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High affinity modified ACE2 receptors prevent SARS-CoV-2 infection
Yusuke Higuchi; Tatsuya Suzuki; Takao Arimori; Nariko Ikemura; Yuhei Kirita; Eriko Ohgitani; Osam Mazda; Daisuke Motooka; Shota Nakamura; Yusuke Sakai; Yumi Itoh; Fuminori Sugihara; Yoshiharu Matsuura; Satoaki Matoba; Toru Okamoto; Junichi Takagi; Atsushi Hoshino.
Afiliação
  • Yusuke Higuchi; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Tatsuya Suzuki; Research Institute for Microbial Diseases, Osaka University
  • Takao Arimori; Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University
  • Nariko Ikemura; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Yuhei Kirita; Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine,
  • Eriko Ohgitani; Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Osam Mazda; Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Daisuke Motooka; Osaka University Research Institute for Microbial Diseases
  • Shota Nakamura; Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University
  • Yusuke Sakai; Department of Veterinary Pathology, Yamaguchi University
  • Yumi Itoh; Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University
  • Fuminori Sugihara; The Core Instrumentation Facility, Research Institute for Microbial Diseases, Osaka University
  • Yoshiharu Matsuura; Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
  • Satoaki Matoba; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
  • Toru Okamoto; Research Institute for Microbial Diseases, Osaka University
  • Junichi Takagi; Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University
  • Atsushi Hoshino; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Preprint em En | PREPRINT-BIORXIV | ID: ppbiorxiv-299891
ABSTRACT
The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor via receptor binding domain (RBD) to enter into the cell and inhibiting this interaction is a main approach to inhibit SARS-CoV-2 infection. We engineered ACE2 to enhance the affinity with directed evolution in 293T cells. Three cycles of random mutation and cell sorting achieved 100-fold higher affinity to RBD than wild-type ACE2. The extracellular domain of modified ACE2 fused to the human IgG1-Fc region had stable structure and neutralized SARS-CoV-2 without the emergence of mutational escape. Therapeutic administration protected hamsters from SARS-CoV-2 infection, decreasing lung virus titers and pathology. Engineering ACE2 decoy receptors with human cell-based directed evolution is a promising approach to develop a SARS-CoV-2 neutralizing drug that has affinity comparable to monoclonal antibodies yet displaying resistance to escape mutations of virus. One Sentence SummaryEngineered ACE2 decoy receptor has a therapeutic potential against COVID-19 without viral escape mutation.
Licença
cc_by_nc_nd
Texto completo: 1 Coleções: 09-preprints Base de dados: PREPRINT-BIORXIV Tipo de estudo: Rct Idioma: En Ano de publicação: 2020 Tipo de documento: Preprint
Texto completo: 1 Coleções: 09-preprints Base de dados: PREPRINT-BIORXIV Tipo de estudo: Rct Idioma: En Ano de publicação: 2020 Tipo de documento: Preprint