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Prodrug Activation by a Viral Protease: Evaluating Combretastatin Peptide Hybrids To Selectively Target Infected

Michael Richter1, Mila M Leuthold1, Dominik Graf1

  • 1Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.

ACS Medicinal Chemistry Letters
|August 16, 2019
PubMed

Insights

Researchers developed novel prodrugs targeting viral replication by inhibiting tubulin. These combretastatin peptide hybrids are activated by the dengue virus (DENV) protease, showing reduced toxicity and potent antiviral activity against DENV and Zika virus.

Area of Science:

  • Virology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Flaviviruses, including dengue virus (DENV), cause widespread tropical infections.
  • Viral replication relies on host cell tubulin, a potential broad-spectrum antiviral target.
  • Direct tubulin targeting can cause significant toxic side effects.

Purpose of the Study:

  • To synthesize and evaluate combretastatin peptide hybrids as targeted antiviral prodrugs.
  • To design prodrugs activated by the DENV protease for localized therapeutic effect.
  • To assess the safety and efficacy of these novel compounds against flaviviruses.

Main Methods:

  • Synthesis of combretastatin peptide hybrids incorporating a DENV protease cleavage site.
  • In vitro evaluation of tubulin polymerization inhibition and cytotoxicity.
  • In vitro DENV protease cleavage assays.
  • Antiviral assays against DENV and Zika virus replication in cell cultures.

Main Results:

  • Prodrug candidates showed no in vitro tubulin polymerization activity.
  • Compounds exhibited significantly reduced toxicity (20-2000 fold) compared to combretastatin A-4.
  • Several prodrugs were efficiently cleaved by the DENV protease in vitro.
  • Selected compounds demonstrated antiviral activity against DENV and Zika virus at subcytotoxic concentrations.

Conclusions:

  • Combretastatin peptide prodrugs offer a promising strategy for targeted antiviral therapy.
  • Protease-activated drug delivery minimizes host toxicity while maximizing efficacy.
  • These compounds represent potential new treatments for flavivirus infections.

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