Engineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2

Yusuke Higuchi, Tatsuya Suzuki, Takao Arimori, Nariko Ikemura, Emiko Mihara, Yuhei Kirita, Eriko Ohgitani, Osam Mazda, Daisuke Motooka, Shota Nakamura, Yusuke Sakai, Yumi Itoh, Fuminori Sugihara, Yoshiharu Matsuura, Satoaki Matoba, Toru Okamoto (), Junichi Takagi () and Atsushi Hoshino ()
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Yusuke Higuchi: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Tatsuya Suzuki: Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University
Takao Arimori: Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University
Nariko Ikemura: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Emiko Mihara: Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University
Yuhei Kirita: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Eriko Ohgitani: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Osam Mazda: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Daisuke Motooka: Research Institute for Microbial Diseases, Osaka University
Shota Nakamura: Research Institute for Microbial Diseases, Osaka University
Yusuke Sakai: 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: Research Institute for Microbial Diseases, Osaka University
Satoaki Matoba: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Toru Okamoto: Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University
Junichi Takagi: Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University
Atsushi Hoshino: Graduate School of Medical Science, Kyoto Prefectural University of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24013-y

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