γ‐Substituted Peptide Nucleic Acids Constructed from <scp>L</scp>‐Lysine are a Versatile Scaffold for Multifunctional Display

Englund, Ethan A.; Appella, Daniel H.

doi:10.1002/anie.200603483

Cited by 102 publications

(65 citation statements)

References 48 publications

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“…17 Various substituents can be placed at this position to improve water solubility 18 or cell penetration 19,20 or to incorporate other functions. 21,22 Because of its straightforward access via proline derivatives having well-defined stereochemistries, the pyrrolidine ring has been extensively used as a constraint element in the design of new PNA structures ( Figure 3). However, few studies have fully evaluated the general base-pairing behaviors of nonchimeric mixed-sequence pyrrolidine-containing PNA, 23,24 and none of these offer significant advantages over the well-established aegPNA.…”

Section: Conformationally Constrained Pnamentioning

confidence: 99%

Pyrrolidinyl PNA with α/β-Dipeptide Backbone: From Development to Applications

Vilaivan

2015

Acc. Chem. Res.

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The specific pairing between two complementary nucleobases (A·T, C·G) according to the Watson-Crick rules is by no means unique to natural nucleic acids. During the past few decades a number of nucleic acid analogues or mimics have been developed, and peptide nucleic acid (PNA) is one of the most intriguing examples. In addition to forming hybrids with natural DNA/RNA as well as itself with high affinity and specificity, the uncharged peptide-like backbone of PNA confers several unique properties not observed in other classes of nucleic acid analogues. PNA is therefore suited to applications currently performed by conventional oligonucleotides/analogues and others potentially beyond this. In addition, PNA is also interesting in its own right as a new class of oligonucleotide mimics. Unlimited opportunities exist to modify the PNA structure, stimulating the search for new systems with improved properties or additional functionality not present in the original PNA, driving future research and applications of these in nanotechnology and beyond. Although many structural variations of PNA exist, significant improvements to date have been limited to a few constrained derivatives of the privileged N-2-aminoethylglycine PNA scaffold. In this Account, we summarize our contributions in this field: the development of a new family of conformationally constrained pyrrolidinyl PNA having a nonchimeric α/β-dipeptide backbone derived from nucleobase-modified proline and cyclic β-amino acids. The conformational constraints dictated by the pyrrolidine ring and the β-amino acid are essential requirements determining the binding efficiency, as the structure and stereochemistry of the PNA backbone significantly affect its ability to interact with DNA, RNA, and in self-pairing. The modular nature of the dipeptide backbone simplifies the synthesis and allows for rapid structural optimization. Pyrrolidinyl PNA having a (2'R,4'R)-proline/(1S,2S)-2-aminocyclopentanecarboxylic backbone (acpcPNA) binds to DNA with outstanding affinity and sequence specificity. It also binds to RNA in a highly sequence-specific fashion, albeit with lower affinity than to DNA. Additional characteristics include exclusive antiparallel/parallel selectivity and a low tendency for self-hybridization. Modification of the nucleobase or backbone allowing site-specific incorporation of labels and other functions to acpcPNA via click and other conjugation chemistries is possible, generating functional PNAs that are suitable for various applications. DNA sensing and biological applications of acpcPNA have been demonstrated, but these are still in their infancy and the full potential of pyrrolidinyl PNA is yet to be realized. With properties competitive with, and in some aspects superior to, the best PNA technology available to date, pyrrolidinyl PNA offers great promise as a platform system for future elaboration for the fabrication of new functional materials, nanodevices, and next-generation analytical tools.

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Section: Conformationally Constrained Pnamentioning

confidence: 99%

Pyrrolidinyl PNA with α/β-Dipeptide Backbone: From Development to Applications

Vilaivan

2015

Acc. Chem. Res.

