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Molecules (Basel, Switzerland) Feb 2019Addition of small molecule Retro-1 has been described to enhance antisense and splice switching oligonucleotides. With the aim of assessing the effect of covalently...
Addition of small molecule Retro-1 has been described to enhance antisense and splice switching oligonucleotides. With the aim of assessing the effect of covalently linking Retro-1 to the biologically active oligonucleotide, three different derivatives of Retro-1 were prepared that incorporated a phosphoramidite group, a thiol or a 1,3-diene, respectively. Retro-1⁻oligonucleotide conjugates were assembled both on-resin (coupling of the phosphoramidite) and from reactions in solution (Michael-type thiol-maleimide reaction and Diels-Alder cycloaddition). Splice switching assays with the resulting conjugates showed that they were active but that they provided little advantage over the unconjugated oligonucleotide in the well-known HeLa Luc705 reporter system.
Topics: Cell Line, Tumor; Chemistry Techniques, Synthetic; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Molecular Structure; Oligonucleotides; RNA Splicing; Structure-Activity Relationship
PubMed: 30736307
DOI: 10.3390/molecules24030579 -
Pharmacology & Therapeutics Jan 2017The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating... (Review)
Review
The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.
Topics: Animals; Drug Design; Humans; Lung Diseases; Molecular Targeted Therapy; Oligonucleotides; RNA; RNA Interference; RNA Splicing; RNA, Untranslated
PubMed: 27771436
DOI: 10.1016/j.pharmthera.2016.10.009 -
Cancer Science Sep 2022Oligonucleotide therapeutics, drugs consisting of 10-50 nucleotide-long single- or double-stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or... (Review)
Review
Oligonucleotide therapeutics, drugs consisting of 10-50 nucleotide-long single- or double-stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or proteins, include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and decoys. These oligonucleotide therapeutics could potentially become the third pillar of drug development. In particular, ASOs and siRNAs are advanced tools that are widely used to silence gene expression. They are used in clinical trials, as they have high specificity for target mRNAs and non-coding RNAs and limited toxicity. However, their clinical application remains challenging. Although chemotherapy has benefits, it has severe adverse effects in many patients. Therefore, new modalities for targeted molecular therapy against tumors, including oligonucleotide therapeutics, are required, and they should be compatible with diagnosis using next-generation sequencing. This review provides an overview of the therapeutic uses of ASOs, siRNAs, and miRNAs in clinical studies on malignant tumors. Understanding previous research and development will help in developing novel oligonucleotide therapeutics against malignant tumors.
Topics: Antibodies; Humans; MicroRNAs; Neoplasms; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 35701833
DOI: 10.1111/cas.15461 -
Molecules (Basel, Switzerland) Oct 2017The underlying idea of oligonucleotide conjugates is to provide oligonucleotide with some novel property [...].
The underlying idea of oligonucleotide conjugates is to provide oligonucleotide with some novel property [...].
Topics: Aptamers, Nucleotide; Humans; Oligonucleotides; Oligonucleotides, Antisense; Peptides
PubMed: 29027972
DOI: 10.3390/molecules22101700 -
Biochemistry Mar 2018There is a growing demand for sustainable methods in research and development, where instead of hazardous chemicals, an aqueous medium is chosen to perform biological... (Review)
Review
There is a growing demand for sustainable methods in research and development, where instead of hazardous chemicals, an aqueous medium is chosen to perform biological reactions. In this Perspective, we examine the history and current methodology of using enzymes to generate artificial single-stranded DNA. By using traditional solid-phase phosphoramidite chemistry as a metric, we also explore criteria for the method of template-independent enzymatic oligonucleotide synthesis (TiEOS). As its key component, we delve into the biology of one of the most enigmatic enzymes, terminal deoxynucleotidyl transferase (TdT). As TdT is found to exponentially increase antigen receptor diversity in the vertebrate immune system by adding nucleotides in a template-free manner, researchers have exploited this function as an alternative to the phosphoramidite synthesis method. Though TdT is currently the preferred enzyme for TiEOS, its random nucleotide incorporation presents a barrier in synthesis automation. Taking a closer look at the TiEOS cycle, particularly the coupling step, we find it is comprised of additions > n+1 and deletions. By tapping into the physical and biochemical properties of TdT, we strive to further elucidate its mercurial behavior and offer ways to better optimize TiEOS for production-grade oligonucleotide synthesis.
