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.”
According to the authors, natural proteins that are repurposed as therapeutics often present significant challenges, such as low stability (which can complicate manufacturing, transport, and storage); residual (and undesirable) biological activity; and the risk of eliciting an autoimmune response. “In contrast,” the authors continued, “the de novo protein decoys are amenable for large-scale manufacturing in traditional bacterial systems, and their thermodynamic hyperstability can enable simplified transport and storage.”
CTC-445.2 (which is also designated NL-CVX1) and the other de novo protein decoys were specifically designed to bind the SARS-CoV-2 spike protein with high affinity, preventing its association with the viral receptor ACE2, which is required for infection.
“We believe the development of NL-CVX1 is the fastest development of a therapeutic de novo protein from concept to preclinical validation,” said Daniel-Adriano Silva, PhD, vice president and head of research at Neoleukin. “It represents our most sophisticated design to date.”
“The rapid development of this targeted protein demonstrates the potential of our de novo protein design platform and our team of scientists to address a broad spectrum of important biological problems,” added Jonathan Drachman, MD, CEO of Neoleukin. “NL-CVX1 is designed to be stable and could potentially be administered by intranasal spray or inhalation to prevent and treat infection in the lungs and upper airways by SARS-CoV-2. We are currently evaluating the possibility of advancing this molecule to clinical trials in humans.”