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Sugar-Modified RNA & DNA Oligonucleotides

Custom sugar-modified RNA and DNA oligonucleotides — including 2′-OMe, 2′-F, MOE, LNA/BNA, cEt, UNA, FANA, and 4′-Thio — engineered for enhanced stability, nuclease resistance, binding affinity, and therapeutic research performance.

2′-OMe 2′-F MOE LNA / BNA / cEt UNA / FANA / XNA ISO 9001:2015 ISO 13485:2016

Sugar Modifications for Stability, Affinity & Nuclease Resistance

Bio-Synthesis provides a complete portfolio of sugar-modified nucleotides for custom DNA and RNA oligonucleotide synthesis. By tailoring the ribose/deoxyribose scaffold with chemistries such as 2′-O-methyl, 2′-fluoro, MOE, LNA/BNA, cEt, UNA, FANA, 4′-Thio, and stereochemical variants, researchers can fine-tune hybridization, nuclease resistance, pharmacokinetics, and protein interactions.

2′-substitutions improve nuclease resistance and pharmacokinetics; locked and bridged sugars boost binding affinity and potency; and flexible analogs introduce conformational freedom for structural biology and probe design. These edits can be combined with PS backbones, conjugates, or terminal caps to balance activity, safety, and durability.

STAB

Stability ↑

Improve resistance to nucleases and extend functional lifetime in biological environments.

TM

Affinity & TmControl

Increase or tune duplex melting temperature for ASO, siRNA, qPCR, and probe applications.

PK

PK/PD Tunable

Use sugar chemistry, backbone design, and conjugates to tune pharmacology and durability.

ASO

RNase H Strategy Aware

Design gapmers and steric-blocking oligos with modification placement matched to mechanism.

2′-Deoxy Sugar-Modified Oligonucleotide Variants

Deoxy and stereochemical variants such as 2′-F-dN, ara-dN, and 2′-amino modifications modulate duplex geometry and nuclease sensitivity; dI supports wobble or degenerate pairing.

Product / Modification Function Applications Code
2′-Deoxy-2′-Fluoro-dA/C/G/U Thermal & enzymatic stability ↑. Antisense/probes; hybrid studies. [2′F-dN]
2′-Deoxy-arabinonucleic acids (ara-dN) Alternative stereochemistry. Cross-linking/antisense research. [ara-dN]
2′-Deoxy-2′-Amino RNA Duplex stability ↑. Stability-tuned constructs. [2′NH₂-RNA]
2′-Deoxy-Inosine (dI) Universal/wobble base. Degenerate primers; probes. [dI]
L-DNA base Mirror chirality; nuclease-insensitive. Spiegelmer/chirality studies. [L-DNA]
Technical notes: 2′-F-dN raises Tm in hybrids and resists nucleases; mixing with RNA affects geometry. dI lowers specificity, so placement should be strategic for variant coverage.

Bridged & Locked Sugar-Modified Nucleic Acids

Constrained sugar rings such as LNA/BNA and related bridged systems constrain the ribose structure, delivering large per-residue Tm gains and potent binding — ideal for short probes and ASO wings.

Product / Modification Function Applications Code
LNA (Locked Nucleic Acid) Affinity & Tm ↑↑. ASO/siRNA wings; diagnostics. [LNA]
BNA (Bridged Nucleic Acid) LNA-like; high specificity. Antisense; miRNA work. [BNA]
cEt (Locked Ribose Nucleic Acid) LNA-like; high specificity. ASO gapmer wings, splice-modulation steric blockers, and short probes. [cEt]
ENA (Bridged Nucleic Acid) Excellent stabilization; blend with 2′-OMe/MOE to tune specificity and toxicity. Antisense; high-affinity probes. [ENA]
α-L-LNA (alpha-L) Enantiomeric LNA; selectivity. High-stringency probes. [α-L-LNA]
β-L-DNA Chiral DNA variant. Biophysical/diagnostic probes. [β-L-DNA]
Technical notes for locked and bridged sugars
  • Affinity & Tm: LNA/BNA can yield large per-base Tm increases; use sparingly to reduce off-target effects.
  • Placement: For gapmers, use 3–5 LNA/cEt residues per wing around an 8–10 nt DNA gap; avoid locked bases inside the RNase-H core.
  • Steric-block designs: Fully modified LNA/MOE backbones are compatible and highly stable.
  • Chirality variants: α-L-LNA and β-L-DNA can offer unique specificity and reduce protein binding.
  • Backbone context: Use PS backbones for serum stability; mix PS/PO to tune clearance.
  • Toxicity: Dense LNA runs may increase hepatotoxicity; blend with 2′-OMe/2′-F/MOE to mitigate.
  • Synthesis & QC: LNA/cEt amidites may need longer coupling; verify Tm empirically.

Flexible & Acyclic Sugar-Modified Nucleic Acid Analogs

UNA, GNA, HNA, CeNA, and TNA frameworks tune backbone flexibility and helix geometry, supporting structure probing, specificity control, synthetic biology, and XNA research.

