Protein mimics of fusion core from SARS-CoV-1 can inhibit SARS-CoV-2 entry

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus (subgenus Sarbecovirus) and shares significant genomic and phylogenetic similarities with severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1). SARS-CoV-2 infection occurs through membrane fusion between the virus and host cell membranes, which is facilitated by the spike glycoprotein subunit 2 (S2). The folding of three heptad-repeat regions 1 (HR1) into a central trimeric core structure, along with the binding of three heptad-repeat regions 2 (HR2) in an antiparallel manner within the groove formed between the HR1 regions, which provides the driving force for membrane fusion. In this study, trimeric and monomeric six-helix bundles (6HB) were created by combining various truncations of the sequences from SARS-CoV-2 HR1 and HR2. In addition, monomeric five-helix bundles (5HB) were constructed using a similar method. Finally, we demonstrated a protein mimic, 5HB_V1 (from SARS-CoV-1), that exhibits activity in inhibiting SARS-CoV-2. These findings suggest a strategy to design monomeric 6HB and 5HB based on the SARS-CoV-2 fusion core: maintain the flanking sequences outside the α-helix region in HR2 and introduce point mutations to enhance hydrogen bonding between the helix bundles. The 5HB could be a target for designing new inhibitors against SARS-CoV-1 and SARS-CoV-2.