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      Chemical Modifications of Nucleic Acid Aptamers for Therapeutic Purposes

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          Abstract

          Nucleic acid aptamers have minimal immunogenicity, high chemical synthesis production, low cost and high chemical stability when compared with antibodies. However, the susceptibility to nuclease degradation, rapid excretion through renal filtration and insufficient binding affinity hindered their development as drug candidates for therapeutic applications. In this review, we will discuss methods to conquer these challenges and highlight recent developments of chemical modifications and technological advances that may enable early aptamers to be translated into clinical therapeutics.

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          Most cited references100

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          Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase.

          C Tuerk, L Gold (1990)
          High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species. Multiple rounds exponentially enrich the population for the highest affinity species that can be clonally isolated and characterized. In particular one eight-base region of an RNA that interacts with the T4 DNA polymerase was chosen and randomized. Two different sequences were selected by this procedure from the calculated pool of 65,536 species. One is the wild-type sequence found in the bacteriophage mRNA; one is varied from wild type at four positions. The binding constants of these two RNA's to T4 DNA polymerase are equivalent. These protocols with minimal modification can yield high-affinity ligands for any protein that binds nucleic acids as part of its function; high-affinity ligands could conceivably be developed for any target molecule.
          Article 0 comments Cited 958 times – based on 0 reviews     Review now
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            Aptamers as targeted therapeutics: current potential and challenges

            Jiehua Zhou, John M. Rossi (2016)
            Nucleic acid aptamers offer several advantages over traditional antibodies, but their clinical translation has been delayed by several factors, including insufficient potency, lack of safety data and high production costs. Here, Zhou and Rossi provide an overview of aptamer generation, focusing on recent technological advances and clinical development, as well as challenges and lessons learned.
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              Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.

              Paula J. Bates, Damian Laber, Donald M Miller … (2009)
              Certain guanine-rich (G-rich) DNA and RNA molecules can associate intermolecularly or intramolecularly to form four stranded or "quadruplex" structures, which have unusual biophysical and biological properties. Several synthetic G-rich quadruplex-forming oligodeoxynucleotides have recently been investigated as therapeutic agents for various human diseases. We refer to these biologically active G-rich oligonucleotides as aptamers because their activities arise from binding to protein targets via shape-specific recognition (analogous to antibody-antigen binding). As therapeutic agents, the G-rich aptamers may have some advantages over monoclonal antibodies and other oligonucleotide-based approaches. For example, quadruplex oligonucleotides are non-immunogenic, heat stable and they have increased resistance to serum nucleases and enhanced cellular uptake compared to unstructured sequences. In this review, we describe the characteristics and activities of G-rich oligonucleotides. We also give a personal perspective on the discovery and development of AS1411, an antiproliferative G-rich phosphodiester oligonucleotide that is currently being tested as an anticancer agent in Phase II clinical trials. This molecule functions as an aptamer to nucleolin, a multifunctional protein that is highly expressed by cancer cells, both intracellularly and on the cell surface. Thus, the serendipitous discovery of the G-rich oligonucleotides also led to the identification of nucleolin as a new molecular target for cancer therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 02 August 2017
                Publication date Collection: August 2017
                Volume: 18
                Issue: 8
                Electronic Location Identifier: 1683
                Affiliations
                [1 ]Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China; jack6shuai@ 123456163.com (S.N.); yaohouzong@ 123456163.com (H.Y.); wanglili9413@ 123456163.com (L.W.); ljaaa111@ 123456163.com (J.L.)
                [2 ]Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China
                [3 ]Faculty of Materials Science and Chemical Engineering, the State Key Laboratory Base of Novel Functional Materials and Preparation Science, Ningbo University, Ningbo 315211, Zhejiang, China
                Author notes
                [* ]Correspondence: jiangfeng@ 123456nbu.edu.cn (F.J.); aipinglu@ 123456hkbu.edu.hk (A.L.); zhangge@ 123456hkbu.edu.hk (G.Z.); Tel.: +852-3411-2456 (A.L.); +852-3411-2958 (G.Z.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-3033-6819
                https://orcid.org/0000-0002-7807-7695
                Article
                Publisher ID: ijms-18-01683
                DOI: 10.3390/ijms18081683
                PMC ID: 5578073
                PubMed ID: 28767098
                SO-VID: a31b2f0e-dfd5-4ed1-89e6-f2aa29fd5a17
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 10 July 2017
                Date accepted : 01 August 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: nucleic acid aptamer,nuclease degradation,rapid excretion,binding affinity,chemical modification
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: nucleic acid aptamer, nuclease degradation, rapid excretion, binding affinity, chemical modification

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