Soluble wild-type ACE2 molecules inhibit newer SARS-CoV-2 variants and are a potential antiviral strategy to mitigate disease severity in COVID-19.

SARS-CoV-2, the virus responsible for COVID-19, has caused havoc around the world. While several COVID-19 vaccines and drugs have been authorised for use, these antiviral drugs remain beyond the reach of most low- and middle-income countries. Rapid viral evolution is reducing the efficacy of vaccines and monoclonal antibodies and contributing to deaths of some fully vaccinated persons. Others with normal immunity may have chosen not be vaccinated and remain at risk if they contract the infection. Vaccines may not protect some immunodeficient patients from SARS-CoV-2, who are also at increased risk of chronic COVID-19 infection, a dangerous stalemate between the virus and a suboptimal immune response. Intra-host viral evolution could rapidly lead to the selection and dominance of vaccine and monoclonal antibody resistant clades of SARS-CoV-2. There is thus an urgent need to develop new treatments for COVID-19. The NZACE2-Pātari project, comprising modified soluble ACE2 molecules, seeks to intercept and block SARS-CoV-2 infection of the respiratory mucosa. In vitro data presented here shows that soluble wild-type ACE2 molecules retain the ability to effectively block the Spike (S) glycoprotein of SARS-CoV-2 variants including the ancestral Wuhan, delta (B.1.617.2) and omicron (B.1.1.529) strains. This therapeutic strategy may prove effective if implemented early during the nasal phase of the infection and may act synergistically with other antiviral drugs such as Paxlovid to further mitigate disease severity.