The SARS‐CoV‐2 virus binds to host cell surface ACE2 on the plasma membrane via the spike protein's receptor binding domain. Our work has resulted in the generation of a versatile imaging probe using recombinant Spike receptor binding domain conjugated to fluorescent quantum dots (QDs). This probe is capable of engaging in energy transfer quenching with ACE2‐conjugated gold nanoparticles enabling biochemical monitoring of binding. Neutralizing antibodies and recombinant human ACE2 blocked quenching, demonstrating a specific binding interaction. In cell‐based assays, we observed immediate binding of the probe on the cell surface of ACE2‐expressing cells followed by endocytosis. Neutralizing antibodies and ACE2‐Fc fully prevented binding and endocytosis with low nanomolar potency. Importantly, we can use this QD nanoparticle probe to identify and validate inhibitors of the SARS‐CoV‐2 Spike and ACE2 receptor binding in human cells. This work enables facile, rapid, and high‐throughput biochemical‐ and cell‐based screening of inhibitors for coronavirus Spike‐mediated cell recognition and entry.
Quantum Dot‐Conjugated SARS‐CoV‐2 Spike Nanoparticles for SARS‐CoV‐2 infection modeling and drug discovery