Product / Modification Function Applications Code
Unlocked Nucleic Acids (UNA) Flexible analog; lowers duplex melting temperature (Tm). Structure probing; specificity tuning; reduce aggregation. [UNA]
Glycol Nucleic Acid (GNA) Acyclic sugar mimic; high duplex specificity. Synthetic biology (XNA); structural studies; biosensors. [GNA]
Threose Nucleic Acid (TNA) Four-carbon threose sugar; unique backbone repeat; nuclease-resistant. Synthetic biology, enzyme engineering, stable aptamer and diagnostic probe design. [TNA]
Hexitol Nucleic Acid (HNA) Non-natural hexitol sugar; nuclease-resistant. Aptamer selection (SELEX); stable probes; diagnostics. [HNA]
Cyclohexene Nucleic Acid (CeNA) Rigid cyclohexene sugar; alters helical geometry. Antisense research; structure–function studies. [CeNA]
Technical notes for flexible and acyclic analogs
  • Affinity & Tm: UNA typically lowers Tm; GNA/HNA/CeNA/TNA are context-dependent and should be verified with test duplexes.
  • Pairing rules: Many XNAs pair best with themselves; cross-pairing with DNA/RNA varies. Limit consecutive flexible residues.
  • Placement: Keep flexible analogs out of RNase-H gaps; use them in wings or internal probe positions.
  • Backbone: Use PS for serum stability. If Tm drops, compensate with length or sparse LNA/cEt at termini.
  • Synthesis: Some XNA amidites require longer coupling or alternative activators; pilot synthesis is recommended.
  • QC: Confirm identity by ESI-MS/MALDI with analytical HPLC/CE.
  • Serum stability: Run 10–100% serum panels when evaluating flexible/acyclic sugars.

Strategy & Architecture for Sugar-Modified Oligos

Architecture Guidance

  • Gapmer ASO: LNA/cEt/MOE wings + DNA core on PS backbone; evaluate 8–10 bp DNA gap for RNase H.
  • Steric-block: Fully 2′-modified designs such as 2′-OMe/2′-F mix or LNA on PS/PN for splice modulation.
  • siRNA duplex: 2′-OMe/2′-F patterns balance RISC loading and off-target behavior; terminal LNA may improve stabilization.
  • mRNA/sgRNA: 2′-OMe/Ψ/5-MeC patterns can reduce innate sensing; consult application-specific design rules.

Tm & Pairing Behavior

  • LNA/BNA/cEt: Large Tm increase per residue; useful for shorter, tighter duplexes.
  • 2′-OMe/MOE: Moderate Tm increase; useful for ASO wings and siRNA stabilization.
  • 2′-F: Tm increase versus RNA; commonly blended with 2′-OMe in siRNA.
  • UNA: Lowers Tm; useful as a flexibility breaker to reduce aggregation or tune duplex strength.
  • RNase H: Requires DNA-like geometry in the gap; avoid over-modifying the core in gapmers.

Chemistry, Purification & Quality Documentation

Chemistry Support

  • Supports 2′-OMe, 2′-F, MOE, LNA/BNA, cEt, UNA, FANA, 4′-Thio, ara, and HNA on request.
  • Backbone options include PS, PO, PN in selected contexts, and boranophosphate by request.
  • Conjugations include cholesterol, GalNAc, PEG, peptides, dyes, chelators, and custom linkers.

Purification Options

  • HPLC or PAGE purification as needed.
  • Desalting and diafiltration workflows available.
  • Additional purification planning available for conjugates or difficult sequences.

QC & Documentation

  • Identity by ESI-MS or alternatives for highly modified/degenerate sequences.
  • Purity by HPLC; optional SEC for conjugates.
  • Moisture, salt, and endotoxin testing available on request.
  • COA with yield, method parameters, and impurity profile.
Quality alignment: Bio-Synthesis supports ISO 9001 / ISO 13485-aligned workflows and GLP/GMP-like practices as scoped.

Frequently Asked Questions

FAQ

Can sugar modifications be combined with phosphorothioate backbones?
Yes. Sugar modifications are frequently combined with phosphorothioate backbones to improve nuclease resistance and in vivo durability. Placement and density should be optimized to balance potency, safety, and manufacturability.
Can I add conjugates such as GalNAc, cholesterol, PEG, peptides, or dyes?
Yes. Many sugar-modified oligos can be paired with delivery ligands, fluorescent labels, affinity tags, peptides, PEG, cholesterol, or GalNAc. Bio-Synthesis can advise on linker placement, purification strategy, and QC requirements.
Which sugar modifications are commonly used for siRNA?
2′-OMe and 2′-F are commonly used in siRNA designs to improve stability, reduce immune stimulation, and support activity. LNA or other high-affinity residues may be used selectively depending on the design goal.
How do I choose between 2′-OMe, 2′-F, MOE, LNA, and cEt?
Use 2′-OMe and 2′-F for common siRNA and RNA stabilization strategies, MOE for balanced ASO wing chemistry, and LNA or cEt when stronger affinity and Tm increase are needed. The best choice depends on target, oligo length, mechanism, and toxicity profile.
Will sugar modifications interfere with RNase H activity?
They can. Fully modified strands often block RNase H activity. Gapmer ASOs usually preserve a central DNA-like gap while using sugar-modified wings to improve stability, affinity, and nuclease resistance.
What information should I provide for a quote?
 Include the sequence, oligo type, desired sugar modifications, backbone chemistry, scale, purification requirement, conjugates or labels, QC documentation needs, and intended application.
Can’t find the sugar modification you need? Bio-Synthesis routinely sources or synthesizes specialty phosphoramidites and can align to internal codes or vendor references.

Need help designing a sugar-modified oligonucleotide?

For the fastest review, share your oligo type, sequence length, sugar modification pattern, backbone, scale, purification target, and intended application. Our scientific team can recommend the most suitable sugar-modified oligo strategy and provide a detailed quote.

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Quote Preparation Checklist

Include oligo type, sequence length, modification pattern, backbone, conjugations, purification target, QC needs, and timeline.

Oligo Type Sequence Length Sugar Mods Backbone QC Needs

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