tetano
Editor, Senior Moderator
Vaccine
Volume 30, Issue 51, 7 December 2012, Pages 7374?7380
Fourth ESWI Influenza Conference
Cover image
Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections
Eva B?ttcher-Friebertsh?usera, Corresponding author contact information, E-mail the corresponding author,
Yinghui Lua,
Daniela Meyerb,
Frank Sielaffb,
Torsten Steinmetzerb,
Hans-Dieter Klenka,
Wolfgang Gartena
a Institute of Virology, Philipps-University Marburg, Marburg, Germany
b Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany
http://dx.doi.org/10.1016/j.vaccine.2012.10.001
Abstract
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.
Highlights
► Protease inhibitors provide novel drugs for influenza A and B virus treatment.► Combination chemotherapy using protease inhibitors and neuraminidase inhibitors.► Host factor-directed drugs for influenza treatment.
http://www.sciencedirect.com/science/article/pii/S0264410X12014466
Volume 30, Issue 51, 7 December 2012, Pages 7374?7380
Fourth ESWI Influenza Conference
Cover image
Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections
Eva B?ttcher-Friebertsh?usera, Corresponding author contact information, E-mail the corresponding author,
Yinghui Lua,
Daniela Meyerb,
Frank Sielaffb,
Torsten Steinmetzerb,
Hans-Dieter Klenka,
Wolfgang Gartena
a Institute of Virology, Philipps-University Marburg, Marburg, Germany
b Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany
http://dx.doi.org/10.1016/j.vaccine.2012.10.001
Abstract
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.
Highlights
► Protease inhibitors provide novel drugs for influenza A and B virus treatment.► Combination chemotherapy using protease inhibitors and neuraminidase inhibitors.► Host factor-directed drugs for influenza treatment.
http://www.sciencedirect.com/science/article/pii/S0264410X12014466