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      G-quadruplex-based aptamers against protein targets in therapy and diagnostics

      review-article
      a , a , a , b , a , b , *
      Biochimica et Biophysica Acta. General Subjects
      Elsevier B.V.
      ABTS, 2,2′-azino-bis(3-ethylbenzothiozoline)-6-sulfonic acid, AGR2, Anterior Gradient Homolog 2, ALP, Alkaline Phosphatase, AMC, 7-amino-4-methylcoumarin, AuNP, Gold Nanoparticle, CND, Carbon Nanodot, ECL, Electrochemiluminescence, FAM, Carboxyfluorescein, G4, G-quadruplex, GCE, Glassy Carbon Electrode, GO, Graphene Oxide, GOx, Glucose Oxidase, HIV, Human Immunodeficiency Virus, KCE, Kinetic Capillary Electrophoresis, NECEEM, Non-equilibrium Capillary Electrophoresis of Equilibrium Mixtures, ON, Oligonucleotide, PDDA, Poly(diallyldimethylammonium) chloride, PET, Phosphorescence Energy Transfer, PPK, Polyphosphate Kinase, QCM, Quartz Crystal Microbalance, QDs, Quantum Dots, RT, Reverse Transcriptase, SA, Streptavidin, SARS-CoV, Severe Acute Respiratory Syndrome Coronavirus, SELEX, Systematic Evolution of Ligands by EXponential enrichment, SOMAmers, Slow Off-rate Modified Aptamers, SPR, Surface Plasmon Resonance, TBA, Thrombin Binding Aptamer, TBDPS, tert-butyldiphenylsilyl, TEL, Tetra-end-linker, TMB, 3,3′,5,5′-tetramethylbenzidine, TMPG, 3,4,5-trimethoxylphenylglyoxal, TMPyP4, 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin, TPA, tetra-n-propylammonium hydroxide, VEGF, Vascular Endothelial Growth Factor, Aptamer, G-quadruplex, Protein target, Therapy, Diagnostics, SELEX

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          Abstract

          Nucleic acid aptamers are single-stranded DNA or RNA molecules identified to recognize with high affinity specific targets including proteins, small molecules, ions, whole cells and even entire organisms, such as viruses or bacteria. They can be identified from combinatorial libraries of DNA or RNA oligonucleotides by SELEX technology, an in vitro iterative selection procedure consisting of binding (capture), partitioning and amplification steps. Remarkably, many of the aptamers selected against biologically relevant protein targets are G-rich sequences that can fold into stable G-quadruplex (G4) structures.

          Aiming at disseminating novel inspiring ideas within the scientific community in the field of G4-structures, the emphasis of this review is placed on: 1) recent advancements in SELEX technology for the efficient and rapid identification of new candidate aptamers (introduction of microfluidic systems and next generation sequencing); 2) recurrence of G4 structures in aptamers selected by SELEX against biologically relevant protein targets; 3) discovery of several G4-forming motifs in important regulatory regions of the human or viral genome bound by endogenous proteins, which per se can result into potential aptamers; 4) an updated overview of G4-based aptamers with therapeutic potential and 5) a discussion on the most attractive G4-based aptamers for diagnostic applications. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

          Highlights

          • Oligonucleotide aptamers and methods for their selection against specific targets

          • The recurrence of G-quadruplex (G4) motifs in oligonucleotide aptamers

          • G4-forming aptamers in therapeutic applications as drugs and drug delivery systems

          • G4-forming aptamers in detection and diagnostic applications

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          Most cited references172

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          Aptamers as therapeutics

