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Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins
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New Heights for ProTides?

Carlo Ballatore1

  • 1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.

Journal of Medicinal Chemistry
|November 16, 2021
PubMed
Summary

Researchers improved the antiviral drug tenofovir alafenamide (ProTide) by modifying its structure. Replacing a component with a tyrosine derivative significantly enhanced its effectiveness and safety profile for potential new antiviral therapies.

Area of Science:

  • Medicinal Chemistry
  • Antiviral Drug Development
  • Prodrug Strategies

Background:

  • Aryloxy phosphoramidate (ProTide) prodrugs are crucial for delivering antiviral agents.
  • Tenofovir alafenamide is an acyclic nucleoside phosphonate with antiviral properties.
  • Optimizing the selectivity index and in vitro antiviral activity of prodrugs is essential for therapeutic efficacy.

Purpose of the Study:

  • To investigate the impact of modifying the aryloxy pro-moiety of tenofovir alafenamide.
  • To enhance the in vitro antiviral activity and selectivity index of the ProTide prodrug.
  • To explore the potential of tyrosine derivatives in ProTide drug development.

Main Methods:

  • Synthesis of novel tenofovir alafenamide analogs.
  • Modification of the aryloxy pro-moiety with tyrosine derivatives.

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  • Evaluation of in vitro antiviral activity and selectivity index.

    • Main Results:

    • Replacement of the aryloxy pro-moiety with a tyrosine derivative dramatically improved antiviral activity.
    • The selectivity index of the modified tenofovir alafenamide prodrug was significantly enhanced.
    • These modifications offer a promising strategy for developing improved ProTides.

    Conclusions:

    • Tyrosine derivatives represent a viable alternative for optimizing ProTide prodrugs.
    • The findings suggest a new direction for the development of potent and selective antiviral agents.
    • This research has significant implications for the future of antiviral drug design and ProTide technology.