Abiotic Synthetic Antibody Inhibitor with Broad-Spectrum Neutralization and Antiviral Efficacy against Escaping SARS-CoV‑2 Variants

The rapid emergence and spread of vaccine/antibody-escaping
variants
of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has
posed serious challenges to our efforts in combating corona virus
disease 2019 (COVID-19) pandemic. A potent and broad-spectrum neutralizing
reagent against these escaping mutants is extremely important for
the development of strategies for the prevention and treatment of
SARS-CoV-2 infection. We herein report an abiotic synthetic antibody
inhibitor as a potential anti-SARS-CoV-2 therapeutic agent. The inhibitor,
Aphe-NP14, was selected from a synthetic hydrogel polymer nanoparticle
library created by incorporating monomers with functionalities complementary
to key residues of the SARS-CoV-2 spike glycoprotein receptor binding
domain (RBD) involved in human angiotensin-converting enzyme 2 (ACE2)
binding. It has high capacity, fast adsorption kinetics, strong affinity,
and broad specificity in biologically relevant conditions to both
the wild type and the current variants of concern, including Beta,
Delta, and Omicron spike RBD. The Aphe-NP14 uptake of spike RBD results
in strong blockage of spike RBD–ACE2 interaction and thus potent
neutralization efficacy against these escaping spike protein variant
pseudotyped viruses. It also inhibits live SARS-CoV-2 virus recognition,
entry, replication, and infection in vitro and in vivo. The Aphe-NP14 intranasal administration is found
to be safe due to its low in vitro and in
vivo toxicity. These results establish a potential application
of abiotic synthetic antibody inhibitors in the prevention and treatment
of the infection of emerging or possibly future SARS-CoV-2 variants.