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First and Second Generation Nucleoside Triphosphate Prodrugs: TriPPPro-Compounds for Antiviral Chemotherapy

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Handbook of Chemical Biology of Nucleic Acids

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Abstract

Currently, a number of biologically active nucleoside analogues are extensively used as antiviral, anticancer, antiparasitic, and antibacterial therapeutic agents. However, when considering viruses, their antiviral efficacy is strongly dependent on the intracellular conversion by virus-encoded or, in most cases, host cellular kinases to give the corresponding bioactive nucleoside analogue triphosphates. In this minireview, the recent work on the development of nucleoside triphosphate prodrugs, the so-called TriPPPro-approach is described. First generation TriPPPro-compounds bearing two biodegradable masking units attached to the γ-phosphate group were prepared using the phosphoramidite and H-phosphonate routes, respectively. These TriPPPro-compounds enter cells and deliver the nucleoside triphosphate analogues, and therefore they bypass all steps of the intracellular phosphorylation in contrast to their parent nucleoside analogues. Second generation TriPPPro-compounds comprising a non-cleavable γ-alkyl moiety in addition to a biodegradable prodrug moiety at the γ-phosphate or γ-phosphonate units, respectively, and d4T as a nucleoside analogue will be summarized as well. Such compounds formed γ-alkylated nucleoside triphosphate analogues by chemical hydrolysis or in cell extracts with high selectivity. These γ-alkylated nucleoside triphosphate derivatives proved to be highly resistant toward dephosphorylation and showed a superior selectivity to act as substrates for the viral HIV-RT as compared to three cellular DNA polymerases. The synthesis, the chemical and biological hydrolysis and the antiviral activity of these compounds will be discussed.

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Authors and Affiliations

  1. Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Hamburg, Germany

    Xiao Jia, Chenglong Zhao & Chris Meier

  2. R&D Center for Nucleic Acid Drug, CSPC Pharmaceutical Group Limited, Shanghai, China

    Chenglong Zhao

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  1. Xiao Jia
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  2. Chenglong Zhao
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  3. Chris Meier
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Correspondence to Chris Meier .

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  1. Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, Kobe, Japan

    Naoki Sugimoto

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  1. Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, USA

    Katherine Seley-Radtke

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Jia, X., Zhao, C., Meier, C. (2022). First and Second Generation Nucleoside Triphosphate Prodrugs: TriPPPro-Compounds for Antiviral Chemotherapy. In: Sugimoto, N. (eds) Handbook of Chemical Biology of Nucleic Acids. Springer, Singapore. https://doi.org/10.1007/978-981-16-1313-5_72-1

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