2′F-Arabinonucleic acids (2′F-ANA) — History, properties, and new frontiers

2008 ◽  
Vol 86 (7) ◽  
pp. 641-656 ◽  
Author(s):  
Jonathan K Watts ◽  
Masad J Damha
Keyword(s):  
Gene Silencing ◽  
Enzymatic Synthesis ◽  
Antisense Oligonucleotides ◽  
Hydrolytic Stability ◽  
Rnase H ◽  
Modified Oligonucleotides ◽  
Look Ahead ◽  
Acids And Bases ◽  
Order Structures ◽  
Oligonucleotide Derivatives

The development of arabinonucleosides and oligoarabinonucleotides is described, focusing especially on 2′-deoxy-2′-fluoroarabinonucleosides (araF-N) and -oligonucleotides (2'F-ANA). In addition to their chemical and enzymatic synthesis, we discuss various properties of 2′F-ANA: hydrolytic stability (to nucleases, acids, and bases), binding affinity to complementary strands, structure and conformation, and optimization of RNase H activity. We also discuss the use of 2′F-ANA in gene-silencing approaches (antisense, siRNA), and in the stabilization of higher-order structures (such as triplexes and quadruplexes) including aptamers. Finally, we examine several other oligonucleotide derivatives based on 2′F-ANA and look ahead to the future of 2′-fluoroarabinonucleosides and -oligonucleotides.Key words: arabinonucleic acids, 2′F-ANA, antisense oligonucleotides, siRNA, modified oligonucleotides.

scholarly journals In vitro and in vivo properties of therapeutic oligonucleotides containing non-chiral 3′ and 5′ thiophosphate linkages

2019 ◽  
Vol 48 (1) ◽  
pp. 63-74 ◽  
Author(s):  
Jörg Duschmalé ◽  
Henrik Frydenlund Hansen ◽  
Martina Duschmalé ◽  
Erich Koller ◽  
Nanna Albaek ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Rnase H ◽  
Modified Oligonucleotides ◽  
In Vitro Experiments ◽  
Chemical Modifications ◽  
Pharmacokinetic Properties ◽  
Target Binding ◽  
The Individual

Abstract The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well as improved pharmacokinetic properties. However, due to the chiral nature of the phosphorothioate, every PS group doubles the amount of possible stereoisomers. Thus PS oligonucleotides are generally obtained as an inseparable mixture of a multitude of diastereoisomeric compounds. Herein, we describe the introduction of non-chiral 3′ thiophosphate linkages into antisense oligonucleotides and report their in vitro as well as in vivo activity. The obtained results are carefully investigated for the individual parameters contributing to antisense activity of 3′ and 5′ thiophosphate modified oligonucleotides (target binding, RNase H recruitment, nuclease stability). We conclude that nuclease stability is the major challenge for this approach. These results highlight the importance of selecting meaningful in vitro experiments particularly when examining hitherto unexplored chemical modifications.

Gapmer Antisense Oligonucleotides Containing 2′,3′‐Dideoxy‐2′‐fluoro‐3′‐ C ‐hydroxymethyl‐β‐ d ‐lyxofuranosyl Nucleotides Display Site‐Specific RNase H Cleavage and Induce Gene Silencing

2020 ◽  
Vol 26 (6) ◽  
pp. 1368-1379
Author(s):  
Mathias B. Danielsen ◽  
Chenguang Lou ◽  
Jolanta Lisowiec‐Wachnicka ◽  
Anna Pasternak ◽  
Per T. Jørgensen ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Antisense Oligonucleotides ◽  
Rnase H ◽  
Site Specific

scholarly journals Silencing Antibiotic Resistance with Antisense Oligonucleotides

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 416
Author(s):  
Saumya Jani ◽  
Maria Soledad Ramirez ◽  
Marcelo E. Tolmasky
Keyword(s):  
Antibiotic Resistance ◽  
Nucleic Acids ◽  
Antisense Oligonucleotides ◽  
Bacterial Infections ◽  
Genetic Disorders ◽  
Antibiotic Resistance Genes ◽  
Short Review ◽  
Rnase H ◽  
Biological Processes ◽  
Locked Nucleic Acids

Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics.

Gene Silencing Activity and Hepatic Accumulation of Antisense Oligonucleotides Bearing Cholesterol-Conjugated Thiono Triester at the Gap Region

2017 ◽  
Vol 27 (4) ◽  
pp. 232-237 ◽  
Author(s):  
Mado Nakajima ◽  
Takeshi Kasuya ◽  
Shinnichi Yokota ◽  
Reina Onishi ◽  
Tatsuya Ikehara ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Antisense Oligonucleotides

scholarly journals Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

2021 ◽  
Vol 17 ◽  
pp. 622-629
Author(s):  
Naohiro Horie ◽  
Takao Yamaguchi ◽  
Shinji Kumagai ◽  
Satoshi Obika
Keyword(s):  
Nucleic Acid ◽  
Binding Affinity ◽  
Antisense Oligonucleotides ◽  
Modified Oligonucleotides ◽  
Biophysical Properties ◽  
Chemical Modifications ◽  
Antisense Technology ◽  
Strong Affinity ◽  
The Stability

Chemical modifications have been extensively used for therapeutic oligonucleotides because they strongly enhance the stability against nucleases, binding affinity to the targets, and efficacy. We previously reported that oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing the thymine (T) nucleobase show excellent biophysical properties for applications in antisense technology. In this paper, we describe the synthesis of GuNA[Me] phosphoramidites bearing other typical nucleobases including adenine (A), guanine (G), and 5-methylcytosine (mC). The phosphoramidites were successfully incorporated into oligonucleotides following the method previously developed for the GuNA[Me]-T-modified oligonucleotides. The binding affinity of the oligonucleotides modified with GuNA[Me]-A, -G, or -mC toward the complementary single-stranded DNAs or RNAs was systematically evaluated. All of the GuNA[Me]-modified oligonucleotides were found to have a strong affinity for RNAs. These data indicate that GuNA[Me] could be a useful modification for therapeutic antisense oligonucleotides.

Enzymatic Synthesis of Periodic DNA Nanoribbons for Intracellular pH Sensing and Gene Silencing

2015 ◽  
Vol 137 (11) ◽  
pp. 3844-3851 ◽  
Author(s):  
Gang Chen ◽  
Di Liu ◽  
Chunbai He ◽  
Theodore R. Gannett ◽  
Wenbin Lin ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Intracellular Ph ◽  
Enzymatic Synthesis ◽  
Ph Sensing
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