An ACE2 decamer viral trap as a durable intervention solution for current and future SARS-CoV.

Area of Science:

• Virology
• Immunology
• Drug Discovery

Background:

• The rapid evolution of SARS-CoV-2 necessitates new antiviral strategies beyond vaccines and monoclonal antibodies, which target specific viral sequences.
• Animal coronaviruses (CoVs), particularly within the SARS family, represent a persistent pandemic risk.
• Conventional treatments face challenges due to the receptor binding domain (RBD) variability in emerging SARS-CoV-2 variants.

Purpose of the Study:

• To develop and evaluate a novel inhaled antiviral agent targeting ACE2-dependent coronaviruses.
• To assess the efficacy of a recombinant ACE2 decamer viral trap against current and emerging SARS-CoV-2 variants and other CoVs.
• To determine the stability and delivery feasibility of the viral trap for prophylactic and therapeutic use.

Main Methods:

• A recombinant viral trap was engineered, consisting of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc region.
• The viral trap's neutralization potency was tested against various SARS-CoV-2 variants (including Omicron sublineages), SARS-CoV-1, and other human and animal CoVs.
• Efficacy was evaluated in human ACE2 transgenic mice in both prophylactic and therapeutic settings following intranasal administration.
• The molecule's stability at ambient temperature and during aerosolization was assessed.

Main Results:

• The ACE2 decamer viral trap demonstrated high neutralization potency against all tested SARS-CoV-2 variants, including BQ.1, BQ.1.1, XBB.1, and XBB.1.5.
• The trap was also effective against SARS-CoV-1, human NL63, and bat and pangolin CoVs.
• A single intranasal dose provided protection in mice against viral challenges in both prophylactic and therapeutic models.
• The viral trap remained stable at ambient temperature for over twelve weeks and withstood aerosolization.

Conclusions:

• The decameric ACE2 viral trap is a potent inhibitor of ACE2-dependent coronaviruses, irrespective of RBD sequence variations.
• Inhalation delivery of this viral trap shows promise as a broad-spectrum antiviral for both current and future coronavirus threats.
• The molecule's stability and efficacy in vivo support its potential as a viable therapeutic and prophylactic agent.