Xeno nucleic acid

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Glycol nucleic acid (left) is an example of a xeno nucleic acid because it has a different backbone than DNA (right). GNA-T vs. natural DNA-T.png
Glycol nucleic acid (left) is an example of a xeno nucleic acid because it has a different backbone than DNA (right).

Xenonucleic acids (XNA) are synthetic nucleic acid analogues that are made up of non-natural components such as alternative nucleosides, sugars, or backbones. [1] [2]

Contents

Xenonucleic acids have different properties to endogenous nucleic acids. This means they can be used in different applications, such as therapeutics, probes, or functional molecules. For example, peptide nucleic acids, where the backbone is 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 structure different properties. This may mean it cannot be processed by naturally occurring cellular processes. For example, natural DNA polymerases cannot read and duplicate this information, thus the genetic information stored in XNA is invisible to DNA-based organisms. [3]

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 done to create synthetic polymerases to transform XNA. The study of the production and application of XNA molecules has created the field of current xenobiology. [3]

Background

The structure of DNA was discovered in 1953. Around the early 2000s, researchers created a number of exotic DNA-like structures, XNA. These are synthetic polymers that can carry the same information as DNA, but with different molecular constituents. The "X" in XNA stands for "xeno-", meaning strange or alien, indicating the difference in the molecular structure as compared to DNA or RNA. [4]

Not much was done with XNA until the development of special polymerase enzyme, capable of copying XNA from a DNA template as well as copying XNA back into DNA. [4] Pinheiro et al. (2012), for example, has demonstrated such an XNA-capable polymerase that works on sequences of around 100 base pairs in length. [5] 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 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. [6]

Structure

Endogenous nucleic acids (DNA and RNA) polymers of nucleotides. A nucleotide is made up of three chemical components: a phosphate, a five-carbon sugar group (this can be either a deoxyribose sugar—which gives us the "D" in DNA—or a ribose sugar—the "R" in RNA), and one of five standard bases (adenine, guanine, cytosine, thymine or uracil). Xenonucleic acids can substitute any of these components with a non-natural alternative. These substitutions make XNAs functionally and structurally analogous to DNA and RNA despite being unnatural and artificial.

XNA exhibits a variety of structural chemical changes relative to its natural counterparts. Most work has focused on different chemical structures in place of the ribose, including: [3]

HNA could potentially be used as a drug that can recognize and bind to specified sequences. Scientists have been able to isolate HNAs for the possible binding of sequences that target HIV. [7] Research has also shown that CeNAs with stereochemistry similar to the D form of DNA [8] can create stable duplexes with itself and RNA. It was shown that CeNAs are not as stable when they form duplexes with DNA. [8]

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, 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. [9]

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. [10]

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 nucleotide, which has 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 require the xeno nucleotide to be structural similar to natural nucleotide. XNA can be bio-synthesized with DNA templates, where the information in DNA templates instruct the XNA synthesis. XNA can also be bio-synthesized with XNA templates in some condition, where the XNA bahaves 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. [10] [11]

1,5-Anhydrohexitol Nucleic Acid (HNA) bio-synthesis: HNA polymerases(like TgoT_6G12[1], which is archaeal polymerase from Thermococcus gorgonarius) have been engineered to synthesize HNA polymers. [12]

Cyclohexene Nucleic Acid (CeNA) and 2-F-CeNA bio-synthesis: Vent (exo−) DNA polymerase from the B-family polymerases, Taq DNA polymerase from the A-family polymerases, and HIV reverse transcriptase from the reverse transcriptase family [13] have been developed to facilitate the synthesis of CeNA, enabling its use in synthetic genetics.

