Dokument

Zusammenfassung:
TMPRSS2 ist eine Typ II transmembrane Serinprotease mit einer multidomänen Struktur, die das Oberflächenglykoprotein Hämagglutinin (HA) der Influenzaviren mit einer monobasischen Schnittstelle spaltet. Dies ist eine Voraussetzung für die Virusfusion und Vermehrung. Weiterhin aktiviert sie das Fusionsprotein F des humanen Metapneumovirus sowie das Spike S Protein der SARS Coronaviren. Zudem wurde eine TMPRSS2-Expression in einigen Tumorgeweben beschrieben. Daher scheint, TMPRSS2 eine potentielle Zielstruktur in der Wirkstoffforschung zu sein. Die katalytische Domäne der TMPRSS2 wurde in E.Coli exprimiert und für Inhibitionsstudien mit zuvor synthetisierten Inhibitoren einiger trypsinartiger Serinproteasen verwendet. Es wurden zwei Inhibitortypen identifiziert, die TMPRSS2 im nanomolaren Bereich hemmen. Die erste Serie umfasst substratanaloge Inhibitoren mit einem 4-Amidinobenzylamid-Rest in P1 Position, wobei einige Verbindungen Hemmkonstanten um 20 nM besitzen. Eine gesteigerte Hemmung konnte für den zweiten Inhibitortyp mit einem sulfonylierten 3-Amindinophenylalanylamid gefunden werden. Die beste Verbindung dieser Serie hemmt TMPRSS2 mit einem Ki-Wert von 0,9 nM und zeigt eine effektive Hemmung der Influenzavirus-Ausbreitung in humanen bronchialen Epithelzellen. Basierend auf diesen Inhibitorstudien wurden neue fluorogene Substrate mit einem D-Arginin in P3-Position synthetisiert. Einige dieser Substrate werden effektiv durch TMPRSS2 gespalten.

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32. TMPRSS2,PubMed: NM_005656 atggct ttgaactcag ggtcaccacc agctattgga ccttactatg 181 aaaaccatgg ataccaaccg gaaaacccct atcccgcaca gcccactgtg gtccccactg 241 tctacgaggt gcatccggct cagtactacc cgtcccccgt gccccagtac gccccgaggg 301 tcctgacgca ggcttccaac cccgtcgtct gcacgcagcc caaatcccca tccgggacag 361 tgtgcacctc aaagactaag aaagcactgt gcatcacctt gaccctgggg accttcctcg 421 tgggagctgc gctggccgct ggcctactct ggaagttcat gggcagcaag tgctccaact 481 ctgggataga gtgcgactcc tcaggtacct gcatcaaccc ctctaactgg tgtgatggcg 541 tgtcacactg ccccggcggg gaggacgaga atcggtgtgt tcgcctctac ggaccaaact 601 tcatccttca ggtgtactca tctcagagga agtcctggca ccctgtgtgc caagacgact 661 ggaacgagaa ctacgggcgg gcggcctgca gggacatggg ctataagaat aatttttact 721 ctagccaagg aatagtggat gacagcggat ccaccagctt tatgaaactg aacacaagtg 781 ccggcaatgt cgatatctat aaaaaactgt accacagtga tgcctgttct tcaaaagcag 841 tggtttcttt acgctgtata gcctgcgggg tcaacttgaa ctcaagccgc cagagcagga 901 ttgtgggcgg cgagagcgcg ctcccggggg cctggccctg gcaggtcagc ctgcacgtcc 961 agaacgtcca cgtgtgcgga ggctccatca tcacccccga gtggatcgtg acagccgccc 1021 actgcgtgga aaaacctctt aacaatccat ggcattggac ggcatttgcg gggattttga 1081 gacaatcttt catgttctat ggagccggat accaagtaga aaaagtgatt tctcatccaa 1141 attatgactc caagaccaag aacaatgaca ttgcgctgat gaagctgcag aagcctctga 1201 ctttcaacga cctagtgaaa ccagtgtgtc tgcccaaccc aggcatgatg ctgcagccag 1261 aacagctctg ctggatttcc gggtgggggg ccaccgagga gaaagggaag acctcagaag 1321 tgctgaacgc tgccaaggtg cttctcattg agacacagag atgcaacagc agatatgtct 1381 atgacaacct gatcacacca gccatgatct gtgccggctt cctgcagggg aacgtcgatt 1441 cttgccaggg tgacagtgga gggcctctgg tcacttcgaa gaacaatatc tggtggctga 1501 taggggatac aagctggggt tctggctgtg ccaaagctta cagaccagga gtgtacggga 1561 atgtgatggt attcacggac tggatttatc gacaaatgag ggcagacggc taa Abbildung A.3. Volllängen DNA der TMPRSS2.
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