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Nature Communications Aug 2021Ligand-oligonucleotide transduction provides the critical pathway to integrate non-nucleic acid molecules into nucleic acid circuits and nanomachines for a variety of...
Ligand-oligonucleotide transduction provides the critical pathway to integrate non-nucleic acid molecules into nucleic acid circuits and nanomachines for a variety of strand-displacement related applications. Herein, a general platform is constructed to convert the signals of ligands into desired oligonucleotides through a precise kinetic control. In this design, the ligand-aptamer binding sequence with an engineered duplex stem is introduced between the toehold and displacement domains of the invading strand to regulate the strand-displacement reaction. Employing this platform, we achieve efficient transduction of both small molecules and proteins orthogonally, and more importantly, establish logical and cascading operations between different ligands for versatile transduction. Besides, this platform is capable of being directly coupled with the signal amplification systems to further enhance the transduction performance. This kinetically controlled platform presents unique features with designing simplicity and flexibility, expandable complexity and system compatibility, which may pave a broad road towards nucleic acid-based developments of sophisticated transduction networks.
Topics: Aptamers, Nucleotide; Kinetics; Ligands; Models, Genetic; Models, Molecular; Nucleic Acid Amplification Techniques; Nucleic Acid Conformation; Oligonucleotides; Signal Transduction; Spectrometry, Fluorescence
PubMed: 34341342
DOI: 10.1038/s41467-021-24962-4 -
Current Medicinal Chemistry 2015Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with... (Review)
Review
Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases.
Topics: Animals; Aptamers, Nucleotide; Cell Separation; Clinical Trials as Topic; Humans; Molecular Imaging; Nucleic Acids
PubMed: 25723512
DOI: 10.2174/0929867322666150227144909 -
Journal of Pharmaceutical and... Nov 2021Therapeutic nucleic acids are various chemically modified RNA or DNA with different functions, which mainly play roles at the gene level. Owing to its accurately... (Review)
Review
Therapeutic nucleic acids are various chemically modified RNA or DNA with different functions, which mainly play roles at the gene level. Owing to its accurately targeting at pathogenic genes, nucleic acid based therapeutics have a wide range of application prospects. Recently, the improvement on chemical synthesis and delivery materials accelerated the development of therapeutic nucleic acids rapidly. Up to now, 17 nucleic acid based therapeutics approved by Food and Drug Administration (FDA) or European Medicines Agency (EMA). The development of therapeutics raised higher requirements for analytical methods, both in quality control and in clinical research. The first part of this review introduces different classes of therapeutic nucleic acids, including antisense oligonucleotide (ASO), RNA interference (RNAi) therapy, mRNA, aptamer and other classes which are under research. The second part reviews the therapeutic nucleic acids commercialized from 2019 to now. The third part discusses the analytical methods for nucleic acid based therapeutics, including liquid chromatography-based methods, capillary gel electrophoresis (CGE), hybridization enzyme-linked immunosorbent assay (ELISA) and other infrequently used methods. Finally, the advantages and shortcomings of these methods are summarized, and the future development of analysis methods are prospected.
Topics: DNA; Nucleic Acids; Oligonucleotides; Oligonucleotides, Antisense; RNA
PubMed: 34571322
DOI: 10.1016/j.jpba.2021.114368 -
Nucleic Acids Research Feb 2018DNA self-assembly has proved to be a useful bottom-up strategy for the construction of user-defined nanoscale objects, lattices and devices. The design of these... (Review)
Review
DNA self-assembly has proved to be a useful bottom-up strategy for the construction of user-defined nanoscale objects, lattices and devices. The design of these structures has largely relied on exploiting simple base pairing rules and the formation of double-helical domains as secondary structural elements. However, other helical forms involving specific non-canonical base-base interactions have introduced a novel paradigm into the process of engineering with DNA. The most notable of these is a three-stranded complex generated by the binding of a third strand within the duplex major groove, generating a triple-helical ('triplex') structure. The sequence, structural and assembly requirements that differentiate triplexes from their duplex counterparts has allowed the design of nanostructures for both dynamic and/or structural purposes, as well as a means to target non-nucleic acid components to precise locations within a nanostructure scaffold. Here, we review the properties of triplexes that have proved useful in the engineering of DNA nanostructures, with an emphasis on applications that hitherto have not been possible by duplex formation alone.
