Protective Efficacy of Novel Engineered Human ACE2-Fc Fusion Protein Against Pan-SARS-CoV-2 Infection In Vitro and in Vivo

Bo Yu, Aleksandra Drelich, Jason Hsu, Vivian Tat, Bihung Peng, Qisheng Wei, Jianming Wang, Hong Wang, John Wages, Andrew R. Mendelsohn, James W. Larrick, Chien Te Tseng

Research output: Contribution to journalArticlepeer-review

Abstract

Enduring occurrence of severe COVID-19 for unvaccinated, aged, or immunocompromised individuals remains an urgent need. Soluble human angiotensin-converting enzyme 2 (ACE2) has been used as a decoy receptor to inhibit SARS-CoV-2 infection, which is limited by moderate affinity. We describe an engineered, high-affinity ACE2 that is consistently effective in tissue cultures in neutralizing all strains tested, including Delta and Omicron. We also found that treatment of AC70 hACE2 transgenic mice with hACE2-Fc receptor decoys effectively reduced viral infection, attenuated tissue histopathology, and delayed the onset of morbidity and mortality caused by SARS-CoV-2 infection. We believe that using this ACE2-Fc protein would be less likely to promote the escape mutants of SARS-CoV-2 as frequently as did those neutralizing antibody therapies. Together, our results emphasize the suitability of our newly engineered hACE2-Fc fusion protein for further development as a potent antiviral agent against Pan-SARS-CoV-2 infection.

Original languageEnglish (US)
Pages (from-to)16646-16657
Number of pages12
JournalJournal of medicinal chemistry
Volume66
Issue number24
DOIs
StatePublished - Dec 28 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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