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The Journal of Biological Chemistry Jan 2022Aptamers are oligonucleotides selected from large pools of random sequences based on their affinity for bioactive molecules and are used in similar ways to antibodies.... (Review)
Review
Aptamers are oligonucleotides selected from large pools of random sequences based on their affinity for bioactive molecules and are used in similar ways to antibodies. Aptamers provide several advantages over antibodies, including their small size, facile, large-scale chemical synthesis, high stability, and low immunogenicity. Amyloidogenic proteins, whose aggregation is relevant to neurodegenerative diseases, such as Alzheimer's, Parkinson's, and prion diseases, are among the most challenging targets for aptamer development due to their conformational instability and heterogeneity, the same characteristics that make drug development against amyloidogenic proteins difficult. Recently, chemical tethering of aptagens (equivalent to antigens) and advances in high-throughput sequencing-based analysis have been used to overcome some of these challenges. In addition, internalization technologies using fusion to cellular receptors and extracellular vesicles have facilitated central nervous system (CNS) aptamer delivery. In view of the development of these techniques and resources, here we review antiamyloid aptamers, highlighting preclinical application to CNS therapy.
Topics: Amyloidogenic Proteins; Animals; Aptamers, Nucleotide; Central Nervous System; Humans; Neurodegenerative Diseases; Prion Diseases; SELEX Aptamer Technique
PubMed: 34896392
DOI: 10.1016/j.jbc.2021.101478 -
Molecules (Basel, Switzerland) Dec 2022Many potent antibiotics fail to treat bacterial infections due to emergence of drug-resistant strains. This surge of antimicrobial resistance (AMR) calls in for the...
Many potent antibiotics fail to treat bacterial infections due to emergence of drug-resistant strains. This surge of antimicrobial resistance (AMR) calls in for the development of alternative strategies and methods for the development of drugs with restored bactericidal activities. In this context, we surmised that identifying aptamers using nucleotides connected to antibiotics will lead to chemically modified aptameric species capable of restoring the original binding activity of the drugs and hence produce active antibiotic species that could be used to combat AMR. Here, we report the synthesis of a modified nucleoside triphosphate equipped with a vancomycin moiety on the nucleobase. We demonstrate that this nucleotide analogue is suitable for polymerase-mediated synthesis of modified DNA and, importantly, highlight its compatibility with the SELEX methodology. These results pave the way for bacterial-SELEX for the identification of vancomycin-modified aptamers.
Topics: Vancomycin; DNA-Directed DNA Polymerase; DNA; Nucleotides; Oligonucleotides; Anti-Bacterial Agents; SELEX Aptamer Technique; Aptamers, Nucleotide
PubMed: 36558056
DOI: 10.3390/molecules27248927 -
Genes Dec 2021Nucleic-acid-based small molecule and oligonucleotide therapies are attractive topics due to their potential for effective target of disease-related modules and specific... (Review)
Review
Nucleic-acid-based small molecule and oligonucleotide therapies are attractive topics due to their potential for effective target of disease-related modules and specific control of disease gene expression. As the non-naturally occurring biomolecules, modified DNA/RNA nucleoside and oligonucleotide analogues composed of -(deoxy)riboses, have been designed and applied as innovative therapeutics with superior plasma stability, weakened cytotoxicity, and inexistent immunogenicity. Although all the chiral centers in the backbone are mirror converted from the natural -nucleic acids, -nucleic acids are equipped with the same nucleobases (A, G, C and U or T), which are critical to maintain the programmability and form adaptable tertiary structures for target binding. The types of -nucleic acid drugs are increasingly varied, from chemically modified nucleoside analogues that interact with pathogenic polymerases to nanoparticles containing hundreds of repeating -nucleotides that circulate durably in vivo. This article mainly reviews three different aspects of -nucleic acid therapies, including pharmacological -nucleosides, Spiegelmers as specific target-binding aptamers, and -nanostructures as effective drug-delivery devices.
