Amido-bridged nucleic acids with small hydrophobic residues enhance hepatic tropism of antisense oligonucleotides in vivo

2015 ◽  
Vol 13 (12) ◽  
pp. 3757-3765 ◽  
Author(s):  
Tsuyoshi Yamamoto ◽  
Aiko Yahara ◽  
Reiko Waki ◽  
Hidenori Yasuhara ◽  
Fumito Wada ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Building Block ◽  
Antisense Oligonucleotides ◽  
Hydrophobic Residues ◽  
Pharmacokinetic Properties ◽  
High Scalability ◽  
Small Hydrophobic

High scalability of a novel bicyclic nucleoside building block, amido-bridged nucleic acid (AmNA), to diversify pharmacokinetic properties of therapeutic antisense oligonucleotides is described.

scholarly journals Barcoding chemical modifications into nucleic acids improves drug stability in vivo

2018 ◽  
Vol 6 (44) ◽  
pp. 7197-7203 ◽  
Author(s):  
Cory D. Sago ◽  
Sujay Kalathoor ◽  
Jordan P. Fitzgerald ◽  
Gwyneth N. Lando ◽  
Naima Djeddar ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Drug Stability ◽  
Chemical Modifications

The efficacy of nucleic acid therapies can be limited by unwanted degradation.

scholarly journals Modified Nucleic Acids: Expanding the Capabilities of Functional Oligonucleotides

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4659 ◽  
Author(s):  
Steven Ochoa ◽  
Valeria T. Milam
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Chemical Structure ◽  
Chemical Diversity ◽  
Physiochemical Properties ◽  
Phosphate Backbone ◽  
Modified Nucleic Acids ◽  
Recent Developments ◽  
Diagnostic Applications

In the last three decades, oligonucleotides have been extensively investigated as probes, molecular ligands and even catalysts within therapeutic and diagnostic applications. The narrow chemical repertoire of natural nucleic acids, however, imposes restrictions on the functional scope of oligonucleotides. Initial efforts to overcome this deficiency in chemical diversity included conservative modifications to the sugar-phosphate backbone or the pendant base groups and resulted in enhanced in vivo performance. More importantly, later work involving other modifications led to the realization of new functional characteristics beyond initial intended therapeutic and diagnostic prospects. These results have inspired the exploration of increasingly exotic chemistries highly divergent from the canonical nucleic acid chemical structure that possess unnatural physiochemical properties. In this review, the authors highlight recent developments in modified oligonucleotides and the thrust towards designing novel nucleic acid-based ligands and catalysts with specifically engineered functions inaccessible to natural 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.

The reaction of the psoralens with deoxyribonucleic acid

1984 ◽  
Vol 17 (1) ◽  
pp. 1-44 ◽  
Author(s):  
John E. Hearst ◽  
Stephen T. Isaacs ◽  
David Kanne ◽  
Henry Rapoport ◽  
Kenneth Straub
Keyword(s):  
Natural Selection ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Chemical Modification ◽  
Deoxyribonucleic Acid ◽  
Molecular Level ◽  
Virus Particles ◽  
Cross Links ◽  
High Concentrations

Psoralen photochemistry is specific for nucleic acids and is better understood at the molecular level than are all other methods of chemical modification of nucleic acids. These compounds are used both for in vivo structure analysis and for photochemotherapy since they easily penetrate both cells and virus particles. Apparently, natural selection has selected for membrane and virus penetrability during the evolution of these natural products. Most cells are unaffected by relatively high concentrations of psoralens in the absence of ultraviolet light, and the metabolites of the psoralens have thus far not created a problem. Finally, psoralens form both monoadduct and cross-links in nucleic acid helices, the yield of each being easily controlled by the conditions used during the photochemistry.

