title: 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.
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.
authors.affiliation: Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6-10, 35032 Marburg, Germany.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.affiliation: Protein Crystallography Group, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Sven O
authors.initials: SO
authors.lastname: Dahms
authors.affiliation: Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Böttcher-Friebertshäuser
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6-10, 35032 Marburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.affiliation: Protein Crystallography Group, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Than
authors.affiliation: Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Klenk
authors.affiliation: Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany. Electronic address: garten@staff.uni-marburg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Garten
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D004285:Dogs; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D045683:Furin / Q000037:antagonists & inhibitors*; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000254:growth & development; D057916:Influenza A Virus, H7N1 Subtype / Q000187:drug effects* / Q000254:growth & development; D061985:Madin Darby Canine Kidney Cells; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000378:metabolism*; D057786:Peptidomimetics / Q000378:metabolism*; D012254:Ribavirin / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D050505:Mutant Proteins; D057786:Peptidomimetics; D014764:Viral Proteins; D053139:Oseltamivir; D012254:Ribavirin; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D045683:Furin
keywords: Combinatorial drug treatment; Delayed resistance; Peptidomimetic furin inhibitor