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Oligonucleotide, Therapy, and Applications 2.0
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Oligonucleotide, Therapy, and Applications 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (29 June 2022) | Viewed by 16360

Special Issue Editors

Prof. Dr. Salvador Aliño

E-Mail Website
Guest Editor
Pharmacogenetics Platform, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
Interests: pharmacogenetics; genetic variants; non-viral vector; transfection; hydrodynamic transfection; ex vivo organ; therapeutic oligonucleotides; antisense oligonucleotides
Special Issues, Collections and Topics in MDPI journals
Dr. Luis Sendra

E-Mail Website
Guest Editor
Pharmacogenetic Unit, Instituto de Investigación Sanitaria La Fe, Gene Therapy Group, Universitat de València, Valencia, Spain
Interests: gene therapy; non viral; oligonucleotides; vaccines; pharmacogenetic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oligonucleotides (ON) constitute a new group of molecular agents, the object of significant interest due to their potential value as drugs for diagnostic and therapeutic applications. Their special interest derives from the intrinsic characteristics of ONs: (a) ONs are informative agents, a property that derives from the order in which the nucleotides of each particular ON are arranged; (b) ONs can act as ligands (ASO, TFO, aptamers, G-quadruplex, etc.) of complementary nucleic acid sequences (DNA or RNA) due to their high capacity to hybridize (by means of Watson and Crick or Hoogsteen links) with other nucleotide sequences, resulting in specific gene modulatory effects. However, nonspecific sequences may also be of interest, as is the case with repetitive nucleotide sequences (CpG) with adjuvant effects of vaccines; (c) ONs can also rapidly evolve to achieve specific advantages of utility (targeting, stability, efficacy, toxicity, etc.) or high-sensitivity diagnostic technology (markers, analyzes, biosensors, FISH, microarrays, etc.), by chemical modification of nucleotides in any of their atoms. These properties show that ONs are first-order molecules due to their potential usefulness in practice.

In this collection of research articles and review papers, we aim to highlight their therapeutic, but also diagnostic and technological utility as drugs.

Prof. Salvador Aliño
Dr. Luis Sendra
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antisene
  • silencing
  • splicing
  • aptamer
  • gapmer
  • siRNA
  • CpG
  • editing
  • targeting
  • delivery
  • release
  • analysis
  • bioassay
  • biosensor
  • array
  • disease
  • diagnostics
  • FISH
  • beacons
  • vaccine
  • adjuvant
  • immunomodulation

Related Special Issues

Published Papers (7 papers)

