Researchers have designed a protein «decoy» that mimics the interface where the SARS-CoV-2 spike protein binds a human cell, one version of which could neutralize virus infection in cells and protect hamsters from viral challenge. The SARS-CoV-2 virus enters human cells when the spike protein binds to the human ACE2 receptor. While neutralizing antibodies to the spike protein have been isolated, the spike can develop «escape mutations» that help it evade them. A pressing need, therefore, is to develop therapeutics that can be more resistant to SARS-CoV-2 mutational escape. Here, to address this challenge, Thomas Linsky and colleagues developed a computational protein design strategy that enabled the rapid design of stable de novo protein «decoys» that replicate the protein receptor interface in hACE2 where SARS-CoV-2 binds. After using their approach to generate approximately 35,000 computational decoys, the researchers selected the top-ranking designs for further testing, identifying one particularly strong candidate. Administering a version of it prevented infection of multiple human cell lines by SARS-CoV-2. In a Syrian hamster model, a single prophylactic dose administered 12 hours before viral challenge allowed all animals to survive the lethal dose, with modest weight loss. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape, the authors say.

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