Topics: Antineoplastic Agents; Antiviral Agents; Aptamers, Nucleotide; Drug Delivery Systems; Nucleic Acid Conformation; Nucleosides; Stereoisomerism
PubMed: 35052385
DOI: 10.3390/genes13010046 -
Molecules (Basel, Switzerland) Oct 2019Aptamers are small oligonucleotides that are capable of binding specifically to a target, with impressive potential for analysis, diagnostics, and therapeutics... (Review)
Review
Aptamers are small oligonucleotides that are capable of binding specifically to a target, with impressive potential for analysis, diagnostics, and therapeutics applications. Aptamers are isolated from large nucleic acid combinatorial libraries using an iterative selection process called SELEX (Systematic Evolution of Ligands by EXponential enrichment). Since being implemented 30 years ago, the SELEX protocol has undergone many modifications and improvements, but it remains a laborious, time-consuming, and costly method, and the results are not always successful. Each step in the aptamer selection protocol can influence its results. This review discusses key technical points of the SELEX procedure and their influence on the outcome of aptamer selection.
Topics: Aptamers, Nucleotide; DNA Primers; DNA, Single-Stranded; Gene Library; High-Throughput Nucleotide Sequencing; Nucleic Acid Amplification Techniques; Nucleic Acids; Polymerase Chain Reaction; SELEX Aptamer Technique
PubMed: 31591283
DOI: 10.3390/molecules24193598 -
International Journal of Molecular... Apr 2021Aptamers are single-stranded DNA or RNA sequences that bind target molecules with high specificity and affinity. Aptamers exhibit several notable advantages over... (Review)
Review
Aptamers are single-stranded DNA or RNA sequences that bind target molecules with high specificity and affinity. Aptamers exhibit several notable advantages over protein-based therapeutics. Aptamers are non-immunogenic, easier to synthesize and modify, and can bind targets with greater affinity. Due to these benefits, aptamers are considered a promising therapeutic candidate to treat various conditions, including hematological disorders and cancer. An active area of research involves developing aptamers to target blood coagulation factors. These aptamers have the potential to treat cardiovascular diseases, blood disorders, and cancers. Although no aptamers targeting blood coagulation factors have been approved for clinical use, several aptamers have been evaluated in clinical trials and many more have demonstrated encouraging preclinical results. This review summarized our knowledge of the aptamers targeting proteins involved in coagulation, anticoagulation, fibrinolysis, their extensive applications as therapeutics and diagnostics tools, and the challenges they face for advancing to clinical use.
Topics: Animals; Aptamers, Nucleotide; Blood Coagulation; Blood Coagulation Factors; Carrier Proteins; Drug Evaluation, Preclinical; Fibrinolysis; Gene Targeting; Humans; Protein Binding; SELEX Aptamer Technique; Signal Transduction
PubMed: 33918821
DOI: 10.3390/ijms22083897 -
Cell Biochemistry and Function Jul 2020G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors,... (Review)
Review
G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors, including the type of loops and cations, the nucleotide strand number, and the main strand polarity of the G-quadruplex. Meanwhile, the different conformations of G-quadruplexes have certain influences on their biological functions, such as the inhibition of transcription, translation, and DNA replication. In addition, G-quadruplex binding proteins also affect the structure and function of G-quadruplexes. Some chemically synthesized G-quadruplex sequences have been shown to have biological activities. For example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs that inhibit the proliferation of malignant tumours. G-quadruplexes are also used as vehicles to deliver nanoparticles. Thus, it is important to identify the factors that influence G-quadruplex structures and maintain the stability of G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review summarizes the factors that influence G-quadruplexes and the functions of the synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for drug delivery in tumour therapy.
