Glycol nucleic acids (GNAs) and their applications

Glycol Nucleic Acids (GNAs), sometimes also called glycerol nucleic acids, are unnatural nucleic acid analogs, based on a glycol monomer unit, with an acyclic three-carbon sugar-phosphate backbone that contains one stereogenic center per repeating unit. Stereogenic compounds or centers in molecules consist of a central atom and four distinguishable ligands. The interchange of any two of these ligands results in a stereoisomer. Stereoisomers only differ in the spatial arrangement of their atoms.

Glycol Nucleic Acid (GNA) is a xeno nucleic acid (XNA) with a 3'-2' linked glycol-phosphate backbone. A GNA molecule contains a 3-carbon unit fused with a nucleobase.

The polymer structure of GNAs is similar to DNA and RNA but differs in the composition of its sugar-phosphodiester backbone. Compared to DNA and RNA, the GNA backbone is shortened by one atom. The GNA unit is a simple phosphodiester-based oligomer building block.

While DNA and RNA have a deoxyribose and ribose sugar backbone, GNA comprises repeating glycol units linked by phosphodiester bonds.

Glycol Nucleic Acid Structure


Figure 1: Chemical structures of GNA, DNA, and RNA. Several crystal structures of GNA duplexes have been determined between 0.97 and 1.83 Å resolution (Schlegel et al. and Johnson et al.).

The groups of Ueda and Imoto first synthesized racemic GNA nucleosides in 1971 and 1972. The Holy group synthesized enantiomerically pure compounds in 1974 and Cook et al. and the Wengel group synthesized the first GNA phosphoramidites and GNA-containing oligonucleotides in 1995 and 1999. A few years later, in 2006 and 2009, Meggers and colleagues published improved and simplified methods.

To further reduce the total number of synthetic steps for GNA phosphoramidites and allow for the synthesis on a kilogram scale, the Alnylam group developed a procedure that allows for the ring opening of enantiopure DMT-glycidol using protected purine nucleobases.

Unlike its natural counterparts, GNA is chemically stable and not known to occur naturally.

GNA potentially allows for a wide range of applications, including:

  • Antisense therapy: GNA's ability to form stable duplexes with RNA makes it a promising candidate for designing antisense oligonucleotides to inhibit the expression of specific genes.
  • Development of aptamers: GNA aptamers can bind to specific targets with high affinity and specificity. Possible applications are molecular diagnostics, therapeutics, and biosensors.
  • Gene therapy: GNAs may allow the delivery of genes into cells for therapeutic purposes.
  • Design of artificial molecules: GNA could enable the creation of synthetic DNA or RNA molecules.
  • siRNA: Schlegel et al. (2020) observed that a siRNA duplex design with a single GNA substitution at position 6 of the guide strand, and without any further changes in sequence or chemistry, minimized off-target dysregulation without compromising on-target activity. 

GNAs are well-suited for applications in which stability is critical, such as in antisense therapy and aptamer development. 

Antisense Therapy

Antisense therapy uses nucleic acids to inhibit the expression of specific genes. GNA is a promising candidate for synthesizing antisense oligonucleotides used in antisense therapy because it can form stable duplexes with RNA, thereby preventing the targeted RNA from being translated into a protein. GNA oligonucleotides can inhibit the expression of various genes in vitro and in vivo.


Aptamers recognize and bind to specific targets with high affinity and specificity. GNA aptamers are particularly attractive because they are more stable than natural nucleic acid-based aptamers. Hence, GNAs are well-suited for developing diagnostics, therapeutics, and biosensors. GNA aptamers can bind to various targets, including proteins, cells, and viruses.

Gene Therapy

Gene therapy uses nucleic acids to deliver genes into cells for therapeutic purposes. GNAs may allow the delivery of genes into cells because it is stable and can be modified to incorporate targeting sequences.


siRNA duplex designs with a single GNA substitution at position 6 of the guide strand minimize off-target effects without compromising on-target activity.

Other Applications

In addition to the applications mentioned above, GNAs could be helpful for a variety of other applications, including:

  • Nanotechnology: The use of GNAs may allow the creation of self-assembling nanostructures.
  • Biocatalysis: GNA may enable the development of new enzymes with improved catalytic activity.
  • Imaging: GNA could be used to develop new imaging probes.

GNAs are versatile molecules with a wide range of potential applications. As research into GNA continues, scientists may discover more applications for these molecules.


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