2. Academic Validation
  3. Membrane-permeable tenofovir-di- and monophosphate analogues

Membrane-permeable tenofovir-di- and monophosphate analogues

  • Eur J Med Chem. 2024 Jan 15:264:116020. doi: 10.1016/j.ejmech.2023.116020.
Xiao Jia 1,  Giuliano A Kullik 1,  Marianna Bufano 2,  Andrea Brancale 3,  Dominique Schols 4,  Chris Meier 5
Affiliations

Affiliations

  • 1 Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, D-20146, Hamburg, Germany.
  • 2 Dipartimento Chimica e Tecnologie del Farmaco, Facoltà di Farmacia e Medicina, University of Rome "La Sapienza", Piazzale Aldo Moro 5, 00185, Rome, Italy.
  • 3 Department of Organic Chemistry, Vysoká Škola Chemicko-Technologická v Praze, Technická 5, 16628, Prague, Czech Republic.
  • 4 Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
  • 5 Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, D-20146, Hamburg, Germany; Centre for Structural Systems Biology (CSSB), Hamburg, DESY Campus, Notkestrasse 85, D-22607, Hamburg, Germany. Electronic address: [email protected].
PMID: 38086193 DOI: 10.1016/j.ejmech.2023.116020
Abstract

The development of new Antiviral agents such as nucleoside analogues or acyclic nucleotide analogues (ANPs) and prodrugs thereof is an ongoing task. We report on the synthesis of three types of lipophilic triphosphate analogues of (R)-PMPA and dialkylated diphosphate analogues of (R)-PMPA. A highly selective release of the different nucleotide analogues ((R)-PMPA-DP, (R)-PMPA-MP, and (R)-PMPA) from these compounds was achieved. All dialkylated (R)-PMPA-prodrugs proved to be very stable in PBS as well as in CEM/0 cell extracts and human plasma. In primer extension assays, both the monoalkylated and the dialkylated (R)-PMPA-DP derivatives acted as (R)-PMPA-DP as a substrate for HIV-RT. In contrast, no incorporation events were observed using human polymerase γ. The dialkylated (R)-PMPA-compounds exhibited significant anti-HIV efficacy in HIV-1/2 infected cells (CEM/0 and CEM/TK-). Remarkably, the dialkylated (R)-PMPA-MP derivative 9a showed a 326-fold improved activity as compared to (R)-PMPA in HIV-2 infected CEM/TK- cells as well as a very high SI of 14,000. We are convinced that this study may significantly contribute to advancing Antiviral agents developed based on nucleotide analogues in the future.

Keywords

Antiviral compounds; DNA polymerase; Nucleoside; Prodrug; Reverse transcriptase; Triphosphate.

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