          Key Points Aptamers are single-stranded oligonucleotides that fold into defined architectures and bind to targets such as proteins. In binding proteins they often inhibit protein–protein interactions and thereby may elicit therapeutic effects such as antagonism. Aptamers are discovered using SELEX (systematic evolution of ligands by exponential enrichment), a directed in vitro evolution technique in which large libraries of degenerate oligonucleotides are iteratively and alternately partitioned for target binding. They are then amplified enzymatically until functional sequences are identified by the sequencing of cloned individuals. For most therapeutic purposes, aptamers are truncated to reduce synthesis costs, modified at the sugars and capped at their termini to increase nuclease resistance, and conjugated to polyethylene glycol or another entity to reduce renal filtration rates. The first aptamer approved for a therapeutic application was pegaptanib sodium (Macugen; Pfizer/Eyetech), which was approved in 2004 by the US Food and Drug Administration for macular degeneration. Eight other aptamers are currently undergoing clinical evaluation for various haematology, oncology, ocular and inflammatory indications. Aptamers are ultimately chemically synthesized in a readily scalable process in which specific conjugation points are introduced with defined stereochemistry. Unlike some protein therapeutics, aptamers do not elicit antibodies, and because aptamers generally contain sugars modified at their 2′-positions, Toll-like receptor-mediated innate immune responses are also abrogated. As aptamers are oligonucleotides they can be readily assembled into supramolecular multi-component structures using hybridization. Owing to the fact that binding to appropriate cell-surface targets can lead to internalization, aptamers can also be used to deliver therapeutic cargoes such as small interfering RNA. Supramolecular assemblies of aptamers and delivery agents have already been demonstrated in vivo and may pave the way for further therapeutic strategies with this modality in the future.
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            The biology of vascular endothelial growth factor.

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              Functional nucleic acid sensors.

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                Author and article information

                Contributors
                Journal
                Biochim Biophys Acta Gen Subj
                Biochim Biophys Acta Gen Subj
                Biochimica et Biophysica Acta. General Subjects
                Elsevier B.V.
                0304-4165
                1872-8006
                16 November 2016
                May 2017
                16 November 2016
                : 1861
                : 5
                : 1429-1447
                Affiliations
                [a ]Department of Chemical Sciences, University of Napoli Federico II, Napoli, Italy
                [b ]Institute of Biostructures and Bioimages, CNR, Napoli, Italy
                Author notes
                [* ]Corresponding author at: Department of Chemical Sciences, University of Napoli Federico II, Via Cintia, 21, I-80126 Napoli, Italy. domenica.musumeci@ 123456unina.it
                Article
                S0304-4165(16)30447-0
                10.1016/j.bbagen.2016.11.027
                7117017
                27865995
                becb05eb-d67b-4381-88f9-a81d7269bc8f
                © 2016 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 13 October 2016
                : 14 November 2016
                : 15 November 2016
                Categories
                Article

                abts, 2,2′-azino-bis(3-ethylbenzothiozoline)-6-sulfonic acid,agr2, anterior gradient homolog 2,alp, alkaline phosphatase,amc, 7-amino-4-methylcoumarin,aunp, gold nanoparticle,cnd, carbon nanodot,ecl, electrochemiluminescence,fam, carboxyfluorescein,g4, g-quadruplex,gce, glassy carbon electrode,go, graphene oxide,gox, glucose oxidase,hiv, human immunodeficiency virus,kce, kinetic capillary electrophoresis,neceem, non-equilibrium capillary electrophoresis of equilibrium mixtures,on, oligonucleotide,pdda, poly(diallyldimethylammonium) chloride,pet, phosphorescence energy transfer,ppk, polyphosphate kinase,qcm, quartz crystal microbalance,qds, quantum dots,rt, reverse transcriptase,sa, streptavidin,sars-cov, severe acute respiratory syndrome coronavirus,selex, systematic evolution of ligands by exponential enrichment,somamers, slow off-rate modified aptamers,spr, surface plasmon resonance,tba, thrombin binding aptamer,tbdps, tert-butyldiphenylsilyl,tel, tetra-end-linker,tmb, 3,3′,5,5′-tetramethylbenzidine,tmpg, 3,4,5-trimethoxylphenylglyoxal,tmpyp4, 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin,tpa, tetra-n-propylammonium hydroxide,vegf, vascular endothelial growth factor,aptamer,g-quadruplex,protein target,therapy,diagnostics,selex

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