Locked Nucleic Acid (LNA) / Bridged Nucleic Acid (BNA) bio-synthesis: These nucleic acids are synthesized through the engineering of polymerases that can accommodate their unique structural features, which include modifications that lock the nucleic acid structure. KOD DNA polymerases, a family B DNA polymerase derived from Thermococcus kodakarensis KOD1, are effective LNA decoders and encoders. [14]

Threofuranosyl Nucleic Acid (TNA) bio-synthesis: TNA has been synthesized using mutants of archaeal DNA polymerases, such as Kod-RI, [15] Tgo and Therminator DNA polymerases (9°N, A485L). [10]

Arabino-Nucleic Acid (ANA)/2′-Fluoro-Arabinonucleic Acid (FANA) bio-synthesis: ANA/FANA is synthesized using engineered polymerases that can handle its specific backbone chemistry. [10]

Spiegelmers bio-synthesis: Spiegelmers are created by selecting RNA or DNA aptamers against enantiomeric target molecules, followed by the chemical synthesis of their non-natural L-RNA or L-DNA isomers. This process involves preparing mirror-image targets through chemical synthesis, which can be challenging.

Implications

The study of XNA is not intended to give scientists a better understanding of biological evolution as it has occurred historically, but rather to explore ways in which humans might control and reprogram the genetic makeup of biological organisms in future. XNA has shown significant potential in solving the current issue of genetic pollution in genetically modified organisms. [16] While DNA is incredibly efficient in its ability to store genetic information and lend complex biological diversity, its four-letter genetic alphabet is relatively limited. Using a genetic code of six XNAs rather than the four naturally occurring DNA nucleotide bases yields greater opportunities for genetic modification and expansion of chemical functionality. [17]

The development of various hypotheses and theories about XNAs have altered a key factor in the current understanding of nucleic acids: heredity and evolution are not limited to DNA and RNA as once thought, but are processes that have developed from polymers capable of storing information. [5] Investigations into XNAs will allow researchers to assess whether DNA and RNA are the most efficient and desirable building blocks of life, or if these two molecules emerged randomly after evolving from a larger class of chemical ancestors. [18]

Applications

One theory of XNA utilization is its incorporation into medicine as a disease-fighting agent. Some enzymes and antibodies that are currently administered for various disease treatments are broken down too quickly in the stomach or bloodstream. Because XNA is foreign and because it is believed that humans have not yet evolved the enzymes to break them down, XNAs may be able to serve as a more durable counterpart to the DNA and RNA-based treatment methodologies that are currently in use. [19]

Experiments with XNA have already allowed for the replacement and enlargement of this genetic alphabet, and XNAs have shown complementarity with DNA and RNA nucleotides, suggesting potential for its transcription and recombination. One experiment conducted at the University of Florida led to the production of an XNA aptamer by the AEGIS-SELEX (artificially expanded genetic information system - systematic evolution of ligands by exponential enrichment) method, followed by successful binding to a line of breast cancer cells. [20] Furthermore, experiments in the model bacterium E. coli have demonstrated the ability for XNA to serve as a biological template for DNA in vivo. [21]

In moving forward with genetic research on XNAs, various questions must come into consideration regarding biosafety, biosecurity, ethics, and governance/regulation. [3] One of the key questions here is whether XNA in an in vivo setting would intermix with DNA and RNA in its natural environment, thereby rendering scientists unable to control or predict its implications in genetic mutation. [19]

XNA also has potential applications to be used as catalysts, much like RNA has the ability to be used as an enzyme. Researchers have shown XNA is able to cleave and ligate DNA, RNA and other XNA sequences, with the most activity being XNA catalyzed reactions on XNA molecules. This research may be used in determining whether DNA and RNA's role in life emerged through natural selection processes or if it was simply a coincidental occurrence. [22]

XNA may be employed as molecular clamps in quantitative real-time polymerase chain reactions (qPCR) by hybridizing with target DNA sequences. [23] In a study published in PLOS ONE, an XNA-mediated molecular clamping assay detected mutant cell-free DNA (cfDNA) from precancerous colorectal cancer (CRC) lesions and colorectal cancer. [23] XNA may also act as highly specific molecular probes for detection of nucleic acid target sequence. [24]

Related Research Articles

<span class="mw-page-title-main">Nucleic acid</span> Class of large biomolecules essential to all known life

Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). If the sugar is ribose, the polymer is RNA; if the sugar is deoxyribose, a variant of ribose, the polymer is DNA.

