Insights into the structural features and stability of peptide nucleic acid with a D-prolyl-2-aminocyclopentane carboxylic acid backbone that binds to DNA and RNA

We have investigated the incorporation of C6 derivatives of uracil into polypyrimidine peptide nucleic acid oligomers. Starting with uracil-6-carboxylic acid (orotic acid), a peptide nucleic acid monomer compatible with Fmoc-based synthesis was prepared. This monomer then served as a convertible nucleobase whereupon treatment of the resin-bound methyl orotate containing hexamers with hydroxide or amines cleanly converted the ester to an orotic acid or orotamide-containing peptide nucleic acid. Peptide nucleic acid hexamers containing the C6-modified nucleobase hybridized to both poly(riboadenylic acid) and poly(deoxyriboadenylic acid) via triplex formation. Complexes formed with poly(riboadenylic acid) were more stable than those formed with poly(dexoyriboadenylic acid), as measured by temperature-dependent UV spectroscopy. However, both of these complexes were destabilized relative to the complexes formed by an unmodified peptide nucleic acid oligomers. Internal or doubly substituted hexamers are destabilized more strongly than a terminally substituted one, and the type of substitution (carboxamide, ester, carboxylic acid) affects the overall triplex stability. These results clearly show that incorporation of a C6-substituted uracil into polypyrimidine PNA is detrimental to triplex formation. We have also extended this chemistry to incorporate uracil-5-methylcarboxylate into a peptide nucleic acid hexamer. After on-resin conversion of the C5 ester to the 3-(N,N-dimethylamino)propylamide, significant stabilization of the triplex formed with poly(riboadenylic acid) was observed, which illustrates the compatibility of C5 substitution with peptide nucleic acid directed triple helix formation. Key words: peptide nucleic acid, triple helix, orotic acid, orotamide, PNA.

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Backbone Modifications of Aromatic Peptide Nucleic Acid (APNA) Monomers and Their Hybridization Properties with DNA and RNA

The Journal of Organic Chemistry ◽

10.1021/jo001650o ◽

2001 ◽

Vol 66 (10) ◽

pp. 3372-3379 ◽

Cited By ~ 12

Author(s):

Lee D. Fader ◽

Michael Boyd ◽

Youla S. Tsantrizos

Keyword(s):

Nucleic Acid ◽

Peptide Nucleic Acid ◽

Dna And Rna

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Synthesis and physicochemical properties of 20-mer peptide nucleic acid conjugates with testosterone 17β-carboxylic acid

Tetrahedron Letters ◽

10.1016/j.tetlet.2020.151781 ◽

2020 ◽

Vol 61 (17) ◽

pp. 151781

Author(s):

Ryotaro Yagita ◽

Kazuma Murakami ◽

Hisafumi Ikeda ◽

Kazuhiro Irie

Keyword(s):

Nucleic Acid ◽

Carboxylic Acid ◽

Physicochemical Properties ◽

Peptide Nucleic Acid

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Synthesis of α-(R)-/γ-(S)-Dimethyl Substituted Peptide Nucleic Acid Submonomer Using Mitsunobu Reaction

Letters in Organic Chemistry ◽

10.2174/1570178616666190118155031 ◽

2019 ◽

Vol 16 (5) ◽

pp. 437-446

Author(s):

Ahmed S. Abdelbaky ◽

Ivan A. Prokhorov ◽

Igor P. Smirnov ◽

Kristina M. Koroleva ◽

Vitaliy I. Shvets ◽

...

Keyword(s):

Nucleic Acid ◽

Peptide Nucleic Acid ◽

Solid Phase ◽

Genetic Diseases ◽

Mitsunobu Reaction ◽

Phase Synthesis ◽

Dna And Rna ◽

Pna Synthesis ◽

Biomedical Technologies

One of the major challenges facing modern biochemical and biomedical technologies are finding molecular tools for diagnosis and detection of genetic diseases. In this connection, several classes of oligonucleotides have been developed that can recognize and bind to DNA and RNA with high affinity and sequence selectivity and withstand enzymatic degradation by proteases and nucleases; however, few can traverse the cell membrane on their own. One such promising class of nucleic acid mimics developed in the last two decades which showed good results in vitro, are the peptide nucleic acids (PNAs). New chiral α- and γ-peptide Nucleic Acid (PNA) submonomer with methyl substituents in pseudopeptide backbone were synthesized via Mitsunobu reaction. The α-(R)-/γ-(S)-configuration of the chiral centres will ensure the preorganization of the PNA oligomer into a right-handed helix. The results obtained showed that Boc/Fmoc-submonomer compatible with Boc-protocol PNAs solid-phase synthesis on an MBHA resin. We synthesized simple and efficient α-R-, γ-S-disubstituted PNA submonomer based on L-Ala and D-Ala with the construction of the intermediate pseudopeptide moiety by Mitsunobu reaction for subsequent use in the Boc-Protocol of solid phase PNA synthesis.

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Structural Insights on Tiny Peptide Nucleic Acid (PNA) Analogues of miRNA-34a: An in silico and Experimental Integrated Approach

Frontiers in Chemistry ◽

10.3389/fchem.2020.568575 ◽

2020 ◽

Vol 8 ◽

Author(s):

Maria Moccia ◽

Flavia Anna Mercurio ◽

Emma Langella ◽

Valerio Piacenti ◽

Marilisa Leone ◽

...

Keyword(s):

Nucleic Acid ◽

Peptide Nucleic Acid ◽

Uv Spectroscopy ◽

Integrated Approach ◽

Structural Features ◽

Seed Region ◽

Rna Sequences ◽

Nmr Characterization ◽

Rna Targeting ◽

Fluorescent Tag

In the present work, structural features of the interaction between peptide nucleic acid (PNA)-based analogs of the tumor-suppressor microRNA-34a with both its binding sites on MYCN mRNA were investigated. In particular, the region from base 1 to 8 (“seed” region) of miR-34a was reproduced in the form of an 8-mer PNA fragment (tiny PNA), and binding to target 3'UTR MYCN mRNA, was studied by a seldom reported and detailed NMR characterization, providing evidence for the formation of anti-parallel duplexes with a well-organized structural core. The formation of PNA-3'UTR duplexes was also confirmed by Circular Dichroism, and their melting curves were measured by UV spectroscopy. Nevertheless, this study offered a valuable comparison between molecular dynamics predictions and experimental evidence, which showed great correlation. Preliminary uptake assays were carried out in Neuroblastoma Kelly cells, using short peptide conjugates as carriers and FITC fluorescent tag for subcellular localization. Moderate internalization was observed without the use of transfecting agents. The reported results corroborate the interest toward the design and development of chimeric PNA/RNA sequences as effective RNA-targeting agents.

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