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      The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold

      review-article
      ,
      Antiviral Research
      Elsevier B.V.
      Nucleoside, History, Modification, Antiviral, Anticancer, Analogue

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          Abstract

          This is the first of two invited articles reviewing the development of nucleoside-analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. Rather than providing a simple chronological account, we have examined and attempted to explain the thought processes, advances in synthetic chemistry and lessons learned from antiviral testing that led to a few molecules being moved forward to eventual approval for human therapies, while others were discarded. The present paper focuses on early, relatively simplistic changes made to the nucleoside scaffold, beginning with modifications of the nucleoside sugars of Ara-C and other arabinose-derived nucleoside analogues in the 1960's. A future paper will review more recent developments, focusing especially on more complex modifications, particularly those involving multiple changes to the nucleoside scaffold. We hope that these articles will help virologists and others outside the field of medicinal chemistry to understand why certain drugs were successfully developed, while the majority of candidate compounds encountered barriers due to low-yielding synthetic routes, toxicity or other problems that led to their abandonment.

          Highlights

          • This is the first of two invited articles reviewing the development of nucleoside-analogue antiviral drugs.

          • It is written for a target audience of virologists and other non-chemists, and for chemists unfamiliar with the field.

          • Numerous modifications have been made to the nucleoside scaffold in order to impart therapeutic benefits.

          • Nucleoside modifications led to the development of potent antivirals such as acyclovir, entecavir, and tenofovir.

          • We examine thought processes, progress in synthetic chemistry and results of antiviral testing that led to approved drugs.

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          Most cited references311

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          Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases.

          Nucleoside analogues have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with cancer or viral infections. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Here, we review new nucleoside analogues and associated compounds that are currently in preclinical or clinical development for the treatment of cancer and viral infections, and that aim to provide increased response rates and reduced side effects. We also highlight the different approaches used in the development of these drugs and the potential of personalized therapy.
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            Fluorine in medicinal chemistry.

            Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.
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              Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance.

              A combinatorial disulfide cross-linking strategy was used to prepare a stalled complex of human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase with a DNA template:primer and a deoxynucleoside triphosphate (dNTP), and the crystal structure of the complex was determined at a resolution of 3.2 angstroms. The presence of a dideoxynucleotide at the 3'-primer terminus allows capture of a state in which the substrates are poised for attack on the dNTP. Conformational changes that accompany formation of the catalytic complex produce distinct clusters of the residues that are altered in viruses resistant to nucleoside analog drugs. The positioning of these residues in the neighborhood of the dNTP helps to resolve some long-standing puzzles about the molecular basis of resistance. The resistance mutations are likely to influence binding or reactivity of the inhibitors, relative to normal dNTPs, and the clustering of the mutations correlates with the chemical structure of the drug.
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                Author and article information

                Contributors
                Journal
                Antiviral Res
                Antiviral Res
                Antiviral Research
                Elsevier B.V.
                0166-3542
                1872-9096
                10 April 2018
                June 2018
                10 April 2018
                : 154
                : 66-86
                Affiliations
                [1]1000 Hilltop Circle, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA
                Author notes
                []Corresponding author. kseley@ 123456umbc.edu
                Article
                S0166-3542(18)30050-0
                10.1016/j.antiviral.2018.04.004
                6396324
                29649496
                0b0e308e-bcbf-4fcb-9c4d-eb0e0406043c
                © 2018 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
                : 25 January 2018
                : 22 March 2018
                : 4 April 2018
                Categories
                Article

                Infectious disease & Microbiology
                nucleoside,history,modification,antiviral,anticancer,analogue
                Infectious disease & Microbiology
                nucleoside, history, modification, antiviral, anticancer, analogue

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