Insights from crystal structures into the opposite effects on RNA affinity caused by the S- and R-6'-methyl backbone modifications of 3'-fluoro hexitol nucleic acid.
Locked nucleic acid (LNA) analogues with 2',4'-bridged sugars show promise in antisense applications. S-5'-Me-LNA has high RNA affinity, and modified oligonucleotides show weakened immune stimulation in vivo. Conversely, an R-5'-methyl group dramatically lowers RNA affinity. To test the effects of S- and R-6'-methyl groups on 3'-fluoro hexitol nucleic acid (FHNA) stability, we synthesized S- and R-6'-Me-FHNA thymidine and incorporated them into oligo-2'-deoxynucleotides. As with LNA, S-6'-Me is stabilizing whereas R-6'-Me is destabilizing. Crystal structures of 6'-Me-FHNA-modified DNAs explain the divergent consequences for stability and suggest convergent origins of these effects by S- and R-6'-Me (FHNA) [-5'-Me (LNA and RNA)] substituents.
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.
Pradeep S
PS
Pallan
Jinghua
J
Yu
Charles R
CR
Allerson
Eric E
EE
Swayze
Punit
P
Seth
Martin
M
Egli
D018360:Crystallography, X-Ray; D006598:Hexosediphosphates / Q000737:chemistry; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D012313:RNA / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000737:chemistry*; D013816:Thermodynamics
D006598:Hexosediphosphates; D009692:Nucleic Acid Heteroduplexes; D016376:Oligonucleotides, Antisense; D013402:Sugar Alcohols; C543192:hexitol; D012313:RNA