Modifications of nucleic acids alter their physical properties, stability, interaction potential, and biological function. Naturally modified nucleic acids regulate vital cellular processes, including gene expression, DNA repair, and protein synthesis. Artificial modifications have become essential tools in biotechnology, drug development, and therapeutic strategies, such as gene editing and RNA-based therapies, over the past few decades.
Many of these modifications occur naturally. Presently, there are 143 known modified ribonucleosides. Important examples are methylation and acetylation. The artificial introduction of nucleic acid modifications can stabilize oligonucleotides, making them more resistant to nucleases.
Understanding the effect of modifications on nucleic acid properties is essential for insights into genetic regulation, biotechnology, and therapeutic applications.
Structural Changes
Nucleic acid modifications often alter the three-dimensional structure of DNA or RNA, affecting how these molecules fold and interact.
Adding methyl groups, for example, to cytosine to generate 5-methylcytosine in DNA changes the flexibility and conformation of the DNA helix. Methylation makes DNA less accessible to transcription factors.
A phosphorothioate is a common non-natural modification in which a sulfur atom replaces a non-bridging oxygen atom in the phosphate backbone, thereby enhancing the resistance of nucleic acids against nucleases and making them useful in therapeutic oligonucleotides, such as antisense molecules.
Modified RNA bases such as pseudouridine (Ψ) can improve base-pairing stability, influence RNA secondary structures, and enhance protein interactions. Nucleic acid modifications can either enhance or reduce the stability of the modified molecules, affecting their lifespan and functionality:
Methylation of DNA, for example, in CpG islands, protects DNA from degradation. Methylation is essential in epigenetic regulation. Methylation at CpG sites prevents recognition by specific proteins, such as transcription factors, while promoting binding by others, for example, to methyl-CpG-binding proteins.
A variety of modifications are available for RNA. One example is the addition of a 2'-O-methyl group, which increases their resistance to degradation by exonucleases and stabilizes the RNA structure. Modified mRNAs, for example, those used in mRNA vaccines, often utilize pseudouridine instead of uridine to increase stability and decrease immune recognition.
Modifications Affecting Base Pairing and Hybridization
Nucleic acid modifications may influence the hydrogen bonding patterns and base-pairing properties of oligonucleotides: Methylation of bases often alters Watson-Crick hydrogen bonding, potentially interfering with base pairing and thereby affecting the fidelity of replication and transcription. In transfer RNA (tRNA), modifications such as inosine or queuosine at specific positions enhance the flexibility of base pairing, crucial for the accurate and efficient translation of the genetic code.
Modifications like BNA and LNA constrain the ribose ring via a methylene-based bridge, significantly increasing the melting temperature of DNA/RNA duplexes and improving the affinity and stability of hybridization.
Impact on Gene Expression and Regulation
Epigenetic modifications, such as DNA methylation and histone modifications, can regulate gene expression. Specifically, DNA methylation of promoter regions, particularly in CpG islands, can lead to the repression of gene transcription. DNA methylation is a significant mechanism in gene regulation and cellular differentiation. While not directly modifying DNA, histone modifications, such as acetylation or methylation, alter the accessibility of DNA by loosening or tightening the DNA-histone interaction, thereby modulating the transcriptional activity of nearby genes.
Effects on Enzymatic Processes
Enzymes involved in nucleic acid metabolism, such as polymerases, endonucleases, and ligases, can be sensitive to modifications:
DNA modifications, such as 5-methylcytosine, can interfere with the recognition and repair of DNA mismatches, thereby impacting mutation rates. Modifications in pre-mRNA or mRNA, such as the addition of a 5’-cap and poly-A tail, are necessary for proper splicing, transport, and translation. Additionally, mRNA modifications, such as N6-methyladenosine (m6A), affect splicing efficiency and translation rates, thereby influencing gene expression.
Therapeutic and Biotechnological Applications
Chemical modifications of nucleic acids enable drug development in biotechnology and therapeutic applications:
In therapeutic Antisense Oligonucleotides (ASOs) and siRNA phosphorothioate backbones or 2'-O-methyl modifications increase resistance to nuclease degradation. Modification of guide RNAs (gRNAs) can improve their stability and efficiency in directing Cas9 to specific genomic locations.
