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Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein.
Svilenov, Hristo L; Sacherl, Julia; Reiter, Alwin; Wolff, Lisa S; Cheng, Cho-Chin; Stern, Marcel; Grass, Vincent; Feuerherd, Martin; Wachs, Frank-Peter; Simonavicius, Nicole; Pippig, Susanne; Wolschin, Florian; Keppler, Oliver T; Buchner, Johannes; Brockmeyer, Carsten; Protzer, Ulrike.
  • Svilenov HL; Department of Chemistry, Technical University of Munich, Garching, Germany.
  • Sacherl J; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany.
  • Reiter A; Formycon AG, Martinsried/Planegg, Germany.
  • Wolff LS; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany.
  • Cheng CC; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany; German Center for Infection Research, Munich Partner Site, Munich, Germany.
  • Stern M; Max von Pettenkofer Institute & Gene Center, Virology, LMU München, Munich, Germany; German Center for Infection Research, Munich Partner Site, Munich, Germany.
  • Grass V; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany.
  • Feuerherd M; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany.
  • Wachs FP; Formycon AG, Martinsried/Planegg, Germany.
  • Simonavicius N; Formycon AG, Martinsried/Planegg, Germany.
  • Pippig S; Formycon AG, Martinsried/Planegg, Germany.
  • Wolschin F; Formycon AG, Martinsried/Planegg, Germany.
  • Keppler OT; Max von Pettenkofer Institute & Gene Center, Virology, LMU München, Munich, Germany; German Center for Infection Research, Munich Partner Site, Munich, Germany.
  • Buchner J; Department of Chemistry, Technical University of Munich, Garching, Germany.
  • Brockmeyer C; Formycon AG, Martinsried/Planegg, Germany. Electronic address: carsten.brockmeyer@formycon.com.
  • Protzer U; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany; German Center for Infection Research, Munich Partner Site, Munich, Germany. Electronic address: protzer@tum.de.
Antiviral Res ; 196: 105197, 2021 12.
Article in English | MEDLINE | ID: covidwho-1509565
ABSTRACT
SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Immunoglobulin G / Virus Internalization / Angiotensin-Converting Enzyme 2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Antiviral Res Year: 2021 Document Type: Article Affiliation country: J.antiviral.2021.105197

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Immunoglobulin G / Virus Internalization / Angiotensin-Converting Enzyme 2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Antiviral Res Year: 2021 Document Type: Article Affiliation country: J.antiviral.2021.105197