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International Journal of Molecular... Mar 2023Non-small-cell lung cancer (NSCLC) is the second most diagnosed type of malignancy and the first cause of cancer death worldwide. Despite recent advances, the treatment... (Review)
Review
Non-small-cell lung cancer (NSCLC) is the second most diagnosed type of malignancy and the first cause of cancer death worldwide. Despite recent advances, the treatment of choice for NSCLC patients remains to be chemotherapy, often showing very limited effectiveness with the frequent occurrence of drug-resistant phenotype and the lack of selectivity for tumor cells. Therefore, new effective and targeted therapeutics are needed. In this context, short RNA-based therapeutics, including Antisense Oligonucleotides (ASOs), microRNAs (miRNAs), short interfering (siRNA) and aptamers, represent a promising class of molecules. ASOs, miRNAs and siRNAs act by targeting and inhibiting specific mRNAs, thus showing an improved specificity compared to traditional anti-cancer drugs. Nucleic acid aptamers target and inhibit specific cancer-associated proteins, such as "nucleic acid antibodies". Aptamers are also able of receptor-mediated cell internalization, and therefore, they can be used as carriers of secondary agents giving the possibility of producing very highly specific and effective therapeutics. This review provides an overview of the proposed applications of small RNAs for NSCLC treatment, highlighting their advantageous features and recent advancements in the field.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; RNA, Small Interfering; Oligonucleotides; Oligonucleotides, Antisense; MicroRNAs; RNA, Messenger; Aptamers, Nucleotide
PubMed: 37047090
DOI: 10.3390/ijms24076121 -
Journal of the American Chemical Society May 2023Nucleosides are essential cornerstones of life, and nucleoside derivatives and synthetic analogues have important biomedical applications. Correspondingly, production of...
Nucleosides are essential cornerstones of life, and nucleoside derivatives and synthetic analogues have important biomedical applications. Correspondingly, production of non-canonical nucleoside derivatives in animal model systems is of particular interest. Here, we report the discovery of diverse glucose-based nucleosides in and related nematodes. Using a mass spectrometric screen based on all-ion fragmentation in combination with total synthesis, we show that selectively glucosylates a series of modified purines but not the canonical purine and pyrimidine bases. Analogous to ribonucleosides, the resulting gluconucleosides exist as phosphorylated and non-phosphorylated forms. The phosphorylated gluconucleosides can be additionally decorated with diverse acyl moieties from amino acid catabolism. Syntheses of representative variants, facilitated by a novel 2'- to 3'--dibenzyl phosphoryl transesterification reaction, demonstrated selective incorporation of different nucleobases and acyl moieties. Using stable-isotope labeling, we further show that gluconucleosides incorporate modified nucleobases derived from RNA and possibly DNA breakdown, revealing extensive recycling of oligonucleotide catabolites. Gluconucleosides are conserved in other nematodes, and biosynthesis of specific subsets is increased in germline mutants and during aging. Bioassays indicate that gluconucleosides may function in stress response pathways.
Topics: Animals; Nucleosides; Caenorhabditis elegans; Oligonucleotides; Ribonucleosides
PubMed: 37192367
DOI: 10.1021/jacs.3c01151 -
Cells Sep 2023The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system... (Review)
Review
The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.
Topics: Endosomes; Central Nervous System; Liver; Muscles; Oligonucleotides
PubMed: 37759475
DOI: 10.3390/cells12182253 -
European Journal of Cell Biology Jun 2023Spinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the... (Review)
Review
Spinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the death of motor neurons and progressive muscle weakness. SMN1 normally produces an essential protein called SMN. Although humans possess a paralogous gene called SMN2, ∼90% of the SMN it produces is non-functional. This is due to a mutation in SMN2 that causes the skipping of a required exon during splicing of the pre-mRNA. The first treatment for SMA, nusinersen (brand name Spinraza), was approved by the FDA in 2016 and by the EMU in 2017. Nusinersen is an antisense oligonucleotide-based therapy that alters the splicing of SMN2 to make functional full-length SMN protein. Despite the recent advancements in antisense oligonucleotide therapy and SMA treatment development, nusinersen is faced with a multitude of challenges, such as intracellular and systemic delivery. In recent years, the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) in antisense therapy has gained interest. These are antisense oligonucleotides conjugated to cell-penetrating peptides such as Pips and DG9, and they have the potential to address the challenges associated with delivery. This review focuses on the historic milestones, development, current challenges, and future perspectives of antisense therapy for SMA.
