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Engineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2.
Higuchi, Yusuke; Suzuki, Tatsuya; Arimori, Takao; Ikemura, Nariko; Mihara, Emiko; Kirita, Yuhei; Ohgitani, Eriko; Mazda, Osam; Motooka, Daisuke; Nakamura, Shota; Sakai, Yusuke; Itoh, Yumi; Sugihara, Fuminori; Matsuura, Yoshiharu; Matoba, Satoaki; Okamoto, Toru; Takagi, Junichi; Hoshino, Atsushi.
  • Higuchi Y; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Suzuki T; Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • Arimori T; Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan.
  • Ikemura N; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Mihara E; Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan.
  • Kirita Y; Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Ohgitani E; Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Mazda O; Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Motooka D; Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • Nakamura S; Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • Sakai Y; Department of Veterinary Pathology, Yamaguchi University, Yamaguchi, Japan.
  • Itoh Y; Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • Sugihara F; The Core Instrumentation Facility, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • Matsuura Y; Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • Matoba S; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Okamoto T; Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. toru@biken.osaka-u.ac.jp.
  • Takagi J; Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan. takagi@protein.osaka-u.ac.jp.
  • Hoshino A; Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. a-hoshi@koto.kpu-m.ac.jp.
Nat Commun ; 12(1): 3802, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1387351
ABSTRACT
SARS-CoV-2 has mutated during the global pandemic leading to viral adaptation to medications and vaccinations. Here we describe an engineered human virus receptor, ACE2, by mutagenesis and screening for binding to the receptor binding domain (RBD). Three cycles of random mutagenesis and cell sorting achieved sub-nanomolar affinity to RBD. Our structural data show that the enhanced affinity comes from better hydrophobic packing and hydrogen-bonding geometry at the interface. Additional disulfide mutations caused the fixing of a closed ACE2 conformation to avoid off-target effects of protease activity, and also improved structural stability. Our engineered ACE2 neutralized SARS-CoV-2 at a 100-fold lower concentration than wild type; we also report that no escape mutants emerged in the co-incubation after 15 passages. Therapeutic administration of engineered ACE2 protected hamsters from SARS-CoV-2 infection, decreased lung virus titers and pathology. Our results provide evidence of a therapeutic potential of engineered ACE2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 / Mutation Type of study: Randomized controlled trials Topics: Vaccines Limits: Animals / Humans / Male Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-24013-Y

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 / Mutation Type of study: Randomized controlled trials Topics: Vaccines Limits: Animals / Humans / Male Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-24013-Y