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Primer (molecular biology)</span> Short strand of RNA or DNA that serves as a starting point for DNA synthesis

A primer is a short, single-stranded nucleic acid used by all living organisms in the initiation of DNA synthesis. A synthetic primer may also be referred to as an oligo, short for oligonucleotide. DNA polymerase enzymes are only capable of adding nucleotides to the 3’-end of an existing nucleic acid, requiring a primer be bound to the template before DNA polymerase can begin a complementary strand. DNA polymerase adds nucleotides after binding to the RNA primer and synthesizes the whole strand. Later, the RNA strands must be removed accurately and replace them with DNA nucleotides forming a gap region known as a nick that is filled in using an enzyme called ligase. The removal process of the RNA primer requires several enzymes, such as Fen1, Lig1, and others that work in coordination with DNA polymerase, to ensure the removal of the RNA nucleotides and the addition of DNA nucleotides. Living organisms use solely RNA primers, while laboratory techniques in biochemistry and molecular biology that require in vitro DNA synthesis usually use DNA primers, since they are more temperature stable. Primers can be designed in laboratory for specific reactions such as polymerase chain reaction (PCR). When designing PCR primers, there are specific measures that must be taken into consideration, like the melting temperature of the primers and the annealing temperature of the reaction itself. Moreover, the DNA binding sequence of the primer in vitro has to be specifically chosen, which is done using a method called basic local alignment search tool (BLAST) that scans the DNA and finds specific and unique regions for the primer to bind.

<span class="mw-page-title-main">RNA</span> Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids. The nucleic acids constitute one of the four major macromolecules essential for all known forms of life. RNA is assembled as a chain of nucleotides. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

<span class="mw-page-title-main">RNA world</span> Hypothetical stage in the early evolutionary history of life on Earth

The RNA world is a hypothetical stage in the evolutionary history of life on Earth in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence of this stage. Alexander Rich first proposed the concept of the RNA world in 1962, and Walter Gilbert coined the term in 1986.

<span class="mw-page-title-main">Nucleotide base</span> Nitrogen-containing biological compounds that form nucleosides

Nucleotide bases are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic building blocks of nucleic acids. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are called primary or canonical. They function as the fundamental units of the genetic code, with the bases A, G, C, and T being found in DNA while A, G, C, and U are found in RNA. Thymine and uracil are distinguished by merely the presence or absence of a methyl group on the fifth carbon (C5) of these heterocyclic six-membered rings. In addition, some viruses have aminoadenine (Z) instead of adenine. It differs in having an extra amine group, creating a more stable bond to thymine.

<span class="mw-page-title-main">Nucleoside</span> Any of several glycosylamines comprising a nucleobase and a sugar molecule

Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase and a five-carbon sugar whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and one or more phosphate groups. In a nucleoside, the anomeric carbon is linked through a glycosidic bond to the N9 of a purine or the N1 of a pyrimidine. Nucleotides are the molecular building blocks of DNA and RNA.

Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small fragments of nucleic acids can be manufactured as single-stranded molecules with any user-specified sequence, and so are vital for artificial gene synthesis, polymerase chain reaction (PCR), DNA sequencing, molecular cloning and as molecular probes. In nature, oligonucleotides are usually found as small RNA molecules that function in the regulation of gene expression, or are degradation intermediates derived from the breakdown of larger nucleic acid molecules.

<span class="mw-page-title-main">Ribozyme</span> Type of RNA molecules

Ribozymes are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonstrated that RNA can be both genetic material and a biological catalyst, and contributed to the RNA world hypothesis, which suggests that RNA may have been important in the evolution of prebiotic self-replicating systems.