Topics: Humans; Oligonucleotides, Antisense; Muscular Atrophy, Spinal; Morpholinos; Motor Neurons; RNA Splicing
PubMed: 37295266
DOI: 10.1016/j.ejcb.2023.151326 -
Science (New York, N.Y.) Sep 2021The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration...
The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides, by far most of which contain modified phosphate linkages. These unnatural linkages have desirable biological and physical properties but are often accessed with difficulty using phosphoramidite chemistry. We report a flexible and efficient [P(V)]–based platform that can install a wide variety of phosphate linkages at will into oligonucleotides. This approach uses readily accessible reagents and can install not only stereodefined or racemic thiophosphates but any combination of (, or )–PS with native phosphodiester (PO) and phosphorodithioate (PS) linkages into DNA and other modified nucleotide polymers. This platform easily accesses this diversity under a standardized coupling protocol with sustainably prepared, stable P(V) reagents.
Topics: Oligonucleotides
PubMed: 34516793
DOI: 10.1126/science.abi9727 -
Molecules (Basel, Switzerland) Jan 2022Aptamers are RNA/DNA oligonucleotide molecules that specifically bind to a targeted complementary molecule. As potential recognition elements with promising diagnostic... (Review)
Review
Aptamers are RNA/DNA oligonucleotide molecules that specifically bind to a targeted complementary molecule. As potential recognition elements with promising diagnostic and therapeutic applications, aptamers, such as monoclonal antibodies, could provide many treatment and diagnostic options for blood diseases. Aptamers present several superior features over antibodies, including a simple in vitro selection and production, ease of modification and conjugation, high stability, and low immunogenicity. Emerging as promising alternatives to antibodies, aptamers could overcome the present limitations of monoclonal antibody therapy to provide novel diagnostic, therapeutic, and preventive treatments for blood diseases. Researchers in several biomedical areas, such as biomarker detection, diagnosis, imaging, and targeted therapy, have widely investigated aptamers, and several aptamers have been developed over the past two decades. One of these is the pegaptanib sodium injection, an aptamer-based therapeutic that functions as an anti-angiogenic medicine, and it is the first aptamer approved by the U.S. Food and Drug Administration (FDA) for therapeutic use. Several other aptamers are now in clinical trials. In this review, we highlight the current state of aptamers in the clinical trial program and introduce some promising aptamers currently in pre-clinical development for blood diseases.
Topics: Aptamers, Nucleotide
PubMed: 35056696
DOI: 10.3390/molecules27020383 -
Methods in Molecular Biology (Clifton,... 2022During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated...
During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated into successful clinical applications. Depending on the specific OND mechanism, chemistry, and design, the DMPK and toxicity properties can vary significantly between different OND classes and delivery approaches, the latter including lipid formulations or conjugation approaches to enhance productive OND uptake. At the same time, with the only difference between compounds being the nucleobase sequence, ONDs with same mechanism of action, chemistry, and design show relatively consistent behavior, allowing certain extrapolations between compounds within an OND class. This chapter provides a summary of the most common toxicities, the improved mechanistic understanding and the safety assessment activities performed for therapeutic oligonucleotides during the drug discovery and development process. Several of the considerations described for therapeutic applications should also be of value for the scientists mainly using oligonucleotides as research tools to explore various biological processes.
