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

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.

Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor

“…All of our peptides are based on the subsequence of the α1-helix ACE2 region [ 23 ], which have also been utilized in similar peptide-based strategies described elsewhere [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. It is worthwhile to notice that peptides proposed by other groups are based on the assumption that larger parts of the interaction interface should be mimicked to retain strong binding affinity to S protein.…”

“…Peptides derived from native protein–protein interaction (PPI) sites of interacting partners are valuable starting points in developing effective inhibitors of protein–protein interactions, and have already been proven to be useful for the design of efficient PPI modulators [ 11 , 12 ]. As ACE2-S complex structures have been solved by experimental techniques, a rational starting point for the development of molecules disrupting the formation of protein–protein of the complex is available, and has already been utilized to propose several peptides against SARS-CoV [ 13 , 14 ], and even recently SARS-CoV-2 [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Engineering single pan-specific ubiquibodies for targeted degradation of all forms of endogenous ERK protein kinase

“…These results add to a growing body of evidence that reveals the effectiveness of designer uAb constructs in promoting the clearance of POIs 22,[26][27][28][29][30][31][32][33][34] including some that have been classified as difficult-to-drug.…”

“…Importantly, neither of the POIs was a natural substrate for CHIP and the degradation that we observed did not depend on the biological function or interaction partners of the POIs. Also noteworthy is the highly modular architecture of uAbs: swapping synthetic binding proteins enables generation of new uAbs that recognize completely different POIs [26][27][28][29][30][31][32][33][34] while swapping E3 domains enables tailoring of the catalytic efficiency and/or E2 specificity 27,34 . It is even possible to deplete certain protein subpopulations (e.g., active/inactive, posttranslationally modified/unmodified, wild-type (wt)/mutant, etc.)…”

Sub-Picomolar Detection of SARS-CoV-2 RBD via Computationally-Optimized Peptide Beacons

“…The reported peptide beacon designs consisted of the 21mer conjugated with a binding ligand and one of the three basic peptides: C13, C17, C21 ( 14 ). We designed our peptide beacons by replacing the binding portion of the sequences designed by Grossman with our previously engineered 23mer peptide that can bind to S-RBD and induce its degradation via the ubiquitin-proteasomal pathway ( 16 ).…”