XNA

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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).

Xeno nucleic acids (XNA) are synthetic nucleic acid analogues that have a different sugar backbone than the natural nucleic acids DNA and RNA.[1] 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 its production and application has created a field known as xenobiology.


Xeno nucleic acids (XNA) are synthetic nucleic acid analogues that have a different sugar backbone than the natural nucleic acids DNA and RNA. 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 its production and application has created a field known as xenobiology.

外源核酸(XNA)是一类人工合成的核酸类似物，与天然核酸 DNA 和 RNA 具有不同的糖基结构。截至2011年，至少有六种合成糖已被证明可以形成核酸骨架，从而存储和检索基因信息。目前正在研究合成聚合酶来转化 XNA。对其生产和应用的研究创造了一个被称为异生物学的领域。

Although the genetic information is still stored in the four canonical base pairs (unlike other nucleic acid analogues), natural DNA polymerases cannot read and duplicate this information. Thus the genetic information stored in XNA is "invisible" and therefore useless to natural DNA-based organisms.[2]

Although the genetic information is still stored in the four canonical base pairs (unlike other nucleic acid analogues), natural DNA polymerases cannot read and duplicate this information. Thus the genetic information stored in XNA is "invisible" and therefore useless to natural DNA-based organisms.

虽然遗传信息仍然存储在四个典型的碱基对(不像其他核酸类似物) ，自然的 DNA 聚合酶不能读取和复制这些信息。因此，存储在 XNA 中的遗传信息是“看不见的”，因此对于天然的 dna 为基础的生物体来说是无用的。

Background

The structure of DNA was discovered in 1953. Around the early 2000s, researchers created a number of exotic DNA-like structures, XNA. XNA is a synthetic polymer that can carry the same information as DNA, but with different molecular constituents. The "X" in XNA stands for "xeno," meaning stranger or alien, indicating the difference in the molecular structure as compared to DNA or RNA.[3]

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

DNA 的结构是在1953年发现的。大约在21世纪初，研究人员创造了许多奇特的类 dna 结构，XNA。XNA 是一种人工合成的聚合物，可以携带与 DNA 相同的信息，但具有不同的分子成分。XNA 中的“ x”代表“ xeno”，意思是陌生人或外星人，表示分子结构与 DNA 或 RNA 相比的差异。

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.[3] Pinheiro et al. (2012), for example, has demonstrated such an XNA-capable polymerase that works on sequences of ~100bp in length.[4] More recently, synthetic biologists Philipp Holliger and Alexander Taylor managed to create XNAzymes, the XNA equivalent of a ribozyme, enzymes made of DNA or ribonucleic acid. 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.[5]

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. Pinheiro et al. (2012), for example, has demonstrated such an XNA-capable polymerase that works on sequences of ~100bp in length. More recently, synthetic biologists Philipp Holliger and Alexander Taylor managed to create XNAzymes, the XNA equivalent of a ribozyme, enzymes made of DNA or ribonucleic acid. 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.

在特殊的聚合酶开发出来之前，对 XNA 的研究并不多，这种酶能够从 DNA 模板中复制 XNA，并将 XNA 复制回 DNA 中。Pinheiro et al.例如，2012年的一项研究已经证明，这种可以在大约100bp 长度的序列上工作的 dna 聚合酶可以进行分析。最近，合成生物学家 Philipp Holliger 和 Alexander Taylor 成功地创造了 XNAzymes---- 一种 XNA 相当于核酶的酶---- 由 DNA 或核糖核酸组成。这表明，转录因子不仅可以储存遗传信息，还可以作为酶，提高了其他地方的生命可能起源于 RNA 或 DNA 以外的其他物质的可能性。

Structure

This image displays the differences in the sugar backbones used in XNAs compared to common and biologically used DNA and RNA.

Strands of DNA and RNA are formed by stringing together long chains of molecules called 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).

thumb|369x369px|This image displays the differences in the sugar backbones used in XNAs compared to common and biologically used DNA and RNA. Strands of DNA and RNA are formed by stringing together long chains of molecules called 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).

