In Vivo CTC-445.2 protein Diverted SARS-CoV-2 from Real Target

Drawing fire from SARS-CoV-2, a computer-designed protein-protected research animal protected them against severe infection consequences. The protein, referred to as CTC-445.2, imitated the preferred target of SARS-CoV-2, the host cell receptor known as angiotensin converting enzyme 2 (ACE2). Since the protein is so similar to ACE2, it is likely that its usefulness as a decoy will continue. That is, for viral mutational escape, the protein is fundamentally robust.

      

Information about the protein appeared in the journal Science on November 5, in an article entitled, "De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2" The authors of the paper, mainly researchers at Neoleukin, a biopharmaceutical company, explained how they "developed a strategy for de novo protein design to quickly engineer decoys."

The researchers selected the top-ranking prototypes for further testing after using their strategy to produce approximately 35,000 computational decoys, selecting one especially strong candidate. Administering a variant of it stopped SARS-CoV-2 from infecting multiple human cell lines. A single prophylactic dose administered 12 hours before the viral challenge in the Syrian hamster model allowed all animals to survive the lethal dose, with minimal weight loss.

"The best decoy, CTC-445.2, binds to the receptor-binding domain of the spike protein with low nanomolar affinity and high specificity," the writers of the article wrote. "Cryogenic electron microscopy shows that the architecture is precise and that a single spike protein can bind to all three receptor binding domains simultaneously."

According to the authors, there are often significant challenges to natural proteins that are repurposed as therapeutics, such as low stability (which can complicate development, transport , and storage); residual (and undesirable) biological activity; and the possibility of an autoimmune reaction. "The authors went on to claim that" de novo protein decoys, on the other hand, are suitable for large-scale production in conventional bacterial systems, and their thermodynamic hyperstability can allow for simplified transport and storage.

CTC-445.2 (also known as NL-CVX1) and other de novo protein decoys were explicitly designed to bind the highly affinity SARS-CoV-2 spike protein, preventing its interaction with the infection-requiring viral receptor ACE2.

Daniel-Adriano Silva, PhD, vice president and head of research at Neoleukin, said, "We believe the development of NL-CVX1 is the fastest development of a therapeutic de novo protein from concept to preclinical validation." "It illustrates our most innovative concept to date."

"The rapid production of this targeted protein demonstrates the potential for a wide range of important biological problems to be solved by our de novo protein design framework and our team of scientists," added Jonathan Drachman, MD, CEO of Neoleukin. 'NL-CVX1 is intended to be safe and may theoretically be provided by intranasal spray or inhalation to prevent and treat SARS-CoV-2 infection of the lungs and upper airways. We are currently assessing the prospect of bringing this molecule forward to human clinical trials.