Design, Synthesis, and Properties of Boat-Shaped Glucopyranosyl Nucleic Acid

Mori, Kazuto; Kodama, Tetsuya; Obika, Satoshi

doi:10.1021/ol2025229

Cited by 8 publications

(4 citation statements)

References 30 publications

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“…To explain the destabilizing behavior of the cANA incorporation, we speculated that the conformation of the cANA monomer in the duplex differs somewhat from that of Me-ANA. Recently, it has been suggested that very slight perturbations in the lean of the nucleobase or the rotation angle of the glycosidic bond axis can result in a large destabilizing effect . While the crystal structure of 15a suggests that a nearly perfect overlay with Me-ANA or HNA is possible, it is also likely that the addition of the 3′,5′-CH 2 O- bridge may introduce additional steric effects modifying the preferred conformation.…”

supporting

confidence: 70%

Synthesis and Biophysical Properties of Constrained d-Altritol Nucleic Acids (cANA)

et al. 2013

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The first synthesis of constrained altritol nucleic acids (cANA) containing antisense oligonucleotides (ASOs) was carried out to ascertain how conformationally restricting the D-altritol backbone-containing ASO (Me-ANA) would affect their ability to form duplexes with RNA. It was found that the thermal stability was reduced (cANA/RNA -1.1 °C/modification) compared to DNA/RNA, suggesting the constrained system results in a small destabilizing perturbation in the duplex structure.

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supporting

confidence: 70%

Synthesis and Biophysical Properties of Constrained d-Altritol Nucleic Acids (cANA)

et al. 2013

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“…182 Expansion of the 2.2.1 ring system in LNA to a 2.2.2 ring system as exemplified by boat-shaped glucopyranosyl nucleic acid (bsNA) was also unsuccessful. 183 The poor result observed with the 2.2.2 scaffold was rationalized by changes in the lean of the base and the glycosidic torsion angles which presumably interferes with duplex formation. Interestingly, an analogue which represents the 2.2.2 version of α-L-LNA was slightly more successful but still less stabilizing as compared to α-L-LNA (Figure 14).…”

Section: ′-O-methoxyethyl Rna (Moe)mentioning

confidence: 99%

“…Expansion of the 2.2.1 ring system in LNA to a 2.2.2 ring system as exemplified by boat-shaped glucopyranosyl nucleic acid (bsNA) was also unsuccessful . The poor result observed with the 2.2.2 scaffold was rationalized by changes in the lean of the base and the glycosidic torsion angles which presumably interferes with duplex formation.…”

Section: Furanose Sugar Modificationsmentioning

confidence: 99%

The Medicinal Chemistry of Therapeutic Oligonucleotides

2016

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Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and conjugation strategies which can improve the nuclease stability, RNA-binding affinity, and pharmacokinetic properties of oligonucleotides for therapeutic applications. In this perspective, we present a summary of the most commonly used nucleobase, sugar and backbone modification, and conjugation strategies used in oligonucleotide medicinal chemistry.

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“…The following TRPC3/C6/C7 activators were employed in the current study: L687 ( Supplementary Figure S1 , WO/2022/118966) ( 29 ), Cannabidiol (CBD) (#Axon1234; Axon Medchem, VA, USA), and GSK1702934A (#6508; Tocris Bioscience, Bristol, UK). SKF96365 (#1147/10; R&D Systems, MN, USA) was used as the TRPC channel inhibitor.…”

Section: Methodsmentioning

confidence: 99%

A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides

Kohashi,

Nagata,

Tamenori

et al. 2024

Nucleic Acids Research

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Antisense oligonucleotide (ASO) therapy is a novel therapeutic approach in which ASO specifically binds target mRNA, resulting in mRNA degradation; however, cellular uptake of ASOs remains critically low, warranting improvement. Transient receptor potential canonical (TRPC) channels regulate Ca2+ influx and are activated upon stimulation by phospholipase C-generated diacylglycerol. Herein, we report that a novel TRPC3/C6/C7 activator, L687, can induce cellular ASO uptake. L687-induced ASO uptake was enhanced in a dose- and incubation-time-dependent manner. L687 enhanced the knockdown activity of various ASOs both in vitro and in vivo. Notably, suppression of TRPC3/C6 by specific siRNAs reduced ASO uptake in A549 cells. Application of BAPTA-AM, a Ca2+ chelator, and SKF96365, a TRPC3/C6 inhibitor, suppressed Ca2+ influx via TRPC3/C6, resulting in reduced ASO uptake, thereby suggesting that Ca2+ influx via TRPC3/C6 is critical for L687-mediated increased ASO uptake. L687 also induced dextran uptake, indicating that L687 increased endocytosis. Adding ASO to L687 resulted in endosome accumulation; however, the endosomal membrane disruptor UNC7938 facilitated endosomal escape and enhanced knockdown activity. We discovered a new function for TRPC activators regarding ASO trafficking in target cells. Our findings provide an opportunity to formulate an innovative drug delivery system for the therapeutic development of ASO.

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Design, Synthesis, and Properties of Boat-Shaped Glucopyranosyl Nucleic Acid

Cited by 8 publications

References 30 publications

Synthesis and Biophysical Properties of Constrained d-Altritol Nucleic Acids (cANA)

Synthesis and Biophysical Properties of Constrained d-Altritol Nucleic Acids (cANA)

The Medicinal Chemistry of Therapeutic Oligonucleotides

A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides

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