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Research

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12 pages, 1720 KiB  
Article
Inhibition of Respiratory Syncytial Virus Infection by Small Non-Coding RNA Fragments
by Sandra Axberg Pålsson, Vaishnovi Sekar, Claudia Kutter, Marc R. Friedländer and Anna-Lena Spetz
Int. J. Mol. Sci. 2022, 23(11), 5990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115990 - 26 May 2022
Cited by 2 | Viewed by 1727
Abstract
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infection in infants, immunocompromised individuals and the elderly. As the only current specific treatment options for RSV are monoclonal antibodies, there is a need for efficacious antiviral treatments against RSV to be developed. We [...] Read more.
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infection in infants, immunocompromised individuals and the elderly. As the only current specific treatment options for RSV are monoclonal antibodies, there is a need for efficacious antiviral treatments against RSV to be developed. We have previously shown that a group of synthetic non-coding single-stranded DNA oligonucleotides with lengths of 25–40 nucleotides can inhibit RSV infection in vitro and in vivo. Based on this, herein, we investigate whether naturally occurring single-stranded small non-coding RNA (sncRNA) fragments present in the airways have antiviral effects against RSV infection. From publicly available sequencing data, we selected sncRNA fragments such as YRNAs, tRNAs and rRNAs present in human bronchoalveolar lavage fluid (BALF) from healthy individuals. We utilized a GFP-expressing RSV to show that pre-treatment with the selected sncRNA fragments inhibited RSV infection in A549 cells in vitro. Furthermore, by using a flow cytometry-based binding assay, we demonstrate that these naturally occurring sncRNAs fragments inhibit viral infection most likely by binding to the RSV entry receptor nucleolin and thereby preventing the virus from binding to host cells, either directly or via steric hindrance. This finding highlights a new function of sncRNAs and displays the possibility of using naturally occurring sncRNAs as treatments against RSV. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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15 pages, 2876 KiB  
Article
Study of Oligonucleotides Access and Distribution in Human Peripheral Blood Mononuclear Cells
by Manuel Fernández-Delgado, Luis Sendra, María José Herrero, Gladys G. Olivera-Pasquini, Alexander Batista-Duharte and Salvador F. Aliño
Int. J. Mol. Sci. 2022, 23(10), 5839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105839 - 23 May 2022
Cited by 1 | Viewed by 1785
Abstract
Therapeutic oligonucleotides have achieved great clinical interest since their approval as drug agents by regulatory agencies but their access and distribution in blood cells are not completely known. We evaluated by flow cytometry the ability of short fluorescent scramble oligonucleotides (ON*) to access [...] Read more.
Therapeutic oligonucleotides have achieved great clinical interest since their approval as drug agents by regulatory agencies but their access and distribution in blood cells are not completely known. We evaluated by flow cytometry the ability of short fluorescent scramble oligonucleotides (ON*) to access human peripheral blood mononuclear cells (PBMC) after incubating with ON* during 1 h and 7 days of culture follow-up ‘in vitro’. Blood samples were treated with chemically modified oligonucleotides (phosphorothioate backbone and 2′ O-Me ends) to resist nuclease digestion under culture conditions. The ON* internalization was determined after discarding the membrane-associated fluorescence by trypan blue quenching. Whereas the oligonucleotide accessed neutrophils and monocytes rapidly, achieving their maximum in 1 h and 24 h, respectively, lymphocytes required 7 days to achieve the maximum (80% of cells) transfection. The ON*ability to access lymphocyte types (T, B, and NK) and T cell subtypes (CD4+, CD8+, and CD4-CD8-) were similar, with T cells being more accessible. Regulatory CD4+ and CD8+ T cells were classified in low and high Foxp3 expressers, whose expression proved not to alter the ON* internalization during the first hour, achieving 53% of CD4+Foxp3+ and 40% of CD8+Foxp3+ cells. Our results contribute to understanding and improving the management of therapeutic ONs. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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12 pages, 5511 KiB  
Article
Anticoagulant Oligonucleotide–Peptide Conjugates: Identification of Thrombin Aptamer Conjugates with Improved Characteristics
by Vladimir B. Tsvetkov, Irina V. Varizhuk, Nikolay N. Kurochkin, Sergei A. Surzhikov, Igor P. Smirnov, Andrey A. Stomakhin, Natalia A. Kolganova and Edward N. Timofeev
Int. J. Mol. Sci. 2022, 23(7), 3820; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073820 - 30 Mar 2022
Cited by 3 | Viewed by 1816
Abstract
Oligonucleotide–peptide conjugates (OPCs) are a promising class of biologically active compounds with proven potential for improving nucleic acid therapeutics. OPCs are commonly recognized as an efficient instrument to enhance the cellular delivery of therapeutic nucleic acids. In addition to this application field, OPCs [...] Read more.
