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TitleAn inhaled ACE2 decoy confers protection against SARS-CoV-2 infection in preclinical models.
Journal, issue, pagesSci Transl Med, Vol. 15, Issue 711, Page eadi2623, Year 2023
Publish dateAug 30, 2023
AuthorsEmiko Urano / Yumi Itoh / Tatsuya Suzuki / Takanori Sasaki / Jun-Ichi Kishikawa / Kanako Akamatsu / Yusuke Higuchi / Yusuke Sakai / Tomotaka Okamura / Shuya Mitoma / Fuminori Sugihara / Akira Takada / Mari Kimura / Shuto Nakao / Mika Hirose / Tadahiro Sasaki / Ritsuko Koketsu / Shunya Tsuji / Shota Yanagida / Tatsuo Shioda / Eiji Hara / Satoaki Matoba / Yoshiharu Matsuura / Yasunari Kanda / Hisashi Arase / Masato Okada / Junichi Takagi / Takayuki Kato / Atsushi Hoshino / Yasuhiro Yasutomi / Akatsuki Saito / Toru Okamoto /
PubMed AbstractThe Omicron variant continuously evolves under the humoral immune pressure exerted by vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the resulting Omicron ...The Omicron variant continuously evolves under the humoral immune pressure exerted by vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the resulting Omicron subvariants display further immune evasion and antibody escape. An engineered angiotensin-converting enzyme 2 (ACE2) decoy composed of high-affinity ACE2 and an IgG1 Fc domain could offer an alternative modality to neutralize SARS-CoV-2. We previously reported its broad spectrum and therapeutic potential in rodent models. Here, we demonstrate that the engineered ACE2 decoy retains neutralization activity against Omicron subvariants, including the currently emerging XBB and BQ.1 strains, which completely evade antibodies currently in clinical use. SARS-CoV-2, under the suboptimal concentration of neutralizing drugs, generated SARS-CoV-2 mutants escaping wild-type ACE2 decoy and monoclonal antibodies, whereas no escape mutant emerged against the engineered ACE2 decoy. Furthermore, inhalation of aerosolized decoys improved the outcomes of rodents infected with SARS-CoV-2 at a 20-fold lower dose than that of intravenous administration. Last, the engineered ACE2 decoy exhibited therapeutic efficacy for cynomolgus macaques infected with SARS-CoV-2. These results indicate that this engineered ACE2 decoy represents a promising therapeutic strategy to overcome immune-evading SARS-CoV-2 variants and that liquid aerosol inhalation could be considered as a noninvasive approach to enhance the efficacy of COVID-19 treatments.
External linksSci Transl Med / PubMed:37647387
MethodsEM (single particle)
Resolution3.2 - 3.9 Å
Structure data

EMDB-35029: SARS-CoV2 spike protein with ACE2, no ACE2 binding.
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-35030: SARS-CoV2 spike protein with ACE2. 1 ACE2 bound form.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-35031: SARS-CoV2 spike protein with ACE2. 2 ACE2 bound form.
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-35032: SARS-CoV2 spike protein with ACE2. 3 ACE2 bound form.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-35036: SARS-CoV2 spike protein with ACE2 decoy.no ACE2 decoy binding
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-35037: SARS-CoV2 spike protein with ACE2 decoy. 1 ACE2 decoy bound form.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-35038: SARS-CoV2 spike protein with ACE2 decoy. 1 ACE2 decoy bound and 2 RBD up form.
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-35039: SARS-CoV2 spike protein with ACE2 decoy. 2 ACE2 decoy bound form.
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-35040: SARS-CoV2 spike protein with ACE2 decoy. 3 ACE2 decoy bound form.
Method: EM (single particle) / Resolution: 3.5 Å

36345

8jje

EMDB-36345, PDB-8jje:
RBD of SARS-CoV2 spike protein with ACE2 decoy
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ZN:
Unknown entry

ChemComp-SO4:
SULFATE ION

ChemComp-HOH:
WATER

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsVIRAL PROTEIN/PROTEIN BINDING / SARS-CoV2 / spike protein / ACE2 / ACE2 decoy / VIRAL PROTEIN / VIRAL PROTEIN-PROTEIN BINDING complex

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