Development of substrate analogue inhibitors for the human airway trypsin-like protease HAT |
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Authors: | Sielaff Frank Böttcher-Friebertshäuser Eva Meyer Daniela Saupe Sebastian M Volk Ines M Garten Wolfgang Steinmetzer Torsten |
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Institution: | a Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany b Institute of Virology, Philipps University Marburg, Hans-Meerwein-Str. 2, D-35043 Marburg, Germany |
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Abstract: | A series of substrate analogue inhibitors of the serine protease HAT, containing a 4-amidinobenzylamide moiety as the P1 residue, was prepared. The most potent compounds possess a basic amino acid in the d-configuration as P3 residue. Whereas inhibitor 4 (Ki 13 nM) containing proline as the P2 residue completely lacks selectivity, incorporation of norvaline leads to a potent inhibitor (15, Ki 15 nM) with improved selectivity for HAT in comparison to the coagulation proteases thrombin and factor Xa or the fibrinolytic plasmin. Selected inhibitors were able to suppress influenza virus replication in a HAT-expressing MDCK cell model. |
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Keywords: | HAT Protease inhibitor Serine protease Influenza Hemagglutinin cleavage |
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