Topics: Drug Discovery; Oligonucleotides; Oligonucleotides, Antisense
PubMed: 35213031
DOI: 10.1007/978-1-0716-2010-6_25 -
Cells Jan 2022A wide variety of nanomaterials have emerged in recent years with advantageous properties for a plethora of therapeutic and diagnostic applications. Such applications... (Review)
Review
A wide variety of nanomaterials have emerged in recent years with advantageous properties for a plethora of therapeutic and diagnostic applications. Such applications include drug delivery, imaging, anti-cancer therapy and radiotherapy. There is a critical need for further components which can facilitate therapeutic targeting, augment their physicochemical properties, or broaden their theranostic applications. Aptamers are single-stranded nucleic acids which have been selected or evolved to bind specifically to molecules, surfaces, or cells. Aptamers can also act as direct biologic therapeutics, or in imaging and diagnostics. There is a rich field of discovery at the interdisciplinary interface between nanomaterials and aptamer science that has significant potential across biomedicine. Herein, we review recent progress in aptamer-enabled materials and discuss pending challenges for their future biomedical application.
Topics: Aptamers, Nucleotide; Drug Delivery Systems; Humans; Nanostructures; Neoplasms
PubMed: 35011722
DOI: 10.3390/cells11010159 -
Proceedings of the National Academy of... Jun 2023We previously demonstrated that the polycomb repressive complex 2 chromatin-modifying enzyme can directly transfer between RNA and DNA without a free-enzyme intermediate...
We previously demonstrated that the polycomb repressive complex 2 chromatin-modifying enzyme can directly transfer between RNA and DNA without a free-enzyme intermediate state. Simulations suggested that such a direct transfer mechanism may be generally necessary for RNA to recruit proteins to chromatin, but the prevalence of direct transfer capability is unknown. Herein, we used fluorescence polarization assays and observed direct transfer for several well-characterized nucleic acid-binding proteins: three-prime repair exonuclease 1, heterogeneous nuclear ribonucleoprotein U, Fem-3-binding factor 2, and MS2 bacteriophage coat protein. For TREX1, the direct transfer mechanism was additionally observed in single-molecule assays, and the data suggest that direct transfer occurs through an unstable ternary intermediate with partially associated polynucleotides. Generally, direct transfer could allow many DNA- and RNA-binding proteins to conduct a one-dimensional search for their target sites. Furthermore, proteins that bind both RNA and DNA might be capable of readily translocating between those ligands.
Topics: DNA-Binding Proteins; Polynucleotides; RNA; RNA-Binding Proteins; DNA; Chromatin
PubMed: 37339225
DOI: 10.1073/pnas.2220537120 -
Nature Communications Aug 2019The versatile and tunable self-assembly properties of nucleic acids and engineered nucleic acid constructs make them invaluable in constructing microscale and nanoscale...
The versatile and tunable self-assembly properties of nucleic acids and engineered nucleic acid constructs make them invaluable in constructing microscale and nanoscale devices, structures and circuits. Increasing the complexity, functionality and ease of assembly of such constructs, as well as interfacing them to the macroscopic world requires a multifaceted and programmable fabrication approach that combines efficient and spatially resolved nucleic acid synthesis with multiple post-synthetic chemical and enzymatic modifications. Here we demonstrate a multi-level photolithographic patterning approach that starts with large-scale in situ surface synthesis of natural, modified or chimeric nucleic acid molecular structures and is followed by chemical and enzymatic nucleic acid modifications and processing. The resulting high-complexity, micrometer-resolution nucleic acid surface patterns include linear and branched structures, multi-color fluorophore labeling and programmable targeted oligonucleotide immobilization and cleavage.
Topics: Biosensing Techniques; Cross-Linking Reagents; Fluorescence; Light; Microtechnology; Nucleic Acid Conformation; Nucleic Acids; Oligonucleotides; Photochemical Processes
PubMed: 31444344
DOI: 10.1038/s41467-019-11670-3