Abstract
The viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly its cell-binding spike protein gene, has undergone rapid evolution during the coronavirus disease 2019 (COVID-19) pandemic. Variants including Omicron BA.1 and Omicron BA.2 now seriously threaten the efficacy of therapeutic monoclonal antibodies and vaccines that target the spike protein. Viral evolution over a much longer timescale has generated a wide range of genetically distinct sarbecoviruses in animal populations, including the pandemic viruses SARS-CoV-2 and SARS-CoV-1. The genetic diversity and widespread zoonotic potential of this group complicates current attempts to develop drugs in preparation for the next sarbecovirus pandemic. Receptor-based decoy inhibitors can target a wide range of viral strains with a common receptor and may have intrinsic resistance to escape mutant generation and antigenic drift. We previously generated an affinity-matured decoy inhibitor based on the receptor target of the SARS-CoV-2 spike protein, angiotensin-converting enzyme 2 (ACE2), and deployed it in a recombinant adeno-associated virus vector (rAAV) for intranasal delivery and passive prophylaxis against COVID-19. Here, we demonstrate the exceptional binding and neutralizing potency of this ACE2 decoy against SARS-CoV-2 variants including Omicron BA.1 and Omicron BA.2. Tight decoy binding tracks with human ACE2 binding of viral spike receptor-binding domains across diverse clades of coronaviruses. Furthermore, in a coronavirus that cannot bind human ACE2, a variant that acquired human ACE2 binding was bound by the decoy with nanomolar affinity. Considering these results, we discuss a strategy of decoy-based treatment and passive protection to mitigate the ongoing COVID-19 pandemic and future airway virus threats.
【초록키워드】 COVID-19, Treatment, coronavirus disease, Evolution, SARS-CoV-2, Coronavirus disease 2019, Efficacy, ACE2, Coronaviruses, Vaccine, coronavirus, pandemic, COVID-19 pandemic, monoclonal antibody, variant, SARS-CoV-2 variant, drug, severe acute respiratory syndrome Coronavirus, omicron, virus, SARS-CoV-1, angiotensin-converting enzyme 2, variants, Spike protein, airway, Prophylaxis, human ACE2, Receptor-binding domain, SARS-CoV-2 variants, viral evolution, zoonotic, SARS-CoV-2 spike protein, therapeutic, clade, Neutralizing, genetic diversity, mutant, receptor, inhibitor, intranasal, Sarbecoviruses, affinity, binding, sarbecovirus, antigenic drift, Angiotensin-converting enzyme, angiotensin, adeno-associated virus, viral genome, decoy, can not, viral strain, viral strains, acute respiratory syndrome, Threats, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, preparation, antigenic, nanomolar affinity, viral spike, widespread, mitigate, populations, intrinsic, develop, virus, the spike protein, exceptional, complicate, sarbecovirus, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, ACE2, coronavirus,