Item type:Thesis, Open Access

Klonierung, Expression und enzymkinetische Charakterisierung der hämagglutininspaltenden Protease TMPRSS2

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Date

2014-09-08

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Philipps-Universität Marburg
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Abstract

TMPRSS2 is a multidomain type II transmembrane serine protease that cleaves the surface glycoprotein hemagglutinin (HA) of influenza viruses with 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 coronavirus. Increased TMPRSS2 expression was also described in several tumor entities. Therefore, TMPRSS2 emerged as a potential target for drug design. The catalytic domain of TMPRSS2 was expressed in E. 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 in P1 position, whereby some of these analogues possess inhibition constants around 20 nM. An improved potency was found for second type derived from sulfonylated 3-amindinophenylalanylamide derivates. The most potent derivative of this series inhibits TMPRSS2 with a Ki value of 0.9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells. Based on the inhibitor studies a series of new fluorogenic substrates containing a D-arginine residue in P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2.

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Dates
Created: 2014Issued: 2014-09-08Updated: 2014-09-08
DOI
https://doi.org/10.17192/z2014.0384
Faculty
Fachbereich Pharmazie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
influenza virusTMPRSS2Influenzavirustransmembrane SerinproteaseTMPRSS2ProteaseinhibitorenTTSPprotease inhibitor
DFG-subjects
Grippe
DDC-Numbers
610
License
https://rightsstatements.org/vocab/InC-NC/1.0/
URI
https://open.uni-marburg.de/handle/10.17192/z2014.0384
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Meyer, Daniela (120964236): Klonierung, Expression und enzymkinetische Charakterisierung der hämagglutininspaltenden Protease TMPRSS2. : Philipps-Universität Marburg 2014-09-08. DOI: https://doi.org/10.17192/z2014.0384.

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This item has been published with the following license: In Copyright