Immune Response Modulation
Nucleic acid modifications are also critical in immune system recognition:
Modified RNA, such as mRNA with pseudouridine, reduces innate immune activation, which is crucial in therapeutic applications like mRNA vaccines, as it prevents rapid degradation and reduces inflammatory responses.
Certain modifications, like CpG oligodeoxynucleotides, are known to stimulate the immune system and are being explored as adjuvants in cancer immunotherapy.
Modifications for siRNAs, ASOs, AMOs, and Gapmers
Inserting mismatches into oligonucleotides will decrease a duplex's melting temperature (Tm) and prevent hybridization or polymerization. A higher Tm value correlates with improved binding affinity, resulting in a more robust duplex. More energy is required to destabilize the connection between the two molecules. The sugar ring and the backbone are targets for most modifications. The C2′ position is the site selected for modification. The C2′ position defines the conformation of the sugar ring. Many introduced changes at this position shift the conformation of the sugar moiety from a C2′-endo (southern conformation, typical of DNA duplexes) to a C3′-endo sugar pucker (northern conformation, typical of RNA duplexes), improving the binding affinity of ASOs and AMOs for RNA complements. Also, in this conformation, the 2′-modification is closer to the 3′-phosphate group, conferring higher nuclease resistance to the oligonucleotide.
Modification at the 2′-carbon of the ribose, for example, 2′-OMe, 2′-MOE, and 2′-F, increases binding affinity in the following order of increased potency:
2′-OMe ≅ 2′-MOE < 2′-F.
Several substitutions can be combined to improve potency. For example, MOE/LNA, 2′-OMe/LNA, or 2′-F/MOE are examples of oligonucleotide mixmers with enhanced binding affinity compared to oligonucleotides containing only one type of substitution.
Figure 1: Illustration of various chemical modifications to the DNA structure. Modifications can range from simple side-specific atomic substitutions to more exotic molecular replacements (adapted from Ochoa and Milam, 2020).
Table 1: Examples of effects of chemical modifications on oligonucleotide properties (adapted from Ochoa and Milam, 2020).
| Modifications | Nuclease Resistance | Polymerase compatible | Duplex Stability | Watson-Crick Base Pairing |
| Sugar | 2’-F | Increase | Yes | Increase | Yes |
| 2’-OMe | Increase | Yes | Increase | Yes |
| 2’-NH2 | Increase | Yes | Decrease | Yes |
| BNA/LNA | Increase | Yes | Increase | Yes |
| HNA | Increase | Yes | Increase | Yes |
| Phosphodiester Linkage | Triazole-linked | Increase | No | Decrease | N/A |
| PS | Increase | Yes | Decrease | N/A |
| phNA | Increase | Yes | Decrease | N/A |
| Base | 7-deaza-dA | Increase | Yes | Decrease | No |
| Z/P | Unreported | Yes | Increase | Yes (modified) |
| Ds/Px | Unchanged | Yes | Increase | No |
| 5-isobutyl-carboxamide-dU | Unreported | Yes | Increase | no |
Table 2: ΔTm per modification
Disclaimer: The ΔTms reported are taken from the literature (see references). The exact observed ΔTm is specific to the modified oligonucleotide and should be experimentally verified for each oligonucleotide investigated.