Topics: Aptamers, Nucleotide; DNA; G-Quadruplexes; Humans; Oligodeoxyribonucleotides
PubMed: 32056246
DOI: 10.1002/cbf.3505 -
Angewandte Chemie (International Ed. in... Jul 2021Aptamers are short oligonucleotides isolated in vitro from randomized libraries that can bind to specific molecules with high affinity, and offer a number of advantages... (Review)
Review
Aptamers are short oligonucleotides isolated in vitro from randomized libraries that can bind to specific molecules with high affinity, and offer a number of advantages relative to antibodies as biorecognition elements in biosensors. However, it remains difficult and labor-intensive to develop aptamer-based sensors for small-molecule detection. Here, we review the challenges and advances in the isolation and characterization of small-molecule-binding DNA aptamers and their use in sensors. First, we discuss in vitro methodologies for the isolation of aptamers, and provide guidance on selecting the appropriate strategy for generating aptamers with optimal binding properties for a given application. We next examine techniques for characterizing aptamer-target binding and structure. Afterwards, we discuss various small-molecule sensing platforms based on original or engineered aptamers, and their detection applications. Finally, we conclude with a general workflow to develop aptamer-based small-molecule sensors for real-world applications.
Topics: Aptamers, Nucleotide; Biosensing Techniques; Equipment Design; SELEX Aptamer Technique
PubMed: 33559947
DOI: 10.1002/anie.202008663 -
Drug Metabolism and Pharmacokinetics Feb 2022Schizophyllan (SPG), a member of the β-glucan family, can form novel complexes with homo-polynucleotides such as poly(dA) through hydrogen bonding between two main... (Review)
Review
Schizophyllan (SPG), a member of the β-glucan family, can form novel complexes with homo-polynucleotides such as poly(dA) through hydrogen bonding between two main chain glucoses and the one nucleotide base. Dectin-1, one of the major receptors for β-glucans, is known to be expressed on antigen presenting cells (APCs) such as macrophages and dendritic cells. This suggests that the above-mentioned complexes could deliver bound functional oligonucleotides (ODNs) including antisense (AS)-ODNs, small interfering RNA, and CpG-ODNs to the APCs. Analysis using a quartz crystal microbalance revealed that a complex consisting of SPG and dA with a phosphorothioate backbone was recognized by recombinant Dectin-1 protein. Treatment with this complex containing an AS-ODN for tumor necrosis factor alpha protected mice against lipopolysaccharide-induced hepatitis at a very low AS-ODN dose. Moreover, immunization with CpG-ODN/SPG complex and antigenic proteins induced potent antigen specific immune responses. The present review also represents peptide delivery by conjugation with dA and the preparation of a nanogel using DNA-DNA hybridization. These findings indicate that the delivery of a specific ODN using β-glucans could be used for treating various diseases caused by APCs and for activating antigen specific immune responses.
Topics: Animals; Antigen-Presenting Cells; Mice; Oligonucleotides; RNA, Small Interfering; Sizofiran; beta-Glucans
PubMed: 34896749
DOI: 10.1016/j.dmpk.2021.100434 -
Drug Discovery Today Aug 2023The novel coronavirus crisis caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was a global pandemic. Although various therapeutic approaches were... (Review)
Review
The novel coronavirus crisis caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was a global pandemic. Although various therapeutic approaches were developed over the past 2 years, novel strategies with more efficient applicability are required to target new variants. Aptamers are single-stranded (ss)RNA or DNA oligonucleotides capable of folding into unique 3D structures with robust binding affinity to a wide variety of targets following structural recognition. Aptamer-based theranostics have proven excellent capability for diagnosing and treating various viral infections. Herein, we review the current status and future perspective of the potential of aptamers as COVID-19 therapies.
Topics: Humans; COVID-19; SARS-CoV-2; Oligonucleotides; DNA; RNA; Aptamers, Nucleotide
PubMed: 37315763
DOI: 10.1016/j.drudis.2023.103663 -
Science (New York, N.Y.) Feb 2021We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA)...
We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA scaffolds have proven to be essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides, which are of broad interest in immuno-oncology as agonists of the stimulator of interferon genes (STING) pathway.
Topics: Catalysis; Molecular Structure; Nucleotides, Cyclic; Oligonucleotides; Organophosphorus Compounds; Phosphoric Acids; Phosphorothioate Oligonucleotides; Stereoisomerism
PubMed: 33574208
DOI: 10.1126/science.abf4359