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“…1) have recently gained increasing attention, due to their peculiar DNA binding abilities easily tunable according to the different configurations, 6,7 to the new properties induced by the aminoacidic residues 8,9 and to the possibility to use amino acid side chains in order to link new functionalities. 10,11 Since the performances of chiral PNAs in terms of binding specificity and selectivity are strongly affected by the configurations of the stereogenic centers, their optical purity is a primary issue, although often neglected. In particular, PNA synthesis of chiral derivatives substituted in position 2 can be strongly affected by racemization, as demonstrated by a GC method developed by our group.…”

Section: Introductionmentioning

confidence: 99%

A Fmoc-based submonomeric strategy for the solid phase synthesis of optically pure chiral PNAs

Tedeschi

Sforza

Maffei

et al. 2008

Tetrahedron Letters

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“…25 Functionalizing PNA at the gamma position would also allow a peptide to be connected anywhere along the backbone or even at multiple locations to form stable cyclic PNA-peptides. 21,26 Although conjugating fluorescent dyes and other small molecules to peptides or PNA is greatly simplified when performed after synthesis while the product is still on the solid phase, the conjugation efficiency decreases for larger molecules and the cleavage and purification conditions can be detrimental to some molecules, such as metallopeptides 27 or folded peptides and proteins.…”

Section: Introductionmentioning

confidence: 99%

Purification and assembly of thermostable Cy5 labeled γ-PNAs into a 3D DNA nanocage

Flory

Johnson

Simmons

et al. 2014

Artificial DNA: PNA & XNA

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Abbreviations: PNA, peptide nucleic acid; DBCO, dibenzocyclooctyl; PAGE, polyacrylamide gel electrophoresis; RP-HPLC, reversephase high pressure liquid chromatography; MALDI-MS, matrix assisted laser desorption ionization mass spectrometry; IEX-FPLC, ion-exchange fast protein liquid chromatography; EtBr, ethidium bromide; DTNB, 5, 5 0 -dithiobis-(2-nitrobenzoic acid); TCEP, tris(2-carboxyethyl)phosphine.PNA is hybrid molecule ideally suited for bridging the functional landscape of polypeptides with the structural diversity that can be engineered with DNA nanostructures. However, PNA can be more challenging to work with in aqueous solvents due to its hydrophobic nature. A solution phase method using strain promoted, copper free click chemistry was developed to conjugate the fluorescent dye Cy5 to 2 bifunctional PNA strands as a first step toward building cyclic PNA-polypeptides that can be arranged within 3D DNA nanoscaffolds. A 3D DNA nanocage was designed with binding sites for the 2 fluorescently labeled PNA strands in close proximity to mimic protein active sites. Denaturing polyacrylamide gel electrophoresis (PAGE) is introduced as an efficient method for purifying charged, dyelabeled PNA conjugates from large excesses of unreacted dye and unreacted, neutral PNA. Elution from the gel in water was monitored by fluorescence and found to be more efficient for the more soluble PNA strand. Native PAGE shows that both PNA strands hybridize to their intended binding sites within the DNA nanocage. F€ orster resonance energy transfer (FRET) with a Cy3 labeled DNA nanocage was used to determine the dissociation temperature of one PNA-Cy5 conjugate to be near 50 C. Steady-state and time resolved fluorescence was used to investigate the dye orientation and interactions within the various complexes. Bifunctional, thermostable PNA molecules are intriguing candidates for controlling the assembly and orientation of peptides within small DNA nanocages for mimicking protein catalytic sites.

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γ‐Substituted Peptide Nucleic Acids Constructed from L‐Lysine are a Versatile Scaffold for Multifunctional Display

Cited by 102 publications

References 48 publications

Pyrrolidinyl PNA with α/β-Dipeptide Backbone: From Development to Applications

Pyrrolidinyl PNA with α/β-Dipeptide Backbone: From Development to Applications

A Fmoc-based submonomeric strategy for the solid phase synthesis of optically pure chiral PNAs

Purification and assembly of thermostable Cy5 labeled γ-PNAs into a 3D DNA nanocage

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