Targeted intracellular degradation of SARS-CoV-2 via computationally optimized peptide fusions

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has elicited a global health crisis of catastrophic proportions. With only a few vaccines approved for early or limited use, there is a critical need for effective antiviral strategies. In this study, we report a unique antiviral platform, through computational design of ACE2-derived peptides which both target the viral spike protein receptor binding domain (RBD) and recruit E3 ubiquitin ligases for subsequent intracellular degradation of SARS-CoV-2 in the proteasome. Our engineered peptide fusions demonstrate robust RBD degradation capabilities in human cells and are capable of inhibiting infection-competent viral production, thus prompting their further experimental characterization and therapeutic development. Pranam Chatterjee et al. present a novel computational platform for engineering peptide fusions that bind to the SARS-CoV-2 spike protein and tag it for proteasomal degradation. They experimentally validate an optimal variant in human cells, showing that it inhibits production of infection-competent virus.