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Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds
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ProTides for Antiviral Activity Beyond Liver Cells.

Felix Goebel1, Adrian Humboldt1, Heeyoung Kim2,3

  • 1Institute of Organic Chemistry, University of Stuttgart, Stuttgart, Germany.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|March 23, 2026
PubMed
Summary
This summary is machine-generated.

Modifying the alcohol residue in nucleotide prodrugs significantly enhances antiviral activity against RNA viruses. This structural change improves drug efficacy across various cell types, boosting pandemic preparedness.

Keywords:
antiviralsnucleosidesnucleotidespolymerasesprodrugs

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Area of Science:

  • Biochemistry
  • Virology
  • Medicinal Chemistry

Background:

  • Nucleotide prodrugs, known as ProTides, enhance antiviral bioavailability.
  • Some ProTides exhibit limited efficacy in non-liver tissues due to cell-specific activity biases.

Purpose of the Study:

  • To investigate the impact of alcohol residue modifications in ProTide structures on antiviral activity against RNA viruses.
  • To explore the potential for improving antiviral drug distribution and efficacy across diverse cell types.

Main Methods:

  • Synthesis and evaluation of modified ProTide antiviral compounds, including remdesivir (REM) and bemnifosbuvir (BEM) derivatives.
  • Antiviral activity assays against various RNA viruses in different cell lines.
  • Cytotoxicity assessments to determine drug safety profiles.

Main Results:

  • A cycloheptyl residue in a remdesivir derivative demonstrated potent inhibition (≤110 nM EC50) against four RNA viruses.
  • A cyclobutyl derivative of bemnifosbuvir achieved nanomolar EC50 values against dengue virus in multiple cell lines.
  • These modified ProTides showed efficacy in cells with low metabolic activity and maintained low cytotoxicity (up to 50 µM).

Conclusions:

  • Minor structural modifications, specifically the alcohol residue, can significantly broaden the tissue activity of nucleosidic antivirals.
  • Optimized ProTide design holds promise for developing new antivirals with broad-spectrum activity against RNA viruses.
  • These findings are crucial for enhancing pandemic preparedness through improved antiviral drug development.