Synthesis and biophysical characterization of oligonucleotides modified with O2′-alkylated RNA monomers featuring substituted pyrene moieties

Karmakar, Saswata; Horrocks, Tyler; Gibbons, Bradley C.; Guenther, Dale C.; Emehiser, Raymond G; Hrdlicka, Patrick J.

doi:10.1039/c8ob02764a

Org. Biomol. Chem.

2019

DOI: 10.1039/c8ob02764a

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Synthesis and biophysical characterization of oligonucleotides modified with O2′-alkylated RNA monomers featuring substituted pyrene moieties

Saswata Karmakar

Tyler Horrocks

Bradley C. Gibbons

et al.

Abstract: Oligonucleotides modified with monomers V or Y display up to 22-fold increases in pyrene fluorescence emission upon binding with complementary RNA.

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Cited by 3 publications

References 48 publications

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Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Kundu

Ghosh

et al. 2022

J. Org. Chem.

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Phosphorodiamidate morpholino oligonucleotides (PMOs) constitute 3 out of the 11 FDA-approved oligonucleotide-based drugs in the last 6 years. PMOs can effectively silence disease-causing genes and modify splicing. However, PMO synthesis has remained challenging for a variety of reasons: inefficient deprotection and coupling methods and instability of monomers. Here, we report the development of a suitable combination of resin supports, deblocking and coupling reagents for synthesizing PMOs using either trityl or Fmoc-protected chlorophosphoramidate monomers. The synthesized PMOs using both the methods on a solid support have been validated for gene silencing in a zebrafish model. The protocol was successfully transferred into an automated DNA synthesizer to make several sequences of PMOs, demonstrating for the first time the adaptation of regular PMOs in a commercial DNA synthesizer. Moreover, PMOs with longer than 20-mer sequences, including FDA-approved Eteplirsen (30-mer), were achieved in >20% overall yield that is superior to previous reports. Hybridization study shows that PMOs exhibit a higher binding affinity toward complementary DNA relative to the DNA/DNA duplex (>6 °C). Additionally, the introduction of Fmoc chemistry into PMOs opens up the possibility for PMO synthesis in commercial peptide synthesizers for future development.

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Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Kundu

Ghosh

et al. 2022

J. Org. Chem.

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Recognition of double-stranded DNA using LNA-modified toehold Invader probes

et al. 2021

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Sequence-Specific Recognition of Double-Stranded DNA by Peptide Nucleic Acid Forming Double-Duplex Invasion Complex

2022

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Peptide nucleic acid (PNA) is an analog of natural nucleic acids, where the sugar-phosphate backbone of DNA is replaced by an electrostatically neutral N-(2-aminoethyl)glycine backbone. This unique peptide-based backbone enables PNAs to form a very stable duplex with the complementary nucleic acids via Watson–Crick base pairing since there is no electrostatic repulsion between PNA and DNA·RNA. With this high nucleic acid affinity, PNAs have been used in a wide range of fields, from biological applications such as gene targeting, to engineering applications such as probe and sensor developments. In addition to single-stranded DNA, PNA can also recognize double-stranded DNA (dsDNA) through the formation of a double-duplex invasion complex. This double-duplex invasion is hard to achieve with other artificial nucleic acids and is expected to be a promising method to recognize dsDNA in cellula or in vivo since the invasion does not require the prior denaturation of dsDNA. In this paper, we provide basic knowledge of PNA and mainly focus on the research of PNA invasion.

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Synthesis and biophysical characterization of oligonucleotides modified with O2′-alkylated RNA monomers featuring substituted pyrene moieties

Abstract: Oligonucleotides modified with monomers V or Y display up to 22-fold increases in pyrene fluorescence emission upon binding with complementary RNA.

Cited by 3 publications

References 48 publications

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer

Recognition of double-stranded DNA using LNA-modified toehold Invader probes

Sequence-Specific Recognition of Double-Stranded DNA by Peptide Nucleic Acid Forming Double-Duplex Invasion Complex

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