Topics: DNA Nucleotidylexotransferase; History, 20th Century; History, 21st Century; Oligonucleotides
PubMed: 29533604
DOI: 10.1021/acs.biochem.7b00937 -
Theranostics 2020The use of various oligonucleotide (ON) syntheses and post-synthetic strategies for targeted chemical modification enables improving their efficacy as potent modulators... (Review)
Review
The use of various oligonucleotide (ON) syntheses and post-synthetic strategies for targeted chemical modification enables improving their efficacy as potent modulators of gene expression levels in eukaryotic cells. However, the search still continues for new approaches designed for increasing internalization, lysosomal escape, and tissue specific delivery of ON. In this review we emphasized all aspects related to the synthesis and properties of ON derivatives carrying multifluorinated (MF) groups. These MF groups have unique physico-chemical properties because of their simultaneous hydrophobicity and lipophobicity. Such unusual combination of properties results in the overall modification of ON mode of interaction with the cells and making multi-fluorination highly relevant to the goal of improving potency of ON as components of new therapies. The accumulated evidence so far is pointing to high potential of ON probes, RNAi components and ON imaging beacons carrying single or multiple MF groups for improving the stability, specificity of interaction with biological targets and delivery of ONs and potentially .
Topics: Animals; Cell Line; Fluorine; Humans; Magnetic Resonance Imaging; Nanoparticles; Oligonucleotides; Permeability; Precision Medicine
PubMed: 31938071
DOI: 10.7150/thno.37936 -
International Journal of Molecular... Dec 2020Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established... (Review)
Review
Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.
Topics: Animals; Biomarkers; DNA Methylation; Epigenesis, Genetic; Gene Transfer Techniques; Genetic Therapy; Humans; MicroRNAs; Molecular Targeted Therapy; Oligonucleotides; Pulmonary Arterial Hypertension; Vascular Remodeling
PubMed: 33287230
DOI: 10.3390/ijms21239222 -
Drug Discovery Today Nov 2022It is well established that microRNA (miRNA) dysregulation is involved in the development and progression of various diseases, especially cancer. Emerging evidence... (Review)
Review
It is well established that microRNA (miRNA) dysregulation is involved in the development and progression of various diseases, especially cancer. Emerging evidence suggests that small molecule and peptide agents can interfere with miRNA disease pathways. Despite this, very little is known about structural features that drive drug-miRNA interactions and subsequent inhibition. In this review, we highlight the advances made in the development of small molecule and peptide inhibitors of miRNA processing. Specifically, we attempt to draw attention to peptide features that may be critical for interaction with the miRNA secondary structure to regulate miRNA expression. We hope that this review will help to establish peptides as exciting miRNA expression modulators and will contribute towards the development of the first miRNA-targeting peptide therapy.
Topics: Humans; Oligonucleotides; MicroRNAs; Peptides; Neoplasms
PubMed: 35995360
DOI: 10.1016/j.drudis.2022.08.005 -
Advanced Drug Delivery Reviews Jun 2015Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by... (Review)
Review
Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by directly linking targeting ligands with oligonucleotides and the resultant conjugates can selectively bind to cell surface receptors in target cells in diseased tissues. Besides targeted delivery, additional functionality can be incorporated in the conjugates by utilization of carrier molecules, and these larger conjugates are called carrier-associated conjugates. Both molecular and carrier-associated conjugates have achieved initial successes in clinical trials for treating liver diseases; therefore, currently the greater challenge is to deliver oligonucleotides to extrahepatic tissues such as tumors. This review will provide an update on the application of oligonucleotide conjugates for targeted delivery during the last decade. By identifying key elements for successful delivery, it is suggested that oligonucleotide conjugates with intermediate size, cell targeting ability, and endosomal release functionality are superior systems to advance oligonucleotides to achieve their full therapeutic potentials.
Topics: Animals; Drug Carriers; Drug Delivery Systems; Humans; Ligands; Nanoconjugates; Oligonucleotides; Protein Binding; Receptors, Cell Surface
PubMed: 25689735
DOI: 10.1016/j.addr.2015.02.002 -
Biomacromolecules Jun 2023Oligonucleotides are powerful molecules for programming function and assembly. When arrayed on nanoparticle scaffolds in high density, the resulting molecules, spherical...
Oligonucleotides are powerful molecules for programming function and assembly. When arrayed on nanoparticle scaffolds in high density, the resulting molecules, spherical nucleic acids (SNAs), become imbued with unique properties. We used the copper-catalyzed azide-alkyne cycloaddition to graft oligonucleotides on Qβ virus-like particles to see if such structures also gain SNA-like behavior. Copper-binding ligands were shown to promote the click reaction without degrading oligonucleotide substrates. Reactions were first optimized with a small-molecule fluorogenic reporter and were then applied to the more challenging synthesis of polyvalent protein nanoparticle-oligonucleotide conjugates. The resulting particles exhibited the enhanced cellular uptake and protection from nuclease-mediated oligonucleotide cleavage characteristic of SNAs, had similar residence time in the liver relative to unmodified particles, and were somewhat shielded from immune recognition, resulting in nearly 10-fold lower antibody titers relative to unmodified particles. Oligonucleotide-functionalized virus-like particles thus provide an interesting option for protein nanoparticle-mediated delivery of functional molecules.
Topics: Oligonucleotides; Copper; Proteins; Nucleic Acids; Nanoparticles; Azides; Alkynes; Click Chemistry; Cycloaddition Reaction
PubMed: 37257068
DOI: 10.1021/acs.biomac.3c00178