleic acid