| Modification | ΔTm / NA [ºC] | Effect |
| Sugar Modifications |
| 2′-OMe: 2′-O-methyl 
| +0.8 to 1.0 | Improves nuclease resistance, thermal stability, non-toxic. |
| 2’-MOE: 2’-O-methoxyethyl 
| +0.9 to 2.0 | Poor thermal stability. |
| 2’-MCE: 2’-O-[2-(N-methyl-carbamoyl)ethyl 
| ~-1.0 to -2.0 | An MOE-modified RNA/RNA duplex has a higher duplex stability than a 2′-O-methyl RNA/RNA duplex. An MCE-modified RNA/RNA duplex has a similar duplex stability as a 2′-O-methyl RNA/RNA duplex. |
| 2’-O-AECM: 2’-O-(N-(amino-ethyl) carbamoyl)methyl 
| -0.1 to +0.8 | High resistance to nucleases and phosphordiesterases. |
| 2′-F: 2′-fluoro-RNA 
| ~+1.6 | No resistance to exonuclease. |
| BNA: Bridged Nucleic Acid 
| +2 to +4 DNA +4 to +12 RNA | Resistance to exonuclease. |
| LNA: Locked Nucleic Acid 
| +2 to +5 DNA +4 to +8 RNA | Resistance to exonuclease. |
| UNA: Unlocked Nucleic Acid 
| -5 to -18 | ΔTm is depending on placement of the nucleic acid within the siRNA sense oligonucleotide sequence. |
| 2’-Me-UNA 
| -4 to -19 | Improved resistance to degradation by nucleases. For modifications of siRNA in seed region. Mori et al. 2025. |
| 3’-Me-UNA 
| -6 to -19 | Improved resistance to degradation by nucleases. For modifications of siRNA in seed region. Mori et al. 2025. |
| 5’-Me-UNA 
| -5 to -19 | Improved resistance to degradation by nucleases. For modifications of siRNA in seed region. Mori et al. 2025. |
| 2′-O-AP [n, 2′-O-(3-aminopropyl)] 
| ~1.0 | A high nuclease resistance. Inhibit the degradation of single-stranded DNA by the Escherichia coli Klenow fragment (KF) 3′-5′ exonuclease and snake venom phosphor-diesterase. |
| 2’-O-PRL (2′-O-propyl) 
| 0.7 to 0.8 | “ |
| 2’-O-BTL (2′-O-butyl) 
| 0.6 to 0.8 | “ |
| 2’-O-FET (2′-O-[2-(fluoro)ethyl]) 
| 1.1 to 1.4 | “ |
| 2’-O-TFE (2′-O-[2-(trifluoro)-ethyl]) 
| 0.8 to 1.2 | “ |
| 2’-O-ALY (2′-O-allyl) 
| 0.4 to 0.8 | Enables post synthetic labeling. |
| 2’-O-PRG (2′-O-propargyl) 
| 0.4 to 0.7 | Enables post synthetic labeling using click chemistry. |
| 2’-O-BOE (2′-O-[2-(benzyloxy)ethyl]) 
| 0.5 to 0.8 | Oligonucleotides with 2′-O-[2-(benzyloxy)ethyl] substituent are rapidly degraded by exonucleases. Structural data are consistent with a well-ordered benzyl moiety that stacks against the C4′-C5′ bond of the residue 3′-adjacent to the 2′-O-modified thymidine and the benzyl moiety is not in the close vicinity of the phosphate group. |
| 2’-O-DMAOE (2′-O-[2-(N,N-dimethyl-aminooxy)ethyl]) 
| 1.1 to 2.0 | 2′-O-DMAOE-modified oligonucleotides showed superior metabolic stability in mice. Useful for antisense-based therapeutics when either RNase H-dependent or RNase H-independent target reduction mechanisms are employed. |
| 2’-O-MAOE (2′-O-[2-[(methyleneamino)-oxy]ethyl]) 
| 1.0 to 2.0 | 2′-O-(2-methoxyethyl)-modified oligonucleotides (2′-O-MOE) offer a 2°C increase in melting temperature (Tm) per modification as a diester (2′-O-MOE/P=O) compared with the 2′-deoxy-phosphoro-thioate (2′-H/P=S) compounds, exhibiting resistance to snake venom phosphodiesterase at approximately the same level as a 2′-deoxyoligonucleotide phosphorothioate. |
| 2’-O-IME (2′-O-[2-(imidazolyl)ethyl]) 
| 1.1 to 1.4 | 2′-O-IME) exhibited higher Tm enhancement compared to 2′-O-butyl-modified oligonucleotides |
Abbreviations: MOE, 2′-O-[2-(methoxy)ethyl]; PRL, 2′-O-propyl; BTL, 2′-O-butyl; FET, 2′-O-[2-(fluoro)ethyl]; TFE, 2′-O-[2-(trifluoro)- ethyl]; ALY, 2′-O-allyl; PRG, 2′-O-propargyl; BOE, 2′-O-[2-(benzyloxy)ethyl]; DMAOE, 2′-O-[2-(N,N-dimethylaminooxy)ethyl]; MAOE, 2′-O-[2-[(methyleneamino)oxy]ethyl]; IME, 2′-O-[2-(imidazolyl)ethyl]; HAS, human serum albumin; PO, phosphodiester; PS, phosphorothioate; DMF, N,N-dimethylformamide; MeOH, methanol; EtOH, ethanol; DMTCl, 4,4′-dimethoxytrityl chloride.