这张图片显示了转录因子中使用的糖骨与常见的生物学使用的 DNA 和 RNA 的不同之处。DNA 链和 RNA 链是由称为核苷酸的长链分子串联而成的。一个核苷酸由三种化学成分组成: 一种是磷酸盐，一种是五碳糖基(这可以是脱氧核糖糖，它在 dna 中给我们提供了“ d”，也可以是核糖糖，即 RNA 中的“ r”) ，以及五种标准碱基之一(腺嘌呤、鸟嘌呤、胞嘧啶、胸腺嘧啶或尿嘧啶)。

The molecules that piece together to form the six xeno nucleic acids are almost identical to those of DNA and RNA, with one exception: in XNA nucleotides, the deoxyribose and ribose sugar groups of DNA and RNA have been replaced with other chemical structures. These substitutions make XNAs functionally and structurally analogous to DNA and RNA despite being unnatural and artificial.

The molecules that piece together to form the six xeno nucleic acids are almost identical to those of DNA and RNA, with one exception: in XNA nucleotides, the deoxyribose and ribose sugar groups of DNA and RNA have been replaced with other chemical structures. These substitutions make XNAs functionally and structurally analogous to DNA and RNA despite being unnatural and artificial.

组成六种核酸的分子与 DNA 和 RNA 的分子几乎完全相同，只有一个例外: 在 XNA 核苷酸中，DNA 和 RNA 的脱氧核糖和核糖糖基被其他化学结构所取代。这些替换使得转录因子在功能和结构上与 DNA 和 RNA 相似，尽管它们是非自然的和人工的。

XNA exhibits a variety of structural chemical changes relative to its natural counterparts. Types of synthetic XNA created so far include:[2]

  • 1,5-anhydrohexitol nucleic acid (HNA)
  • Cyclohexene nucleic acid (CeNA)
  • Threose nucleic acid (TNA)
  • Glycol nucleic acid (GNA)
  • Locked nucleic acid ([1])
  • Peptide nucleic acid (PNA)
  • FANA (Fluoro Arabino nucleic acid)

XNA exhibits a variety of structural chemical changes relative to its natural counterparts. Types of synthetic XNA created so far include:

  • 1,5-anhydrohexitol nucleic acid (HNA)
  • Cyclohexene nucleic acid (CeNA)
  • Threose nucleic acid (TNA)
  • Glycol nucleic acid (GNA)
  • Locked nucleic acid ()
  • Peptide nucleic acid (PNA)
  • FANA (Fluoro Arabino nucleic acid)

XNA 表现出各种结构的化学变化相对于它的天然同行。迄今为止合成的 XNA 类型包括:

  • 1,5- 脱水己醇核酸(HNA)
  • 环己烯核酸(CeNA)
  • 苏糖核酸(TNA)
  • GNA (GNA)
  • 锁核酸()
  • 肽核酸(PNA)
  • FANA (氟阿拉伯氨基核酸)

HNA could be used to potentially act 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.[6] With cyclohexene nucleic acid, research has shown that CeNAs with stereochemistry similar to the D form can create stable duplexes with itself and RNA. It was shown that CeNAs are not as stable when they form duplexes with DNA.[7]

HNA could be used to potentially act 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. With cyclohexene nucleic acid, research has shown that CeNAs with stereochemistry similar to the D form can create stable duplexes with itself and RNA. It was shown that CeNAs are not as stable when they form duplexes with DNA.

海航可能被用来作为一种潜在的药物，可以识别和结合特定的序列。科学家已经能够分离出可能与艾滋病毒相关的基因序列。利用环己烯核酸，研究表明，具有类似 d 型立体化学结构的二茂铁可以与自身和 RNA 形成稳定的复配体。结果表明，当 CeNAs 与 DNA 形成双链时，CeNAs 不是很稳定。

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 we can control and even reprogram the genetic makeup of biological organisms moving forward. XNA has shown significant potential in solving the current issue of genetic pollution in genetically modified organisms.[8] 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 endless opportunities for genetic modification and expansion of chemical functionality.[9]

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 we can control and even reprogram the genetic makeup of biological organisms moving forward. XNA has shown significant potential in solving the current issue of genetic pollution in genetically modified organisms. 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 endless opportunities for genetic modification and expansion of chemical functionality.