Oligonucleotide–peptide conjugates (OPCs) are a promising class of biologically active compounds with proven potential for improving nucleic acid therapeutics. OPCs are commonly recognized as an efficient instrument to enhance the cellular delivery of therapeutic nucleic acids. In addition to this application field, OPCs have an as yet unexplored potential for the post-SELEX optimization of DNA aptamers. In this paper, we report the preparation of designer thrombin aptamer OPCs with peptide side chains anchored to a particular thymidine residue of the aptamer. The current conjugation strategy utilizes unmodified short peptides and support-bound protected oligonucleotides with activated carboxyl functionality at the T3 thymine nucleobase. The respective modification of the oligonucleotide strand was implemented using N3-derivatized thymidine phosphoramidite. Aptamer OPCs retained the G-quadruplex architecture of the parent DNA structure and showed minor to moderate stabilization. In a series of five OPCs, conjugates bearing T3–Ser–Phe–Asn (SFN) or T3–Tyr–Trp–Asn (YWN) side chains exhibited considerably improved anticoagulant characteristics. Molecular dynamics studies of the aptamer OPC complexes with thrombin revealed the roles of the amino acid nature and sequence in the peptide subunit in modulating the anticoagulant activity. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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17 pages, 3300 KiB  
Article
PolyPurine Reverse Hoogsteen Hairpins Work as RNA Species for Gene Silencing
by Eva Aubets, Miguel Chillon, Carlos J. Ciudad and Véronique Noé
Int. J. Mol. Sci. 2021, 22(18), 10025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810025 - 16 Sep 2021
Cited by 4 | Viewed by 2143
Abstract
PolyPurine Reverse Hoogsteen Hairpins (PPRHs) are gene-silencing DNA-oligonucleotides developed in our laboratory that are formed by two antiparallel polypurine mirror repeat domains bound intramolecularly by Hoogsteen bonds. The aim of this work was to explore the feasibility of using viral vectors to deliver [...] Read more.
PolyPurine Reverse Hoogsteen Hairpins (PPRHs) are gene-silencing DNA-oligonucleotides developed in our laboratory that are formed by two antiparallel polypurine mirror repeat domains bound intramolecularly by Hoogsteen bonds. The aim of this work was to explore the feasibility of using viral vectors to deliver PPRHs as a gene therapy tool. After treatment with synthetic RNA, plasmid transfection, or viral infection targeting the survivin gene, viability was determined by the MTT assay, mRNA was determined by RT-qPCR, and protein levels were determined by Western blot. We showed that the RNA-PPRH induced a decrease in cell viability in a dose-dependent manner and an increase in apoptosis in PC-3 and HeLa cells. Both synthetic RNA-PPRH and RNA-PPRH intracellularly generated upon the transfection of a plasmid vector were able to reduce survivin mRNA and protein levels in PC-3 cells. An adenovirus type-5 vector encoding the PPRH against survivin was also able to decrease survivin mRNA and protein levels, leading to a reduction in HeLa cell viability. In this work, we demonstrated that PPRHs can also work as RNA species, either chemically synthesized, transcribed from a plasmid construct, or transcribed from viral vectors. Therefore, all these results are the proof of principle that viral vectors could be considered as a delivery system for PPRHs. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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14 pages, 1510 KiB  
Article
Evaluation of Floxuridine Oligonucleotide Conjugates Carrying Potential Enhancers of Cellular Uptake
by Anna Aviñó, Anna Clua, Maria José Bleda, Ramon Eritja and Carme Fàbrega
Int. J. Mol. Sci. 2021, 22(11), 5678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115678 - 26 May 2021
Cited by 5 | Viewed by 2505
Abstract
Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, [...] Read more.
Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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13 pages, 2259 KiB  
Article
Polypurine Reverse-Hoogsteen Hairpins as a Tool for Exon Skipping at the Genomic Level in Mammalian Cells
by Véronique Noé and Carlos J. Ciudad
Int. J. Mol. Sci. 2021, 22(7), 3784; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073784 - 06 Apr 2021
Cited by 5 | Viewed by 1950
Abstract
Therapeutic strategies for rare diseases based on exon skipping are aimed at mediating the elimination of mutated exons and restoring the reading frame of the affected protein. We explored the capability of polypurine reverse-Hoogsteen hairpins (PPRHs) to cause exon skipping in NB6 cells [...] Read more.
Therapeutic strategies for rare diseases based on exon skipping are aimed at mediating the elimination of mutated exons and restoring the reading frame of the affected protein. We explored the capability of polypurine reverse-Hoogsteen hairpins (PPRHs) to cause exon skipping in NB6 cells carrying a duplication of exon 2 of the DHFR gene that causes a frameshift abolishing DHFR activity. Methods: Different editing PPRHs were designed and transfected in NB6 cells followed by incubation in a DHFR-selective medium lacking hypoxanthine and thymidine. Surviving colonies were analyzed by DNA sequencing, RT-PCR, Western blotting and DHFR enzymatic activity. Results: Transfection of editing PPRHs originated colonies in the DHFR-selective medium. DNA sequencing results proved that the DHFR sequence in all these colonies corresponded to the wildtype sequence with just one copy of exon 2. In the edited colonies, the skipping of the additional exon was confirmed at the mRNA level, the DHFR protein was restored, and it showed high levels of DHFR activity. Conclusions: Editing-PPRHs are able to cause exon skipping at the DNA level and could be applied as a possible therapeutic tool for rare diseases. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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13 pages, 1021 KiB  
Review
Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer
by Edoardo Troncone, Irene Marafini, Carmine Stolfi and Giovanni Monteleone
Int. J. Mol. Sci. 2021, 22(8), 3922; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083922 - 10 Apr 2021
Cited by 13 | Viewed by 3443
Abstract
In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types [...] Read more.
In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune–inflammatory responses. In patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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