scholarly journals Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins

2019 ◽  
Vol 47 (13) ◽  
pp. 7130-7142 ◽  
Author(s):  
Michiel Vanmeert ◽  
Jamoliddin Razzokov ◽  
Muhammad Usman Mirza ◽  
Stephen D Weeks ◽  
Guy Schepers ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Rational Design ◽  
Dna Ligase ◽  
Processing Enzymes ◽  
First Approximation ◽  
Acid Processing ◽  
First Time ◽  
Nucleic Acid Analogues

AbstractXenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.

scholarly journals Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 159
Author(s):  
Shintaro Fumoto ◽  
Tsuyoshi Yamamoto ◽  
Kazuya Okami ◽  
Yuina Maemura ◽  
Chisato Terada ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Rational Design ◽  
Intracellular Localization ◽  
Blood Stream ◽  
The Body ◽  
Endosomal Escape ◽  
Target Cells ◽  
Endocytosis Pathway

Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs.

Molecular insights on the dynamic stability of peptide nucleic acid functionalized carbon and boron nitride nanotubes

2021 ◽  
Vol 23 (1) ◽  
pp. 219-228
Author(s):  
Nabanita Saikia ◽  
Mohamed Taha ◽  
Ravindra Pandey
Keyword(s):  
Nucleic Acid ◽  
Boron Nitride ◽  
Nucleic Acids ◽  
Dynamic Stability ◽  
Peptide Nucleic Acid ◽  
Rational Design ◽  
Peptide Nucleic Acids ◽  
Boron Nitride Nanotubes ◽  
Molecular Hybrids ◽  
Single Wall Nanotubes

The rational design of self-assembled nanobio-molecular hybrids of peptide nucleic acids with single-wall nanotubes rely on understanding how biomolecules recognize and mediate intermolecular interactions with the nanomaterial's surface.

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.

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.

scholarly journals Iron mediates catalysis of nucleic acid processing enzymes: support for Fe(II) as a cofactor before the great oxidation event

2017 ◽  
Vol 45 (7) ◽  
pp. 3634-3642 ◽  
Author(s):  
C. Denise Okafor ◽  
Kathryn A. Lanier ◽  
Anton S. Petrov ◽  
Shreyas S. Athavale ◽  
Jessica C. Bowman ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Processing Enzymes ◽  
Great Oxidation Event ◽  
Acid Processing

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.

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.

scholarly journals THE INCORPORATION OF FORMATE-C14 INTO THE NUCLEIC ACIDS OF RATS WITH REGENERATING LIVER AND NOVIKOFF HEPATOMA

1959 ◽  
Vol 37 (1) ◽  
pp. 1405-1416 ◽  
Author(s):  
J. C. Nixon ◽  
S. H. Zbarsky
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Mitotic Activity ◽  
Intestinal Mucosa ◽  
Regenerating Liver ◽  
Simultaneous Presence ◽  
Novikoff Hepatoma ◽  
Mitotic Frequency ◽  
Host Tissues

A study was made of the incorporation in vivo of formate-C14 into the purines and thymine of regenerating liver and Novikoff hepatoma in the rat, during the period of maximum mitotic activity of these tissues. The effects of these tissues on one another and on certain host tissues were also studied. The maximum mitotic frequency of Novikoff hepatoma was observed on the 4th day of growth following transplantation. This tumor caused a decrease in formate incorporation into the nucleic acid purines and thymine of the host's spleen and intestinal mucosa but had little effect on liver. The results also indicated that the uptake of formate by the RNA adenine of spleen and intestinal mucosa and the DNA thymine of intestinal mucosa was diminished by the presence of regenerating liver. The simultaneous presence of both regenerating liver and Novikoff hepatoma generally lowered the incorporation of formate-C14 into the nucleic acids of the host spleen and intestinal mucosa. It was observed further that the utilization of formate by the nucleic acids of Novikoff hepatoma and regenerating rat liver was decreased in animals containing both of these rapidly dividing tissues.

Sign in / Sign up

Export Citation Format

Share Document