Xenonucleic acids (XNAs) are synthetic nucleic acid analogues that are engineered with a structurally distinct sugar component, as opposed to the nucleobase or phosphate. XNAs have fundamentally different properties from endogenous nucleic acids, enabling different specialized applications, such as therapeutics, probes, or functional molecules. For instance, peptide nucleic acids, the backbones of which are made up of repeating aminoethylglycine units, are extremely stable and resistant to degradation by nucleases because they are not recognised. The same nucleobases can be used to store genetic information and interact with DNA, RNA, or other XNA bases, but the different backbone gives the compound different properties. Their altered chemical structure means they cannot be processed by naturally occurring cellular processes. For instance, natural DNA polymerases cannot read and duplicate the alien information, thus the genetic information stored in XNA is invisible to DNA-based organisms. As of 2011, at least six types of synthetic sugars have been shown to form nucleic acid backbones that can store and retrieve genetic information. Research is now being focused to create synthetic polymerases to transform XNAs. The study of the production and application of XNA molecules has created the field of current xenobiology.
History The term "xeno nucleic acid" was coined in 2009, being used in a xenobiology context. However, many sugar-modified nucleic acids had been created long before the term was created. Nearly five decades after DNA was first discovered, around the early 2000s, researchers created a number of exotic DNA-like structures which would later be called XNAs. These are synthetic polymers that can carry the same information as a DNA, but with different molecular constituents. The initial X in the term XNA derives from the systematic prefix xeno- (Greek: ξένος, "foreign") and indicates the difference in the molecular structure as compared to those of DNA or RNA. Initial XNA research yielded limited practical utility until the development of a special polymerase enzyme, capable of copying XNA from a DNA template as well as copying XNA back into DNA. Pinheiro et al. (2012) have demonstrated an XNA-capable polymerase that works on sequences of around 100 base pairs in length. More recently, synthetic biologists Philipp Holliger and Alexander Taylor succeeded in creating XNAzymes, the XNA equivalent of a ribozyme, enzymes made of RNA. This demonstrates that XNAs can not only store hereditary information, but can also serve as enzymes, raising the possibility that life elsewhere could have begun with something other than RNA or DNA.
Structure Endogenous nucleic acids (DNA and RNA) are polymers composed of nucleotides. Each nucleotide consists of three chemical components: a phosphate, a five-carbon sugar group (which can be either a deoxyribose in DNA or a ribose in RNA), and one of five standard bases (adenine, guanine, cytosine, thymine, or uracil). Xenonucleic acids substitute the sugar components with a non-natural alternative. These substitutions make XNAs functionally and structurally analogous to DNA and RNA, despite not appearing in nature. Some XNA types substitute the ribose or deoxyribose for another sugar or sugar derivative. Examples include:
2'-O-methyl-substituted RNA Threose nucleic acid (TNA) Locked nucleic acid (LNA) Bridged nucleic acid (BNA) 1,5-Anhydrohexitol nucleic acid (HNA) Fluoroarabino nucleic acid (FANA)
Others substitute a non-sugar unit. Examples include:
Peptide nucleic acid (PNA) Glycol nucleic acid (GNA) Morpholino nucleic acid Cyclohexene nucleic acid (CeNA)
Synthesis XNA monomers are prepared by chemical synthesis and can be formed into XNA polymers using chemical synthesis or biosynthetic techniques.
Monomer synthesis Appropriately protected monomers are required for chemical synthesis of XNA polymers. XNA nucleotides, or triphosphates are required for enzymatic polymerisation. Typically, for sugar-based XNAs, to synthesize the xeno nucleoside, the 5 carbon sugar analog is chemically synthesised first. Then, the nucelobase is attached. To chemically synthesize the XNA oligomer from polymerization of xeno nucleoside, the hydroxyl group corresponding to 5'-OH of 5 carbon sugar needs activation by adding an active group (like MMTr, or monomethoxytrityl), then the activated xeno nucleosides can be attached in polymerization designated chemically. One typical example is CeNA, where the xeno nucleoside repeating units 2′-Cyclohexenylnucleosides are chemically synthesized by attaching the protected base to the protected cyclohexenyl precursor. XNA with a similar chemical structure like DNA can be synthesized by engineered polymerases. HNA, CeNA, LNA/BNA, ANA/FANA, and TNA is suitable for this process, while the Spiegelmers(consists of L-nucleic acids) is suitable for engineered polymerases to synthesize.
Polymer synthesis Solid-phase synthesis is an important technique for synthesis of short XNA sequences. This enables synthesis of defined sequences. Alternatively, XNAs can be assembled enzymatically. As xeno nucleotides are analogs of nucleotides, they have a phosphate group attached to the corresponding hydroxyl group. Xeno nucleotides can be chemically treated to attach the phosphate group. Since the similarity between xeno nucleotides and natural nucleotides, the xeno nucleotides can be used as blocks of the engineered polymerases to synthesize the XNA. Biosynthesis of the XNAs usually requires templates like the DNA replication, and this process requires the XNA to be structurally similar to natural nucleotide. XNA can be bio-synthesized with DNA templates, where the information in DNA templates instructs the XNA synthesis. XNA can also be bio-synthesized with XNA templates in some condition, where the XNA behaves like DNA. The synthesis of DNA molecule of XNA templates are also important. Special engineered polymerases and some reverse transcriptase are utilized in the DNA-to-XNA, XNA-to-XNA, and XNA-to-DNA synthesis.
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