Hydroxyproline-Based DNA Mimics: A Review on Synthesis and Properties

2006 ◽  
Vol 71 (7) ◽  
pp. 929-955 ◽  
Author(s):  
Vladimir A. Efimov ◽  
Oksana G. Chakhmakhcheva
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Phosphonic Acid ◽  
Peptide Nucleic Acids ◽  
Biological Properties ◽  
High Potential ◽  
Physicochemical And Biological Properties

With the aim to improve physicochemical and biological properties of natural oligonucleotides, many types of DNA analogues and mimics are designed on the basis of hydroxyproline and its derivatives, and their properties are evaluated. Among them, two types of DNA mimics representing hetero-oligomers constructed from alternating monomers of phosphono peptide nucleic acids and monomers on the base of trans-1-acetyl-4-hydroxy-L-proline (HypNA-pPNAs) and oligomers constructed from monomers containing (2S,4R)-1-acetyl-4-hydroxypyrrolidine-2-phosphonic acid backbone (pHypNAs) are of particular interest. In a set of in vitro and in vivo assays, it was shown that HypNA-pPNAs and pHypNAs demonstrated a high potential for the use in nucleic acid based diagnostics, isolation of nucleic acids and antisense experiments. A review with 53 references.

Investigation of twisted intercalating nucleic acid (TINA)-modified antisense oligonucleotides for splice modulation by induced exon-skipping in vitro

RSC Advances ◽  
2016 ◽  
Vol 6 (97) ◽  
pp. 95169-95172 ◽  
Author(s):  
Bao T. Le ◽  
Vyacheslav V. Filichev ◽  
Rakesh N. Veedu
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Antisense Oligonucleotides ◽  
Exon Skipping

We have investigated the applicability of twisted intercalating nucleic acids (TINA)-modified antisense oligonucleotides (AOs) in exon skipping. We found that TINA-modified AOs induced exon skipping.

scholarly journals Exploring miR-9 Involvement in Ciona intestinalis Neural Development Using Peptide Nucleic Acids

2020 ◽  
Vol 21 (6) ◽  
pp. 2001
Author(s):  
Silvia Mercurio ◽  
Silvia Cauteruccio ◽  
Raoul Manenti ◽  
Simona Candiani ◽  
Giorgio Scarì ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Neural Development ◽  
Peptide Nucleic Acids ◽  
Model Organism ◽  
Ciona Intestinalis ◽  
Transcriptional Level ◽  
Regulate Gene Expression

The microRNAs are small RNAs that regulate gene expression at the post-transcriptional level and can be involved in the onset of neurodegenerative diseases and cancer. They are emerging as possible targets for antisense-based therapy, even though the in vivo stability of miRNA analogues is still questioned. We tested the ability of peptide nucleic acids, a novel class of nucleic acid mimics, to downregulate miR-9 in vivo in an invertebrate model organism, the ascidian Ciona intestinalis, by microinjection of antisense molecules in the eggs. It is known that miR-9 is a well-conserved microRNA in bilaterians and we found that it is expressed in epidermal sensory neurons of the tail in the larva of C. intestinalis. Larvae developed from injected eggs showed a reduced differentiation of tail neurons, confirming the possibility to use peptide nucleic acid PNA to downregulate miRNA in a whole organism. By identifying putative targets of miR-9, we discuss the role of this miRNA in the development of the peripheral nervous system of ascidians.

Nucleic Acid Therapeutics in Huntington’s Disease

2019 ◽  
Vol 13 (3) ◽  
pp. 187-206 ◽  
Author(s):  
Kuljit Singh ◽  
Ipsita Roy
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Protein Aggregation ◽  
Huntington's Disease ◽  
Antisense Oligonucleotides ◽  
Protein Misfolding ◽  
Mutant Protein ◽  
Mutant Huntingtin ◽  
Nucleic Acid Therapeutics ◽  
Delivery Techniques

