Abstract
New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.
【초록키워드】 COVID-19, Treatment, coronavirus disease, SARS-CoV-2, Coronavirus disease 2019, Efficacy, ACE2, coronavirus, pandemic, Antiviral, antibody, monoclonal antibody, variant, Delta, B.1.617.2, Cryo-electron microscopy, Prophylactic, severe acute respiratory syndrome Coronavirus, omicron, monoclonal antibodies, angiotensin-converting enzyme 2, Spike protein, Receptor binding domain, Viral, pathogen, mice, therapeutic, B.1.1.529, receptor, respiratory, expression, therapeutic strategy, antigenic drift, miniprotein, Angiotensin-converting enzyme, angiotensin, acute respiratory syndrome, treatment of COVID-19, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, inhibitors of SARS-CoV-2, antigenic, viral escape, trimeric spike, receptor binding domains, apex, receptor binding site, Administered, TRIPOD, autoimmune responses, neutralized, greater, tested, intranasally, clinically, form, the spike protein, New, other variant, 【제목키워드】 SARS-CoV-2 variant, Infection, Protein, multivalent, neutralize,