这项研究的目的不是让科学家更好地了解历史上发生过的生物进化，而是探索我们能够控制甚至重新编程生物有机体基因组成的方法。XNA 在解决目前转基因生物的遗传污染问题上显示出巨大的潜力。尽管 DNA 在储存遗传信息和提供复杂生物多样性方面具有令人难以置信的效率，但其四个字母的遗传字母相对有限。使用6个转录因子的遗传密码，而不是4个自然产生的 DNA 核苷酸碱基，可以产生无限的基因工程和扩展化学功能的机会。

The development of various hypotheses and theories about XNAs have altered a key factor in our current understanding of nucleic acids: that heredity and evolution are not limited to DNA and RNA as once thought, but are simply processes that have developed from polymers capable of storing information.[4] Investigations into XNAs will allow for researchers to assess whether DNA and RNA are the most efficient and desirable building blocks of life, or if these two molecules were chosen randomly after evolving from a larger class of chemical ancestors.[10]

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

关于转录因子的各种假说和理论的发展已经改变了我们目前对核酸的理解中的一个关键因素: 遗传和进化并不像人们曾经认为的那样仅仅局限于 DNA 和 RNA，而只是从能够储存信息的聚合物发展而来的简单过程。对于转录因子的研究将允许研究人员评估 DNA 和 RNA 是否是最有效和最理想的生命基石，或者这两个分子是否是从一个更大的化学祖先进化而来的随机选择。

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.[11]

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.

= = 应用 = = 利用 XNA 的一种理论是将其作为抗病剂纳入医学。目前用于各种疾病治疗的一些酶和抗体在胃或血液中分解得太快。由于 XNA 是外来的，而且据信人类尚未进化出能够分解它们的酶，因此 XNA 可能成为目前正在使用的 DNA 和 rna 治疗方法的更持久的对应物。

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.[12] Furthermore, experiments in the model bacterium E. coli have demonstrated the ability for XNA to serve as a biological template for DNA in vivo.[13]

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. Furthermore, experiments in the model bacterium E. coli have demonstrated the ability for XNA to serve as a biological template for DNA in vivo.

用 XNA 进行的实验已经可以替换和扩大这个基因字母表，而且 XNA 已经显示出与 DNA 和 RNA 核苷酸的互补性，这表明它具有转录和重组的潜力。在佛罗里达大学进行的一项实验中，人工扩增的基因信息系统-配体指数增强系统进化技术-人工合成方法产生了一种 XNA 适配子，并成功地与一系列乳腺癌细胞结合。此外，在模型细菌大肠杆菌中的实验表明，XNA 具有在体内作为 DNA 生物模板的能力。

In moving forward with genetic research on XNAs, various questions must come into consideration regarding biosafety, biosecurity, ethics, and governance/regulation.[2] 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.[11]

In moving forward with genetic research on XNAs, various questions must come into consideration regarding biosafety, biosecurity, ethics, and governance/regulation. 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.

在推进对转录因子的基因研究时，必须考虑到有关生物安全、生物安保、伦理和治理/监管的各种问题。这里的一个关键问题是，在体内环境中，XNA 是否会与自然环境中的 DNA 和 RNA 混合，从而使科学家无法控制或预测其在基因突变中的含义。

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.[14]

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.

XNA 也有潜在的应用可以用作催化剂，就像 RNA 可以用作酶一样。研究人员已经表明，XNA 能够切割和连接 DNA、 RNA 和其他 XNA 序列，其中最活跃的是 XNA 对 XNA 分子的催化反应。这项研究可以用来确定 DNA 和 RNA 在生命中的作用是通过自然选择过程还是仅仅是一个巧合。

XNA may be employed as molecular clamps in quantitative real-time polymerase chain reactions (qPCR) by hybridizing with target DNA sequences.[15] 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.[15] XNA may also act as highly specific molecular probes for detection of nucleic acid target sequence.[16]

XNA may be employed as molecular clamps in quantitative real-time polymerase chain reactions (qPCR) by hybridizing with target DNA sequences. 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. XNA may also act as highly specific molecular probes for detection of nucleic acid target sequence.

XNA 可以作为定量实时聚合酶链反应(qPCR)的分子钳，与靶 DNA 序列杂交。在《公共科学图书馆 · 综合》杂志上发表的一项研究中，一种 DNA 介导的分子钳技术检测到了癌前病变大肠癌和大肠癌的无细胞 DNA 突变体。XNA 还可以作为高度特异性的分子探针公司，用于检测核酸靶序列。

