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Peptidomimetic inhibitors of TMPRSS2 block SARS-CoV-2 infection in cell culture.
Wettstein, Lukas; Knaff, Philip Maximilian; Kersten, Christian; Müller, Patrick; Weil, Tatjana; Conzelmann, Carina; Müller, Janis A; Brückner, Maximilian; Hoffmann, Markus; Pöhlmann, Stefan; Schirmeister, Tanja; Landfester, Katharina; Münch, Jan; Mailänder, Volker.
  • Wettstein L; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
  • Knaff PM; Dermatology Clinic of the University Medicine of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
  • Kersten C; Max Planck Institute for Polymer Research, 55128, Mainz, Germany.
  • Müller P; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, 55128, Mainz, Germany.
  • Weil T; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, 55128, Mainz, Germany.
  • Conzelmann C; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
  • Müller JA; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
  • Brückner M; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
  • Hoffmann M; Institute of Virology, Philipps University Marburg, Marburg, Germany.
  • Pöhlmann S; Dermatology Clinic of the University Medicine of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
  • Schirmeister T; Max Planck Institute for Polymer Research, 55128, Mainz, Germany.
  • Landfester K; Infection Biology Unit, German Primate Center, 37077, Göttingen, Germany.
  • Münch J; Faculty of Biology and Psychology, Georg-August-University Göttingen, 37073, Göttingen, Germany.
  • Mailänder V; Infection Biology Unit, German Primate Center, 37077, Göttingen, Germany.
Commun Biol ; 5(1): 681, 2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1927105
ABSTRACT
The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic TMPRSS2 inhibitors. Molecular docking studies identified peptidomimetic binders of the TMPRSS2 catalytic site, which were synthesized and coupled to an electrophilic serine trap. The compounds inhibit TMPRSS2 while demonstrating good off-target selectivity against selected coagulation proteases. Lead candidates are stable in blood serum and plasma for at least ten days. Finally, we show that selected peptidomimetics inhibit SARS-CoV-2 Spike-driven pseudovirus entry and authentic SARS-CoV-2 infection with comparable efficacy as camostat mesylate. The peptidomimetic TMPRSS2 inhibitors also prevent entry of recent SARS-CoV-2 variants of concern Delta and Omicron BA.1. In sum, our study reports antivirally active and stable TMPRSS2 inhibitors with prospects for further preclinical and clinical development as antiviral agents against SARS-CoV-2 and other TMPRSS2-dependent viruses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptidomimetics / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Commun Biol Year: 2022 Document Type: Article Affiliation country: S42003-022-03613-4

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Peptidomimetics / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Commun Biol Year: 2022 Document Type: Article Affiliation country: S42003-022-03613-4