De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
The authors used computational de novo protein design to create small, stable miniproteins that bind the SARS-CoV-2 spike receptor-binding domain and block its interaction with ACE2. Two design strategies were used: incorporating the ACE2 helix into a designed scaffold, and building entirely new binders against the RBD. The best designs bound with picomolar affinity and neutralized the virus, with cryo-EM confirming the binding modes matched the computational models.