Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells

Antiviral Res. 2015 Aug;120:89-100. doi: 10.1016/j.antiviral.2015.05.006. Epub 2015 May 26.

Abstract

Antiviral medication is used for the treatment of severe influenza infections, of which the neuraminidase inhibitors (NAIs) are the most effective drugs, approved so far. Here, we investigated the antiviral efficacy of the peptidomimetic furin inhibitor MI-701 in combination with oseltamivir carboxylate and ribavirin against the infection of highly pathogenic avian influenza viruses (HPAIV) that are activated by the host protease furin. Cell cultures infected with the strains A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Rostock/1934 (H7N1) were treated with each agent alone, or in double and triple combinations. MI-701 alone achieved a concentration-dependent reduction of virus propagation. Double treatment of MI-701 with oseltamivir carboxylate and triple combination with ribavirin showed synergistic inhibition and a pronounced delay of virus propagation. MI-701 resistant mutants were not observed. Emergence of NA mutation H275Y conferring high oseltamivir resistance was significantly delayed in the presence of MI-701. Our data indicate that combination with a potent furin inhibitor significantly enhances the therapeutic efficacy of conventional antivirals drugs against HPAIV infection.

Keywords: Combinatorial drug treatment; Delayed resistance; Peptidomimetic furin inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / metabolism*
  • Dogs
  • Drug Resistance, Viral
  • Drug Synergism
  • Furin / antagonists & inhibitors*
  • Influenza A Virus, H5N1 Subtype / drug effects*
  • Influenza A Virus, H5N1 Subtype / growth & development
  • Influenza A Virus, H7N1 Subtype / drug effects*
  • Influenza A Virus, H7N1 Subtype / growth & development
  • Madin Darby Canine Kidney Cells
  • Microbial Sensitivity Tests
  • Mutant Proteins / genetics
  • Mutation, Missense
  • Neuraminidase / genetics
  • Oseltamivir / metabolism*
  • Peptidomimetics / metabolism*
  • Ribavirin / metabolism*
  • Viral Proteins / genetics

Substances

  • Antiviral Agents
  • Mutant Proteins
  • Peptidomimetics
  • Viral Proteins
  • Oseltamivir
  • Ribavirin
  • NA protein, influenza A virus
  • Neuraminidase
  • Furin