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Oligonucleotide Chemistry

Terminal Cap Modifications

Reference guide for end-blocking groups, functional/conjugation caps, delivery-oriented terminal caps, and RNA-specific caps used in research and therapeutic oligonucleotides.

Overview

“Terminal caps” are chemical groups placed at the 5′ or 3′ end of an oligonucleotide. Some are simple end blockers that prevent exonuclease digestion or chain extension; others are functional tags for detection or conjugation; and some improve delivery and PK in vivo. RNA-specific caps (e.g., Cap 1) modulate translation and innate immunity.

Stability

Block 3′/5′ exonucleases and control polymerase extension.

Function

Add biotin, dyes, thiols/azides, chelators, or lipids.

Therapeutics

Use cholesterol/GalNAc/PEG or mRNA Cap 1 for in vivo performance.

End Blockers (Stability & Nuclease Resistance)

End blockers are terminal modifications added to the 3′ or 5′ ends of DNA/RNA oligonucleotides to prevent exonuclease degradation or unwanted polymerase extension. They are widely used in antisense oligonucleotides (ASOs), siRNA, PCR/qPCR blockers, diagnostic probes, and sequencing adapters.

Hide Products & Notes

common end blockers are listed below

Product / Modification Function Applications Notes / Code
3′-CPR II Strong 3′ nuclease block ASO/siRNA stabilization Block [3′-CPR-II]
3′-Phosphate Blocks 3′ exonucleases & polymerase extension PCR blockers, antisense Block [3′-PO₄]
3′-Inverted dT Reverse-oriented thymidine General stabilization Block [Inv-dT]
3′-Inverted abasic Inverted abasic sugar Probes, antisense Block [Inv-Ab]
3′-Spacer C3 / C6 / C12 Steric end block (alkyl linkers) Blocking probes Block [C3|C6|C12]
Spacer 18 (HEG) Flexible ethylene-glycol spacer Probe designs, FISH Flex [Sp18]
3′-dT / dA / dC / dG (2′–5′ linked) Non-natural 2′–5′ terminal linkage Blocker probes 2′–5′ [3′-2′5′-dN]
2′,3′-dideoxyN (ddA/ddC/ddG/ddT) Lacks 2′ & 3′ OH (chain terminator) Sequencing, blocking Terminator [ddN]
Show Technical Notes
  • For harsh nuclease environments, combine 3′ blocking + PS backbone at termini.
  • 2′–5′-linked bases and ddN are effective at preventing extension by most polymerases.

Functional & Conjugation Caps

Terminal handles and labels for capture, imaging, coupling, or surface attachment.

Show Products & Notes
Product / Modification Function Applications Notes / Code
3′-Amino (C3/C6) Reactive primary amine; also blocks extension NHS-ester labeling; conjugation Conjugation [3′-NH₂]
3′-Biotin / 5′-Biotin-TEG Affinity capture tag Pull-downs, ELISA, qPCR Affinity [Bio-3′|Bio-5′]
5′-Amino / 5′-Amino-dT 5′ reactive amine (universal or on dT) Conjugation, immobilization Conjugation [5′-NH₂|5′-NH₂-dT]
5′-Thiol Terminal -SH for maleimide/Au coupling Protein/PEG coupling; sensors Thiol [5′-SH]
5′-Azide Click-ready azide Bio-orthogonal ligation (CuAAC/SPAAC) Click [5′-N₃]
3′-Fluorescein (FAM) Terminal fluorophore qPCR, beacons, FISH Signal [FAM-3′]
3′-PEG (C3-PEG/C7-PEG) Hydrophilic spacer; PK tuning Therapeutic constructs PK [PEG-3′]
Technical Notes
  • For dense labeling, prefer TEG/PEG spacers to reduce steric hindrance.
  • Thiol/amine at 5′ pairs well with internal spacers for multivalent conjugation.

Therapeutic Terminal Caps (Delivery & PK)

Caps optimized to enhance cellular uptake, distribution, and metabolic stability.

Show Products & Notes
Product / Modification Function Applications Notes / Code
3′-Cholesterol Lipid anchor; uptake ↑ ASO/siRNA delivery Uptake [Chol-3′]
5′-Cholesterol As above at 5′ siRNA/ASO Lipid [Chol-5′]
3′-GalNAc (triantennary) ASGPR-mediated hepatocyte targeting Liver-directed siRNA/ASO Targeting [GalNAc-3′]
3′-PEG (length-tuned) Hydrophilicity & PK tuning Stability/clearance control PK [PEG-3′]
3′-LNA / cEt nucleoside Locked terminal base for protection Gapmers, ASOs Protect [LNA-3′|cEt-3′]
Technical Notes
  • Pair terminal lipids with PS backbones and consider mixed PO/PS to tune exposure.
  • GalNAc clustering and linker geometry are critical for receptor avidity.

RNA-Specific Terminal Caps

mRNA-style caps and terminal phosphate states for translation control and innate-immunity studies, plus non-canonical NAD caps and common 3′ RNA caps.

Show Products & Notes
Product / Modification Function Applications Notes / Code
Cap 0 (m⁷GpppN) 5′–5′ m⁷G triphosphate; translation initiation mRNA research Transl. [Cap0]
Cap 1 (m⁷GpppNm) Cap 0 + 2′-O-Me at first base; innate sensing ↓ Therapeutic mRNA, vaccines Immune ↓ [Cap1]
Cap 2 (m⁷GpppNmN) Cap 1 + 2′-O-Me at second base Advanced therapeutics Immune ↓↓ [Cap2]
ARCA Anti-reverse cap analog (orientation-safe) Co-transcriptional capping Co-Tx [ARCA]
CleanCap™ Co-transcriptional Cap 1/2 reagents; high efficiency GMP IVT mRNA High eff. [CleanCap]
5′-Triphosphate (pppN) RIG-I agonist; modest protection Innate-immunity, adjuvants RIG-I ↑ [5′-ppp]
5′-Diphosphate (ppN) Decapping intermediate; immunogenic Innate sensing research Innate [5′-pp]
5′-Monophosphate (pN) Ligation-ready state Small-RNA cloning, turnover Ligation [5′-p]
5′-NAD Cap Non-canonical metabolite cap Bacterial RNA regulation; syn-bio Alt-cap [NAD-Cap]
2′,3′-Cyclic Phosphate Blocks extension; requires RtcB for ligation Degradation mapping; ligation workflows Block [2′3′-cPO₄]
3′-Phosphate Blocks polymerase; convertible to 3′-OH Controlled ligation; cloning Block [3′-PO₄]
3′-Amino Reactive handle; also terminal block Conjugation; surface coupling Conjugation [3′-NH₂]
3′-Biotin Affinity capture + block Pull-downs; selections Affinity [Bio-3′]
Technical Notes
  • Therapeutic mRNA default: Cap 1 with optimized UTRs, poly(A) tail, and dsRNA removal.
  • Convert 3′ end states (cPO₄/PO₄/-OH) as required by ligase choice (Rtcb vs. T4).

Need help selecting the right terminal cap?

We’ll recommend end-states, conjugation chemistry, and QC panels aligned to your use case.

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FAQ

Is an end blocker the same as a terminal cap?

All end blockers are terminal caps, but not all terminal caps are blockers—many are functional labels or delivery conjugates.

Which cap should I use for therapeutic mRNA?

Cap 1 is the default. Consider Cap 2 if innate sensing remains high in sensitive systems.

Does 5′-ppp RNA have a role?

Yes—use intentionally to activate RIG-I in immunology. For therapeutics, cap or convert to p to reduce immunogenicity.

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