A Crystal Structure of a Functional RNA Molecule Containing an Artificial Nucleobase Pair

Hernandez, Armando R.; Shao, Yaming; Hoshika, Shuichi; Yang, Zunyi; Shelke, Sandip A.; Herrou, Julien; Kim, Hyo‐Joong; Kim, Myong‐Jung; Piccirilli, Joseph A.; Benner, Steven A.

doi:10.1002/ange.201504731

Cited by 7 publications

(6 citation statements)

References 24 publications

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“…The Z nucleobases in both crystals turned out to be fairly planar, including all the functional groups attached to the ring. This observation is the same as for the previously reported Z nucleobase structure in DNA, both in the A and B forms (Georgiadis et al, 2015), but different from Z in the RNA structure (the nitro group is modestly rotated) (Hernandez et al, 2015;Zhang et al, 2015).…”

Section: Tablesupporting

confidence: 90%

“…Indeed, the polarizable nature of the nitro group may indicate why it confers 'general binding potential' to matrices (such as nitrocellulose), a potential that has been used to account for the binding potential of aptamers containing the Z nucleobase (Sefah et al, 2014). This negative charge distribution may also account for the stability of the Z:Z 0 0 0 pair, as reported for the Z:P pair (Georgiadis et al, 2015;Hernandez et al, 2015;Zhang et al, 2015;Chawla et al, 2016). Further, the negative charge distribution suggests a general mechanism by which polymerases might distinguish the deprotonated Z 0 0 0 :G mismatch in their active sites.…”

Section: Discussionsupporting

confidence: 52%

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Crystal structures of deprotonated nucleobases from an expanded DNA alphabet

et al. 2016

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Reported here is the crystal structure of a heterocycle that implements a donor-donor-acceptor hydrogen-bonding pattern, as found in the Z component [6-amino-5-nitropyridin-2(1H)-one] of an artificially expanded genetic information system (AEGIS). AEGIS is a new form of DNA from synthetic biology that has six replicable nucleotides, rather than the four found in natural DNA. Remarkably, Z crystallizes from water as a 1:1 complex of its neutral and deprotonated forms, and forms a `skinny' pyrimidine-pyrimidine pair in this structure. The pair resembles the known intercalated cytosine pair. The formation of the same pair in two different salts, namely poly[[aqua(μ-2-amino-6-oxo-3-nitro-1,6-dihydropyridin-1-ido)sodium]-6-amino-5-nitropyridin-2(1H)-one-water (1/1/1)], denoted Z-Sod, {[Na(CHNO)(HO)]·CHNO·HO}, and ammonium 2-amino-6-oxo-3-nitro-1,6-dihydropyridin-1-ide-6-amino-5-nitropyridin-2(1H)-one-water (1/1/1), denoted Z-Am, NH·CHNO·CHNO·HO, under two different crystallization conditions suggests that the pair is especially stable. Implications of this structure for the use of this heterocycle in artificial DNA are discussed.

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Section: Tablesupporting

confidence: 90%

Section: Discussionsupporting

confidence: 52%

Crystal structures of deprotonated nucleobases from an expanded DNA alphabet

et al. 2016

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“…32 Finally, an RNA riboswitch with a Z:P pair replacing a C:G pair was also recently shown to preserve its conformation and ligand affinity. 33 From the structural point of view, the minor groove of the Z:P base pair is very similar to that of natural A:T and G:C base pairs; thus, these non-natural base pairs could efficiently interact with polymerases. 31,32 A unique feature associated with Z:P-containing DNA is imparted by the Z-nitro group present at the major groove of the Z base, which could potentially be exploited for recognition by proteins.…”

Section: ■ Introductionmentioning

confidence: 99%

Theoretical Characterization of the H-Bonding and Stacking Potential of Two Nonstandard Nucleobases Expanding the Genetic Alphabet

et al. 2016

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We report a quantum chemical characterization of the non-natural (synthetic) H-bonded base pair formed by 6-amino-5-nitro-2(1H)-pyridone (Z) and 2-aminoimidazo[1,2-a]-1,3,5-triazin-4(8H)-one (P). The Z:P base pair, orthogonal to the classical G:C base pair, has been introduced into DNA molecules to expand the genetic code. Our results indicate that the Z:P base pair closely mimics the G:C base pair in terms of both structure and stability. To clarify the role of the NO2 group on the C5 position of the Z base, we compared the stability of the Z:P base pair with that of base pairs having different functional groups at the C5 position of Z. Our results indicate that the electron-donating/-withdrawing properties of the group on C5 have a clear impact on the stability of the Z:P base pair, with the strong electron-withdrawing nitro group achieving the largest stabilizing effect on the H-bonding interaction and the strong electron-donating NH2 group destabilizing the Z:P pair by almost 4 kcal/mol. Finally, our gas-phase and in-water calculations confirm that the Z-nitro group reinforces the stacking interaction with its adjacent purine or pyrimidine ring.

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“…A functional RNA molecule containing an artificial nucleobase pair was designed by Hernandez et al to increase the number of building blocks in nucleic acids.They replaced the C:G pair by a pair between two components of an artificially expanded genetic-information system (AEGIS), Z and P (6-amino-5-nitro-2(1H)-pyridone and 2-amino-imidazo [1,2-a]-1,3,5-triazin-4-(8H)-one). The structure shows that the Z:P pair does not greatly change the conformation of the RNA molecule nor the details of its interaction with a hypoxanthine ligand, with a 3.7 -nM affinity of the riboswitch for guanine [153].…”

Section: Spiegelmersmentioning

confidence: 96%

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

et al. 2019

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Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems. Molecules 2020, 25, 3 2 of 51 molecules [2]. Nowadays, the aptamer field covers various biomedical applications, including [3], therapeutic [4-6], aptasensors [7], biosensors [8,9], diagnostic [10,11], and imaging systems [12].Aptamers need to be stabilized for in vivo use against nuclease degradation, and their small size makes them susceptible to renal filtration. Aptamers' stabilization can be attained by chemically modifying them using different approaches. Moreover, introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of aptamers and thereby their target spectrum [12]. Modified aptamers may show improved chemical diversity relative to aptamers composed entirely of natural DNA or RNA nucleotides and expand their applications in diagnostics, therapeutics, and nanotechnology [1].Chemical modifications of aptamer oligonucleotides are needed mainly to enhance their resistance to nuclease degradation and lowering their renal filtration. Additionally, chemical modifications, in some cases, may increase the aptamer-binding affinity [13]. Many approaches have been introduced to promote the stability of aptamers without altering their binding affinity and specificity against their targets. These approaches include chemical modification of the phosphate...

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A Crystal Structure of a Functional RNA Molecule Containing an Artificial Nucleobase Pair

Cited by 7 publications

References 24 publications

Crystal structures of deprotonated nucleobases from an expanded DNA alphabet

Crystal structures of deprotonated nucleobases from an expanded DNA alphabet

Theoretical Characterization of the H-Bonding and Stacking Potential of Two Nonstandard Nucleobases Expanding the Genetic Alphabet

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies

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