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SARS-CoV-2 Decoyed by De Novo Protein, Diverted from Real Target In Vivo

Drawing fire from SARS-CoV-2, a computationally designed protein protected test animals, sparing them the most serious consequences of infection. The protein, called CTC-445.2, mimicked SARS-CoV-2’s preferred target, the host cell receptor known as angiotensin converting enzyme 2 (ACE2). Because the protein is so like ACE2, its effectiveness as a decoy is likely to persist. That is, the protein is intrinsically resilient to viral mutational escape.

Details about the protein appeared November 5 in the journal Science, in an article titled, “De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.” The article’s authors, primarily researchers at Neoleukin, a biopharmaceutical company, described how they “developed a de novo protein design strategy to swiftly engineer decoys.”

After using their strategy 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.

“The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the receptor-binding domain of the spike protein,” the article’s authors wrote. “Cryogenic electron microscopy shows that the design is accurate and can simultaneously bind to all three receptor binding domains of a single spike protein.”

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