Topics: Aptamers, Nucleotide; Base Pairing; Base Sequence; Biosensing Techniques; DNA; Genetic Engineering; Humans; Hydrogen-Ion Concentration; Nanostructures; Nanotechnology; Nucleic Acid Conformation; Oligodeoxyribonucleotides
PubMed: 29228337
DOI: 10.1093/nar/gkx1230 -
Biomacromolecules Nov 2023The continuous evolution and spread of common pathogenic bacteria is a major challenge in diagnosis and treatment with current biotechnology and modern molecular... (Review)
Review
The continuous evolution and spread of common pathogenic bacteria is a major challenge in diagnosis and treatment with current biotechnology and modern molecular medicine. To confront this challenge, scientists urgently need to find alternatives for traditional antimicrobial agents. Various bacteriostatic aptamers obtained through SELEX screening are one of the most promising strategies. These bacteriostatic aptamers can reduce bacterial infection by blocking bacterial toxin infiltration, inhibiting biofilm formation, preventing bacterial invasion of immune cells, interfering with essential biochemical processes, and other mechanisms. In addition, aptamers may also help enhance the function of other antibacterial materials/drugs when used in combination. This paper has reviewed the bacteriostatic aptamers in the treatment of common pathogenic bacteria infections. For this aspect, first, bacteriostatic aptamers and their screening strategies are summarized. Then, the effect of molecular tailoring and modification on the performance of the bacteriostatic aptamer is analyzed, and the antibacterial mechanism and antibacterial strategy based on aptamers are introduced. Finally, the key technical challenges and their development prospects in clinical treatment are also carefully discussed.
Topics: Humans; Aptamers, Nucleotide; Bacterial Infections; Bacteria; Anti-Bacterial Agents; SELEX Aptamer Technique
PubMed: 37728999
DOI: 10.1021/acs.biomac.3c00634 -
RNA (New York, N.Y.) Apr 2023Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where...
Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.
Topics: Humans; Oligonucleotides; Oligonucleotides, Antisense; Brain; Europe; Brain Diseases
PubMed: 36669889
DOI: 10.1261/rna.079540.122 -
Angewandte Chemie (International Ed. in... Nov 2023DNA nanotechnology provides an approach to create precise, tunable, and biocompatible nanostructures for biomedical applications. However, the stability of these...
DNA nanotechnology provides an approach to create precise, tunable, and biocompatible nanostructures for biomedical applications. However, the stability of these structures is severely compromised in biological milieu due to their fast degradation by nucleases. Recently, we showed how enzymatic polymerization could be harnessed to grow polynucleotide brushes of tunable length and location on the surface of DNA origami nanostructures, which greatly enhances their nuclease stability. Here, we report on strategies that allow for both spatial and temporal control over polymerization through activatable initiation, cleavage, and regeneration of polynucleotide brushes using restriction enzymes. The ability to site-specifically decorate DNA origami nanostructures with polynucleotide brushes in a spatiotemporally controlled way provides access to "smart" functionalized DNA architectures with potential applications in drug delivery and supramolecular assembly.
Topics: Polynucleotides; Nanostructures; DNA; Nanotechnology; Drug Delivery Systems; Nucleic Acid Conformation
PubMed: 37820028
DOI: 10.1002/anie.202311727 -
Current Opinion in Biotechnology Dec 2017Aptamers are short single-stranded oligo(deoxy)nucleotides that are selected to bind to target molecules with high affinity and specificity. Because of their... (Review)
Review
Aptamers are short single-stranded oligo(deoxy)nucleotides that are selected to bind to target molecules with high affinity and specificity. Because of their sophisticated characteristics and versatile applicability, aptamers are thought to become universal molecular probes in biotechnological and therapeutic applications. However, the variety of possible interactions with a putative target molecule is limited by the chemical repertoire of the natural nucleobases. Consequently, many desired targets are not addressable by aptamers. This obstacle is overcome by broadening the chemical diversity of aptamers, mainly achieved by nucleobase-modifications and the introduction of novel bases or base pairs. We discuss these achievements and the characteristics of the respective modified aptamers, reflected by SOMAmers (slow off-rate modified aptamers), clickmers, and aptamers bearing an expanded genetic alphabet.
Topics: Aptamers, Nucleotide; Gene Library; Humans; SELEX Aptamer Technique
PubMed: 28437710
DOI: 10.1016/j.copbio.2017.03.026 -
Cell-specific aptamers as potential drugs in therapeutic applications: A review of current progress.Journal of Controlled Release :... Jun 2022Cell-specific aptamers are a promising emerging player in the field of disease therapy. This paper reviews the multidimensional research progress made in terms of their... (Review)
Review
Cell-specific aptamers are a promising emerging player in the field of disease therapy. This paper reviews the multidimensional research progress made in terms of their classification, modification, and application. Based on the target location of cell-specific aptamers, it is defined and classified cell-specific aptamers into three groups including aptamers for cell surface markers, aptamers for intracellular components, and aptamers for extracellular components. Moreover, the modification methods of aptamers to achieve improved stability and affinity are concluded. In addition, recent advances in the application of cell-specific aptamers are discussed, mainly focusing on the increasing research attraction of cell state improving helpers and cell recruitment mediators in the improvement of cellular microenvironments to achieve successful disease therapy. This review also highlights 11 types of clinical aptamer drugs. Finally, the challenges and future directions of potential clinical applications are presented. In summary, we believe that cell-specific aptamers are promising drugs in disease therapy.
Topics: Aptamers, Nucleotide; Drug Delivery Systems
PubMed: 35489545
DOI: 10.1016/j.jconrel.2022.04.039 -
Drug Discovery Today Jan 2018Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing... (Review)
Review
Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.
Topics: Animals; Drug Discovery; Humans; Oligonucleotides; RNA
PubMed: 28988994
DOI: 10.1016/j.drudis.2017.09.018