Inhibition of SARS-CoV-2 infection with a pan-coronavirus anti-viral peptide

ABSTRACT The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is a serious threat to global public health, necessitating the rapid development of safe and effective medical countermeasures. SARS-CoV-2 pathogenicity requires a series of protein-protein interactions (PPI) involving the virus' S protein that leads to virus attachment and fusion. Initially, the receptor binding domain (RBD) on the S protein S1 subunit binds to ACE2 receptors on the host cell. This triggers a conformational change in the S protein S2 subunit, driving the viral heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains of S2 to form a six-helical bundle (6-HB), enabling the viral envelope to be brought in close proximity to the host membrane, thus promoting viral fusion. Peptides have emerged recently as a therapeutic class capable of targeting and disrupting PPI with high affinity and specificity. We hypothesize antagonism of the virus S protein with a peptide therapeutic will provide an effective anti-viral strategy for SARS-CoV-2 infection, and potentially a pan-coronavirus intervention. We propose a plan to select a lead candidate peptide antagonist based upon target binding and viral neutralization in vitro, with consideration of escape mutants, and attenuation of virus load and shedding in a ferret challenge model in vivo. Successful completion of this program will support advancement of the lead candidate peptide to IND-enabling studies, and provide the rationale for submission of a Phase II SBIR proposal to evaluate inhalation delivery for severe respiratory disease.