title: Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation.
abstract: TMPRSS2 (transmembrane serine proteinase 2) is a multidomain type II transmembrane serine protease that cleaves the surface glycoprotein HA (haemagglutinin) of influenza viruses with a monobasic cleavage site, which is a prerequisite for virus fusion and propagation. Furthermore, it activates the fusion protein F of the human metapneumovirus and the spike protein S of the SARS-CoV (severe acute respiratory syndrome coronavirus). Increased TMPRSS2 expression was also described in several tumour entities. Therefore TMPRSS2 emerged as a potential target for drug design. The catalytic domain of TMPRSS2 was expressed in Escherichia coli and used for an inhibitor screen with previously synthesized inhibitors of various trypsin-like serine proteases. Two inhibitor types were identified which inhibit TMPRSS2 in the nanomolar range. The first series comprises substrate analogue inhibitors containing a 4-amidinobenzylamide moiety at the P1 position, whereby some of these analogues possess inhibition constants of approximately 20 nM. An improved potency was found for a second type derived from sulfonylated 3-amindinophenylalanylamide derivatives. The most potent derivative of this series inhibits TMPRSS2 with a K(i) value of 0.9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells. On the basis of the inhibitor studies, a series of new fluorogenic substrates containing a D-arginine residue at the P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2.
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35037 Marburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Meyer
authors.forename: Frank
authors.initials: F
authors.lastname: Sielaff
authors.forename: Maya
authors.initials: M
authors.lastname: Hammami
authors.forename: Eva
authors.initials: E
authors.lastname: Böttcher-Friebertshäuser
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Garten
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D015195:Drug Design; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000235:genetics / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human