Development of an ultrahigh affinity, trimeric ACE2 biologic as a universal SARS-CoV-2 antagonist

Area of Science:

• Virology
• Structural Biology
• Biochemistry

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme II (ACE2) for cellular entry, driving the COVID-19 pandemic.
• Understanding the interaction between the SARS-CoV-2 spike protein and ACE2 is crucial for developing effective antiviral strategies.

Purpose of the Study:

• To design and characterize an ultrapotent, trivalent biologic antagonist targeting the ACE2 receptor to inhibit SARS-CoV-2 and related coronavirus entry.
• To leverage structural insights of the spike protein-ACE2 interaction for broad-spectrum antiviral development.

Main Methods:

• Development of a trivalent ACE2 entry antagonist with enhanced serum stability and eliminated enzymatic activity.
• Utilized surface plasmon resonance (SPR) for binding kinetics analysis.
• Employed pseudovirus neutralization assays to assess inhibitory potency.
• Conducted single-particle cryo-electron microscopy (cryo-EM) for structural elucidation.

Main Results:

• The developed biologic antagonist demonstrated high-affinity binding to ACE2 and potent inhibition of SARS-CoV-2 variants.
• The antagonist effectively neutralized SARS-CoV-1, indicating cross-reactivity.
• Structural analysis confirmed the antagonist's mechanism of blocking viral entry via ACE2.

Conclusions:

• A universal trivalent ACE2 entry antagonist was successfully designed, demonstrating broad efficacy against tested SARS-CoV-2 variants and SARS-CoV-1.
• The findings suggest this antagonist holds promise for combating current and future coronavirus threats, including emergent mutants.