Stapled Peptides for SARS-CoV-2 Inhibition
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Solution Overview
Problem
Current anti-viral therapies lack effectiveness in preventing or treating COVID-19 caused by SARS-CoV-2 due to the instability and rapid proteolysis of peptide-based inhibitors, which limits their broader application.
Innovation Solution
Development of structurally-stabilized peptides through methods like stapling and stitching to fortify the bioactive helices, making them more resistant to proteases and maintaining their shape, thereby inhibiting SARS-CoV-2 infection by binding to the 5-helix bundle of the S protein and disrupting its interaction with host cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide-based inhibitors are used to inhibit viral fusion processes, then antiviral activity is achieved, but the peptides undergo rapid proteolysis and lose bioactive shape in vivo
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of peptide bonds to create non-natural amino acid analogs with altered backbone rigidity and side chain properties. This changes the physical-chemical parameters of the peptide to resist proteolytic degradation while maintaining bioactive conformation. Specifically, the use of constrained peptide bonds and non-natural amino acids modifies the peptide's susceptibility to proteases while preserving its ability to bind viral targets.
Solution Approach 2:
The patent employs composite materials by combining natural amino acid residues with non-natural constrained peptide bonds and non-natural amino acid side chains. This creates a hybrid peptide structure that integrates the biological recognition capabilities of natural peptides with the enhanced stability and protease resistance of synthetic components. The composite structure allows simultaneous achievement of antiviral activity and metabolic stability.
2Reliability
If peptide-based inhibitors are used to inhibit viral fusion processes, then antiviral activity is achieved, but the peptides require frequent administration due to rapid degradation
Solution Approach 1:
The patent modifies the temporal parameters of peptide stability by introducing constrained peptide bonds and non-natural amino acids that resist proteolytic cleavage. This extends the half-life and duration of action of the peptide in vivo, reducing the frequency of administration required to maintain therapeutic efficacy. The modified peptide structure maintains its bioactive conformation for prolonged periods.
Solution Approach 2:
The composite peptide structure combining natural and synthetic elements provides both the antiviral activity of natural peptides and the extended circulation time of stable synthetic analogs. This hybrid approach enables sustained antiviral protection with reduced dosing frequency.
3Reliability
If natural peptide sequences are used to bind viral proteins, then specific antiviral activity is achieved, but the peptides are susceptible to protease recognition and degradation
Solution Approach 1:
The patent changes the chemical parameters of the peptide backbone by incorporating constrained peptide bonds and non-natural amino acids. This modifies the peptide's susceptibility to protease recognition and cleavage while preserving the side chain interactions necessary for specific viral protein binding. The constrained structure prevents protease access to scissile bonds.
Solution Approach 2:
The patent converts the harmful effect of protease susceptibility into a benefit by designing protease-resistant analogs. The same structural features that provide protease resistance (constrained bonds, non-natural amino acids) are used to maintain or enhance binding affinity to viral targets. The harmful proteolytic degradation pathway is blocked while the beneficial antiviral activity is preserved.
Data Source
AI summary
Disclosed herein are cross-linked peptides useful for interfering with and inhibiting coronavirus infection (e.g., infection by SARS-CoV-2). Also disclosed are methods of treating and/or preventing a coronavirus infection (e.g., COVID-19).