Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections.
Cleavage of the influenza virus hemagglutinin (HA) by host cell proteases is crucial for infectivity and spread of the virus. Some years ago, we identified TMPRSS2 and HAT from human airways as activating proteases of influenza A viruses containing a monobasic HA cleavage site. Therefore, these proteases are considered as potential drug targets. In this report, first we show that HA of influenza B virus is activated by TMPRSS2 and HAT, too. We further demonstrate that benzylsulfonyl-d-arginine-proline-4-amidinobenzylamide (BAPA), which is a potent inhibitor of HAT and TMPRSS2, efficiently suppresses virus propagation in TMPRSS2-expressing human airway epithelial cells by inhibition of HA cleavage. BAPA treatment reduced virus titers of different influenza A and B viruses more than 1000-fold and delayed virus propagation by 24-48 h at non-cytotoxic concentrations. A combination of BAPA with the neuraminidase (NA) inhibitor oseltamivir carboxylate efficiently blocked influenza virus replication in airway epithelial cells at remarkable lower concentrations for each compound than treatment with either inhibitor alone. Our studies provide a novel and potent approach for influenza chemotherapy that should be considered for influenza treatment.
Institute of Virology, Philipps-University Marburg, Marburg, Germany. boettch6@staff.uni-marburg.de
Eva
E
Böttcher-Friebertshäuser
Yinghui
Y
Lu
Daniela
D
Meyer
Frank
F
Sielaff
Torsten
T
Steinmetzer
Hans-Dieter
HD
Klenk
Wolfgang
W
Garten
D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D004151:Dipeptides / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D009981:Influenza B virus / Q000502:physiology*; D011480:Protease Inhibitors / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism; D053585:Virus Attachment
D000998:Antiviral Agents; D004151:Dipeptides; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011480:Protease Inhibitors; D013449:Sulfonamides; C551941:benzylsulfonylargininyl-proline-(4-amidinobenzyl)amide; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; C112256:human airway trypsin-like protease