STTR Phase I: Discovery and Development of Macrocyclic Peptide Inhibitors of SARS-COV-2 Spike Protein for the Treatment of COVID-19

The broader impact /commercial potential of this Small Business Technology Transfer (STTR) Phase I project lies in the discovery and development of first-in-class therapeutics as an anti-viral treatment of COVID-19 viral infection. Within the proposed studies, cyclic peptide-based novel, effective anti-viral drug candidates will be identified. Compared to small molecule-based drugs, peptides will offer advantages in targeting protein-protein interactions. At the same time, peptides and their metabolites, due to their nature as biological building blocks, have more favorable safety profiles. Furthermore, peptide drugs are time- and cost-effective to discover, develop, and manufacture, which makes them more attractive than antibodies and other biologics. The peptide-based drug discovery platform can potentially be applied toward many therapeutic targets for unmet medical needs. The knowledge and experience gained through proposed studies will be readily applied to other indications and potentially future pandemics. This Small Business Technology Transfer (STTR) Phase I project will identify small cyclic peptides as novel drug candidates for the treatment of COVID-19 viral infection. Monoclonal antibodies that disrupt the interaction of SARS-COV-2 Spike protein and its cognate cellular receptor ACE2 have shown promising efficacy in reducing viral burden and shortening recovery time in COVID-19 patients. Unfortunately, a series of challenges hinder their potential utility including high cost of manufacturing and transportation. Small cyclic peptides are capable of disrupting protein-protein interactions following the examples of the antibodies. Unlike antibodies, small peptides can be manufactured in large scales in a time- and cost-effective manner through chemical synthesis and are administered in more patient-friendly routes such as subcutaneous and intramuscular injections. In the proposed project, a proprietary molecular evolution technology will be applied to efficiently screen an extremely large library of peptides (up to 1010 peptides within 4-8 weeks). Hit peptides will be validated for their potency in disrupting the interaction between Spike protein and its host cell receptor, ACE2, and subsequent inhibition of viral entry into ACE2 expressing cells. Upon the completion of proposed studies, selected candidates will be moved into a phase II program for optimization and preclinical development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.