Table 3: Continued
| Modification | ΔTm / NA [ºC] | Effect |
| Backbone Modifications |
| PO: phosphodiester | Natural | |
| PS: phosphorothioate | -5 | Non-specific binding to proteins. Lower binding affinity. |
| PACE: phosphonoacetate 
| -1.3 | Lower binding. |
| Thio-PACE 
| -1.8 | Lower binding. |
| PMO: Phosphorodiamidate Morpholino Oligomers 
| Neutral, but improved binding +0.3 to 1.0 | Poor uptake properties. |
| TMO (Thiomorpholinos) 
| TMO/DNA -0.9 to 0.7 TMO/RNA -0.6 to 1.0 | Fully modified TMOs can block gene expression and are a good candidate for splicing studies. Fully modified TMOs are not recruiting RNase H1. TMOs exhibit efficient exon 23 skipping in the mouse dystrophin transcript at a lower concentration of 5-20 nM, improving the drug safety profile by minimizing the dosage of the drug. |
| Triazole-PMO 
| +3.15 | Bnerjee et al. 2024; Palfman et al. 2016. |
| PNA: Peptide Nucleic Acid 
| Neutral, but improved binding. ~1 to 2 | Poor uptake properties. Affinity: PNA-PNA>PNA-RNA > PNA-DNA>RNA-RNA |
| SNA (Serinol nucleic Acid) 
| -0.5 -12 | SNA AO showed higher Tm (62.3 °C) than the 2′-OMePS AO (60.4 °C) and DNA AO (49.8 °C). A possible explanation for the lower stability of SNA AO compared to PNA AO could be due to the electrostatic repulsion induced by phosphodiester linkage on SNA AO and flexible conformation of SNA compared to PNA. Enhanced stability, high binding affinity, and resistance to enzymatic degradation |
| GNA (glycol nucleic acids) 
| N.A. | The melting temperature (đđ) of GNA depends on factors such as base composition, length, and the presence of stabilizing metal ions, similar to DNA and RNA. |
| TNA (α-L-threose nucleic acid) 
| N.A. | https://www.biosyn.com/tew/What-are-Threofuranosyl-Nucleotides-or-TNAs.aspx Melting temperature (Tm) values are ~10 °C lower for DNA/TNA and DNA/DNA duplexes, compared to RNA/TNA and RNA/RNA duplexes, respectively. |
Table 4: Base Modifications and their Effect
| Modification | Structure | ΔTm duplex per modification | Impact on the efficiency of RNAi | Others |
| 2′ thiouridine (s2U) | 
| 0–2°C | 7% s2U are tolerated by RNAi. s2U can change thermal asymmetry of the duplex and increase the efficiency of siRNA in vitro. | s2U slightly increases nuclease resistance in vitro. |
| Pseudouridine (Ψ) | 
| −1 to +1°C | One Ψ is tolerated by RNA. | Stabilizes 3′endo ribose conformation. Reduces the PKR-induced interferon response. |
| Dehydrouridine (D) | 
| N.A. | The nonaromatic nucleobase disrupts base stacking. | D unit similarly like wobble base pair lead to less stable duplexes. |
R = ribose residue.
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