See also

  • Nucleic acid analogue
  • Xenobiology

= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 核酸类似物生物学

References

  1. ↑ Schmidt, Markus (2012). Synthetic Biology. John Wiley & Sons. pp. 151–. ISBN 978-3-527-65926-5. https://books.google.com/books?id=lr0SgX1Hx2gC&pg=PA151. 
  2. ↑ 2.0 2.1 2.2 Schmidt M (April 2010). "Xenobiology: a new form of life as the ultimate biosafety tool". BioEssays. 32 (4): 322–331. doi:10.1002/bies.200900147. PMC 2909387. PMID 20217844.
  3. ↑ 3.0 3.1 Gonzales R (19 April 2012). "XNA Is Synthetic DNA That's Stronger than the Real Thing". Io9. Retrieved 15 October 2015.
  4. ↑ 4.0 4.1 Pinheiro VB, Taylor AI, Cozens C, Abramov M, Renders M, Zhang S, et al. (April 2012). "Synthetic genetic polymers capable of heredity and evolution". Science. 336 (6079): 341–344. Bibcode:2012Sci...336..341P. doi:10.1126/science.1217622. PMC 3362463. PMID 22517858.
  5. ↑ "World's first artificial enzymes created using synthetic biology". Medical Research Council. 1 December 2014.
  6. ↑ Extance A (19 April 2012). "Polymers perform non-DNA evolution". Royal Society of Chemistry. Retrieved 15 October 2015.
  7. ↑ Gu P, Schepers G, Rozenski J, Van Aerschot A, Herdewijn P (2003). "Base pairing properties of D- and L-cyclohexene nucleic acids (CeNA)". Oligonucleotides. 13 (6): 479–489. doi:10.1089/154545703322860799. PMID 15025914.
  8. ↑ Herdewijn P, Marlière P (June 2009). "Toward safe genetically modified organisms through the chemical diversification of nucleic acids". Chemistry & Biodiversity. 6 (6): 791–808. doi:10.1002/cbdv.200900083. PMID 19554563. S2CID 8572188.
  9. ↑ Pinheiro VB, Holliger P (August 2012). "The XNA world: progress towards replication and evolution of synthetic genetic polymers". Current Opinion in Chemical Biology. 16 (3–4): 245–252. doi:10.1016/j.cbpa.2012.05.198. PMID 22704981.
  10. ↑ Hunter P (May 2013). "XNA marks the spot. What can we learn about the origins of life and the treatment of disease through artificial nucleic acids?". EMBO Reports. 14 (5): 410–413. doi:10.1038/embor.2013.42. PMC 3642382. PMID 23579343.
  11. ↑ 11.0 11.1 "XNA: Synthetic DNA That Can Evolve". Popular Mechanics. 19 April 2012. Retrieved 17 November 2015.
  12. ↑ Sefah K, Yang Z, Bradley KM, Hoshika S, Jiménez E, Zhang L, et al. (January 2014). "In vitro selection with artificial expanded genetic information systems". Proceedings of the National Academy of Sciences of the United States of America. 111 (4): 1449–1454. Bibcode:2014PNAS..111.1449S. doi:10.1073/pnas.1311778111. PMC 3910645. PMID 24379378.
  13. ↑ Pezo V, Liu FW, Abramov M, Froeyen M, Herdewijn P, Marlière P (July 2013). "Binary genetic cassettes for selecting XNA-templated DNA synthesis in vivo". Angewandte Chemie. 52 (31): 8139–8143. doi:10.1002/anie.201303288. PMID 23804524.
  14. ↑ Taylor AI, Pinheiro VB, Smola MJ, Morgunov AS, Peak-Chew S, Cozens C, et al. (February 2015). "Catalysts from synthetic genetic polymers". Nature. 518 (7539): 427–430. Bibcode:2015Natur.518..427T. doi:10.1038/nature13982. PMC 4336857. PMID 25470036.
  15. ↑ 15.0 15.1 Sun Q, Pastor L, Du J, Powell MJ, Zhang A, Bodmer W, et al. (5 October 2021). "A novel xenonucleic acid-mediated molecular clamping technology for early colorectal cancer screening". PLOS ONE. 16 (10): e0244332. Bibcode:2021PLoSO..1644332S. doi:10.1371/journal.pone.0244332. PMC 8491914. PMID 34610014.
  16. ↑ D'Agata R, Giuffrida MC, Spoto G (November 2017). "Peptide Nucleic Acid-Based Biosensors for Cancer Diagnosis". Molecules. 22 (11): 1951. doi:10.3390/molecules22111951. PMC 6150339. PMID 29137122.

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