De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Longxing Cao, Inna Goreshnik, Brian Coventry, David Baker · Full author list: Cao L, Goreshnik I, Coventry B, Case JB, Miller L, Kozodoy L, Chen RE, Carter L, Walls AC, Park YJ, Strauch EM, Stewart L, Diamond MS, Veesler D, Baker D.
Summary
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.
Key findings
- De novo designed miniproteins bound the spike RBD with affinities reaching the picomolar range.
- The top inhibitors potently neutralized SARS-CoV-2 in vitro and are small and hyperstable, easing manufacture and delivery.
- Cryo-EM structures confirmed the binders engaged the RBD essentially as designed.
Subjects & keywords
Cite this paper
Longxing Cao, Inna Goreshnik, Brian Coventry, & David Baker [Full author list: Cao L, Goreshnik I, Coventry B, Case JB, Miller L, Kozodoy L, Chen RE, Carter L, Walls AC, Park YJ, Strauch EM, Stewart L, Diamond MS, Veesler D, Baker D.] (2020). De novo design of picomolar SARS-CoV-2 miniprotein inhibitors. Science. https://doi.org/10.1126/science.abd9909
@article{cao2020novo,
author = {Longxing Cao and Inna Goreshnik and Brian Coventry and David Baker and {Full author list: Cao L, Goreshnik I, Coventry B, Case JB, Miller L, Kozodoy L, Chen RE, Carter L, Walls AC, Park YJ, Strauch EM, Stewart L, Diamond MS, Veesler D, Baker D.}},
title = {De novo design of picomolar SARS-CoV-2 miniprotein inhibitors},
journal = {Science},
year = {2020},
doi = {10.1126/science.abd9909},
url = {https://doi.org/10.1126/science.abd9909}
}