Stapled ACE2 Helix 1 Peptides for SARS-CoV-2 Inhibition
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current anti-viral therapies lack effectiveness in preventing or treating infections caused by novel coronavirus outbreaks, such as SARS-CoV-2, which has caused significant global health issues with no existing therapeutic solution.
Innovation Solution
Development of stapled peptide inhibitors that stabilize the structure of bioactive helices to target and inhibit the interaction between the ACE2 receptor and the SARS-CoV-2 virus, using hydrocarbon staples or stitches to enhance protease resistance and binding affinity, allowing for the prevention, treatment, and diagnosis of COVID-19.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural peptides are used to inhibit ACE2-virus interaction, then they can bind to the target, but they are rapidly degraded by proteases in the blood and tissues
Solution Approach 1:
The patent applies stapling technology that incorporates non-natural amino acids (containing olefinic side chains) into the peptide structure. These non-natural amino acid residues are interspersed throughout the peptide sequence and undergo internal crosslinking to form a stapled structure. This composite structure combines the natural peptide's binding capability with enhanced protease resistance, resolving the contradiction between maintaining target binding and preventing degradation.
Solution Approach 2:
The patent modifies the chemical parameters of the peptide by substituting natural amino acids with non-natural amino acids containing olefinic side chains. This parameter change (chemical composition modification) fundamentally alters the peptide's susceptibility to proteolytic cleavage while preserving its ability to bind ACE2, thereby extending half-life without sacrificing reliability.
2Reliability
If peptide structure is stabilized through stapling, then protease resistance is enhanced, but the complexity of peptide synthesis increases
Solution Approach 1:
The patent incorporates non-natural amino acids with olefinic side chains at specific positions during the initial peptide synthesis stage. The internal crosslinking reaction is then performed to form the stapled structure. This preliminary incorporation of crosslinkable groups simplifies the overall process compared to post-synthesis stapling, as the reactive groups are already in place and can be crosslinked in a single additional step.
Solution Approach 2:
The non-natural amino acids are strategically positioned within the peptide sequence so that their olefinic side chains can undergo spontaneous or catalyzed internal crosslinking. This self-organizing property allows the peptide to form its stabilized structure autonomously, reducing the need for complex external intervention or multi-step assembly processes.
3Ease of manufacture
If natural peptides are used, then they can be produced relatively easily, but they lack sufficient binding affinity and stability for effective therapy
Solution Approach 1:
The patent modifies amino acid parameters by introducing non-natural amino acids with specific side chain properties (olefinic groups) at strategically positioned residues. These parameter changes enhance both binding affinity (through optimized interactions with ACE2) and stability (through protease resistance), while the modular nature of peptide synthesis maintains relative ease of manufacture.
Solution Approach 2:
The non-natural amino acids are not uniformly distributed but are placed at specific local positions within the peptide sequence where they provide maximum benefit - either at binding interface regions to enhance affinity or at structural regions to improve stability. This localized modification approach maintains ease of synthesis while achieving superior performance.
Data Source
AI summary
Disclosed herein are structurally stabilized peptides of ACE2 helix 1 useful for diagnosing, preventing, and treating coronavirus infection by targeting the receptor binding domain of SARS-CoV-2 and thereby blocking its interaction with the human ACE2 receptor, which is involved in coronavirus infection and pathogenesis.