title: Development of substrate analogue inhibitors for the human airway trypsin-like protease HAT.
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 (K(i) 13 nM) containing proline as the P2 residue completely lacks selectivity, incorporation of norvaline leads to a potent inhibitor (15, K(i) 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.
authors: Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
authors: Frank
authors: F
authors: Sielaff
authors: Eva
authors: E
authors: Böttcher-Friebertshäuser
authors: Daniela
authors: D
authors: Meyer
authors: Sebastian M
authors: SM
authors: Saupe
authors: Ines M
authors: IM
authors: Volk
authors: Wolfgang
authors: W
authors: Garten
authors: Torsten
authors: T
authors: Steinmetzer
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000235:genetics; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000578:Amidines; D000998:Antiviral Agents; D001593:Benzyl Compounds; D004151:Dipeptides; D015842:Serine Proteinase Inhibitors; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases