Rationally Designed, ACE2 Mimetic Binder to the SARS Cov-2 Associated Spike Protein for COVID-19 Therapeutics and Beyond

We have developed a 23 residue, optimized helical peptide biomimetic from the SARS-CoV-2 Spike protein binding partner ACE2 that demonstrated a Therapeutic Index (TI) of >[~]20 in authentic viral cell challenge assays, including WT and Omicron strains. The therapeutic is an optimized "peptide decoy" based on the viruss human cell target ACE2 and, as such, may have more general applicability across coronavirus family members that use ACE2 for cellular entry. We experimentally verify a comprehensive, rational optimization strategy of the peptide through improved binding, helical content, and solubility from its native sequence. These techniques may have general applicability for helical peptide optimization for other therapeutic targets as well. Importantly, techniques also exist for protecting helical peptides in vivo for improved delivery. Peptides are readily modifiable with single residue substitutions for quick response to mutated targets, and they typically have relatively low toxicity and ease of manufacturing, making peptides extremely attractive as biological therapeutics against viral pathogens. The general concept of using peptide decoys across other viral human cell targets is also discussed. Author SummaryAlthough the COVID-19 pandemic has ended, SARS-CoV-2 virus still causes hundreds of deaths each week world-wide. The virus uses a human cell receptor called ACE2 to latch on and enter cells. Here, the small critical attachment segment of ACE2 is developed as a "decoy" molecule thereby protecting host cells and significantly reducing viral replication, which is the role of a therapeutic agent. The effective segment in this case is called a helical peptide and it was optimized for better binding, solubility, and stability using rational methods based on our understanding of this class of molecule. Moreover, future viruses from this family of coronaviruses may likely use ACE2 as their host cell receptor, as recently demonstrated in the Middle Eastern Respiratory Syndrome Virus of bats and, therefore, the ACE2 decoy therapeutic may have future applications as well. Development of a broader range of decoy molecules for different viruses using different human cell receptors may represent a forward-thinking approach to prepare for future pandemics and outbreaks.