DNA primase is an enzyme involved in the replication of DNA and is a type of RNA polymerase. Primase catalyzes the synthesis of a short RNA segment called a primer complementary to a ssDNA template. After this elongation, the RNA piece is removed by a 5' to 3' exonuclease and refilled with DNA.

<span class="mw-page-title-main">DNA synthesis</span> Replication of DNA

DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs when these nucleotide units are joined to form DNA; this can occur artificially or naturally. Nucleotide units are made up of a nitrogenous base, pentose sugar (deoxyribose) and phosphate group. Each unit is joined when a covalent bond forms between its phosphate group and the pentose sugar of the next nucleotide, forming a sugar-phosphate backbone. DNA is a complementary, double stranded structure as specific base pairing occurs naturally when hydrogen bonds form between the nucleotide bases.

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

Xenobiology (XB) is a subfield of synthetic biology, the study of synthesizing and manipulating biological devices and systems. The name "xenobiology" derives from the Greek word xenos, which means "stranger, alien". Xenobiology is a form of biology that is not (yet) familiar to science and is not found in nature. In practice, it describes novel biological systems and biochemistries that differ from the canonical DNA–RNA-20 amino acid system. For example, instead of DNA or RNA, XB explores nucleic acid analogues, termed xeno nucleic acid (XNA) as information carriers. It also focuses on an expanded genetic code and the incorporation of non-proteinogenic amino acids, or “xeno amino acids” into proteins.

Threose nucleic acid (TNA) is an artificial genetic polymer in which the natural five-carbon ribose sugar found in RNA has been replaced by an unnatural four-carbon threose sugar. Invented by Albert Eschenmoser as part of his quest to explore the chemical etiology of RNA, TNA has become an important synthetic genetic polymer (XNA) due to its ability to efficiently base pair with complementary sequences of DNA and RNA. The main difference between TNA and DNA/RNA is their backbones. DNA and RNA have their phosphate backbones attached to the 5' carbon of the deoxyribose or ribose sugar ring, respectively. TNA, on the other hand, has its phosphate backbone directly attached to the 3' carbon in the ring, since it does not have a 5' carbon. This modified backbone makes TNA, unlike DNA and RNA, completely refractory to nuclease digestion, making it a promising nucleic acid analog for therapeutic and diagnostic applications.

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

<span class="mw-page-title-main">Nucleic acid analogue</span> Compound analogous to naturally occurring RNA and DNA

Nucleic acid analogues are compounds which are analogous to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pentose sugar, either ribose or deoxyribose, and one of four nucleobases. An analogue may have any of these altered. Typically the analogue nucleobases confer, among other things, different base pairing and base stacking properties. Examples include universal bases, which can pair with all four canonical bases, and phosphate-sugar backbone analogues such as PNA, which affect the properties of the chain . Nucleic acid analogues are also called xeno nucleic acids and represent one of the main pillars of xenobiology, the design of new-to-nature forms of life based on alternative biochemistries.

Masad J. Damha is a Canadian academic and nucleic acid researcher. He is Distinguished James McGill Professor of Chemistry at McGill University in Montreal, Quebec, Canada.

A bridged nucleic acid (BNA) is a modified RNA nucleotide. They are sometimes also referred to as constrained or inaccessible RNA molecules. BNA monomers can contain a five-membered, six-membered or even a seven-membered bridged structure with a "fixed" C3'-endo sugar puckering. The bridge is synthetically incorporated at the 2', 4'-position of the ribose to afford a 2', 4'-BNA monomer. The monomers can be incorporated into oligonucleotide polymeric structures using standard phosphoramidite chemistry. BNAs are structurally rigid oligo-nucleotides with increased binding affinities and stability.

<span class="mw-page-title-main">Philipp Holliger</span> Swiss molecular biologist

Philipp Holliger is a Swiss molecular biologist best known for his work on xeno nucleic acids (XNAs) and RNA engineering. Holliger is a program leader at the MRC Laboratory of Molecular Biology.

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