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      Comparison of the ‘Chemical’ and ‘Structural’ Approaches to the Optimization of the Thrombin-Binding Aptamer

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          Abstract

          Noncanonically structured DNA aptamers to thrombin were examined. Two different approaches were used to improve stability, binding affinity and biological activity of a known thrombin-binding aptamer. These approaches are chemical modification and the addition of a duplex module to the aptamer core structure. Several chemically modified aptamers and the duplex-bearing ones were all studied under the same conditions by a set of widely known and some relatively new methods. A number of the thrombin-binding aptamer analogs have demonstrated improved characteristics. Most importantly, the study allowed us to compare directly the two approaches to aptamer optimization and to analyze their relative advantages and disadvantages as well as their potential in drug design and fundamental studies.

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          Most cited references30

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          Sensitive optical biosensors for unlabeled targets: a review.

          This article reviews the recent progress in optical biosensors that use the label-free detection protocol, in which biomolecules are unlabeled or unmodified, and are detected in their natural forms. In particular, it will focus on the optical biosensors that utilize the refractive index change as the sensing transduction signal. Various optical label-free biosensing platforms will be introduced, including, but not limited to, surface plasmon resonance, interferometers, waveguides, fiber gratings, ring resonators, and photonic crystals. Emphasis will be given to the description of optical structures and their respective sensing mechanisms. Examples of detecting various types of biomolecules will be presented. Wherever possible, the sensing performance of each optical structure will be evaluated and compared in terms of sensitivity and detection limit.
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            SELEX--a (r)evolutionary method to generate high-affinity nucleic acid ligands.

            SELEX stands for systematic evolution of ligands by exponential enrichment. This method, described primarily in 1990 [Ellington, A.D., Szostak, J.W., 1990. In vitro selection of RNA molecules that bind specific ligands. Nature 346, 818-822; Tuerk, C., Gold, L., 1990. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249, 505-510] aims at the development of aptamers, which are oligonucleotides (RNA or ssDNA) binding to their target with high selectivity and sensitivity because of their three-dimensional shape. Aptamers are all new ligands with a high affinity for considerably differing molecules ranging from large targets as proteins over peptides, complex molecules to drugs and organic small molecules or even metal ions. Aptamers are widely used, including medical and pharmaceutical basic research, drug development, diagnosis, and therapy. Analytical and separation tools bearing aptamers as molecular recognition and binding elements are another big field of application. Moreover, aptamers are used for the investigation of binding phenomena in proteomics. The SELEX method was modified over the years in different ways to become more efficient and less time consuming, to reach higher affinities of the aptamers selected and for automation of the process. This review is focused on the development of aptamers by use of SELEX and gives an overview about technologies, advantages, limitations, and applications of aptamers.
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              Generalized born models of macromolecular solvation effects.

              It would often be useful in computer simulations to use a simple description of solvation effects, instead of explicitly representing the individual solvent molecules. Continuum dielectric models often work well in describing the thermodynamic aspects of aqueous solvation, and approximations to such models that avoid the need to solve the Poisson equation are attractive because of their computational efficiency. Here we give an overview of one such approximation, the generalized Born model, which is simple and fast enough to be used for molecular dynamics simulations of proteins and nucleic acids. We discuss its strengths and weaknesses, both for its fidelity to the underlying continuum model and for its ability to replace explicit consideration of solvent molecules in macromolecular simulations. We focus particularly on versions of the generalized Born model that have a pair-wise analytical form, and therefore fit most naturally into conventional molecular mechanics calculations.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                20 February 2014
                : 9
                : 2
                : e89383
                Affiliations
                [1 ]Institute for Physical-Chemical Medicine, Moscow, Russia
                [2 ]Orekhovich Institute of Biomedical Chemistry, Moscow, Russia
                [3 ]Topchiev Institute of Petrochemical Synthesis, Moscow, Russia
                [4 ]Engelhardt Institute of Molecular Biology, Moscow, Russia
                [5 ]Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
                University of Houston, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GP OT. Performed the experiments: OT VT DB NB IS ET DK AC. Analyzed the data: GP DK AV. Contributed reagents/materials/analysis tools: OT VT DB NB IS ET DK AC AV. Wrote the paper: AV. Contributed to drafting and revising the the article: OT VT DB NB IS ET DK AC DK GP.

                Article
                PONE-D-13-39549
                10.1371/journal.pone.0089383
                3930721
                abe7c4f1-6d4e-4b5a-a70c-4801f7207a26
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 September 2013
                : 20 January 2014
                Page count
                Pages: 9
                Funding
                This work was supported by Russian Foundation for Basic Research [14-04-01244; 14-04-01035] and the program of the Presidium of the Russian Academy of Sciences on Molecular and Cell Biology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Bioinorganic chemistry
                Biomacromolecule-ligand interactions
                Drug discovery
                Macromolecular assemblies
                Nucleic acids
                Biotechnology
                Drug discovery
                Molecular cell biology
                Signal transduction
                Signaling in cellular processes
                Thrombin signaling
                Medicine
                Drugs and devices
                Drug research and development
                Drug discovery

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                Uncategorized

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