Abstract
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.
Highlights
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has elicited a global health crisis of catastrophic proportions
We devise a targeted intracellular degradation strategy for SARS-CoV-2 by computationally designing peptides that bind to its spike (S) protein receptor binding domain (RBD) and recruit a human E3 ubiquitin ligase for subsequent proteasomal degradation
Since the 2003 SARS epidemic, it has been widely known that the angiotensin-converting enzyme 2 (ACE2) receptor is critical for SARS-CoV entry into host cells[10]
Summary
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has elicited a global health crisis of catastrophic proportions. As SARS-CoV-2 is a positive-sense RNA virus, Abbott, et al recently devised a CRISPR-Cas13d based strategy, termed PAC-MAN, to simultaneously degrade the positive-sense genome and viral mRNAs6 While this method may serve as a potential prophylactic treatment, introducing foreign and relatively large components such as Cas[13] enzymes into human cells in vivo presents various delivery and safety challenges[7]. We devise a targeted intracellular degradation strategy for SARS-CoV-2 by computationally designing peptides that bind to its spike (S) protein receptor binding domain (RBD) and recruit a human E3 ubiquitin ligase for subsequent proteasomal degradation. Our experimental results identify an optimal peptide variant that mediates robust degradation of the RBD fused to a stable superfolder-green fluorescent protein (sfGFP)[9] in human cells and inhibits infection-competent viral production, motivating further exploration of this strategy from a therapeutic perspective
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