Background: Protein misfolding is a critical factor in the progression of a large number of neurodegenerative diseases. The incorrectly folded protein is prone to aggregation, leading to aberrant interaction with other cellular proteins, elevated oxidative stress, impaired cellular machinery, finally resulting in cell death. Due to its monogenic origin, Huntington’s disease (HD) is a poster child of protein misfolding neurodegenerative disorders. The presence of neuronal inclusions of mutant huntingtin N-terminal fragments, mainly in the cortex and striatum, is a neuropathological hallmark of HD. Inhibition of protein misfolding and aggregation has been attempted using a variety of conventional protein stabilizers. Methods: This review describes how, in recent times, nucleic acid therapeutics has emerged as a selective tool to downregulate the aberrant transcript and reduce expression of mutant huntingtin, thereby alleviating protein aggregation. Different strategies of use of nucleic acids, including antisense oligonucleotides, short inhibitory RNA sequences and aptamers have been discussed. The following patent databases were consulted: European Patent Office (EPO), the United States Patent and Trademark Office (USPTO), Patent scope Search International and National Patent Collections (WIPO) and Google Patents. Results: Tools such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) are potential therapeutic agents which target the post-transcriptional step, accelerating mRNA degradation and inhibiting the production of the mutant protein. These nucleic acid sequences not only target the elongated CAG triplet repeat translating to an expanded polyglutamine tract in the mutant protein, but have also been used to target single nucleotide polymorphisms associated with the mutant allele. The therapeutic sequences have been investigated in a number of cells and animal models of HD. One antisense sequence, with desirable safety properties, has recently shown downregulation of huntingtin protein in a limited clinical trial. RNA aptamers have also shown promising results in inhibiting protein aggregation in a yeast model of HD. Novel drug delivery techniques have been employed to overcome the blood brain barrier for the use of these therapeutic sequences. Conclusion: The selectivity and specificity imparted by nucleic acids, along with novel delivery techniques, make them hopeful candidates for the development of a curative strategy for HD.

Clinical Trials of Functional Nucleic Acids

2018 ◽  
Vol 7 (2) ◽  
pp. 46-60 ◽  
Author(s):  
Martina Traykovska ◽  
Sjoerd Miedema ◽  
Robert Penchovsky
Keyword(s):  
Clinical Trials ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Pharmaceutical Companies ◽  
Nucleic Acid Therapeutics ◽  
Drug Candidates ◽  
Safety Risks ◽  
Functional Nucleic Acids ◽  
Administration Methods

This chapter describes how functional nucleic acids, such as aptamers, antisense oligonucleotides (ASOs), small interfering (si) RNAs, and ribozymes are considered by some researchers as valuable tools to develop therapeutic agents. They have not been particularly fast in reaching the market as medicines, due to endogenous barriers to extracellular trafficking and cellular uptake of nucleic acids and their inherent instability when applied in vivo. However, research carried out by the nucleic acid engineering community and pharmaceutical companies to circumvent these obstacles has led to the approval of a few aptamers and ASOs as drugs. Nucleic acid therapeutics are usually administered locally to diseased tissue. The drug candidates currently in clinical trials commonly use the same administration methods as previously licensed nucleic acid therapeutics. These administration techniques carry their own safety risks and advantages. In this article, the present state is discussed and prospective options for the use ASOs and aptamers as drugs are listed.

Advances in the synthesis and antisense technology applications of bridged nucleic acid monomers

2021 ◽  
Vol 25 ◽  
Author(s):  
Priyanka Mangla ◽  
Balaji Olety ◽  
Vivek K. Sharma
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Antisense Oligonucleotides ◽  
Cost Effective ◽  
Biophysical Properties ◽  
Technology Applications ◽  
Effective Synthesis ◽  
Target Rna ◽  
Ribose Sugar ◽  
Tremendous Impact

: Bridged nucleic acids (BNA) or locked nucleic acids (LNA) are a class of nucleic acids modification, which is obtained by connecting the 2'-O and 4'-C of ribose sugar using a methylene bridge. This ‘bridging or locking’ (hence the name) of ribose sugar has a tremendous impact both on the biological and biophysical properties of therapeutic nucleic acids. They have enhanced stability against nucleases and also have higher binding affinity for the target RNA. Owing to these advantages, BNA is one of the most preferred nucleic acid modifications of antisense oligonucleotides (ASOs). However, the synthesis of BNA monomers which are lengthy and low-yielding, requires extensive protection and deprotection of the sugar functionalities. In this article, we aim to review challenges associated with their synthesis, and discuss recent chemical, chemo-enzymatic, and transglycosylation strategies employed for efficient and cost-effective synthesis of BNA monomers and selected BNA analogues.

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