Ebolavirus Glycoprotein Peptide Stapling for Protease Resistance
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Solution Overview
Problem
Current treatments for Ebola virus disease are limited, and there is a need for effective inhibitors to prevent and treat Ebola virus infections, particularly in outbreak settings.
Innovation Solution
Development of structurally-stabilized peptides, such as hydrocarbon-stapled peptides, conjugated with PEG and/or cholesterol, which mimic and reinforce the bioactive helices of Ebola virus glycoprotein GP2 to inhibit membrane fusion and viral infection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional peptide inhibitors are used, then they can bind to viral proteins, but they are rapidly degraded by proteases and lack sufficient stability
Solution Approach 1:
The patent applies composite materials by combining natural amino acid residues with non-natural hydrocarbon staple moieties to create stapled peptides. The hydrocarbon staples (e.g., dimethylheptenebridged groups) are covalently linked to amino acid side chains, forming a composite structure that maintains the peptide's bioactive sequence while adding protease resistance and structural stability. This composite approach allows the peptide to resist proteolytic degradation while preserving its ability to bind viral proteins.
Solution Approach 2:
The patent changes the physical and chemical parameters of the peptide by introducing hydrocarbon staples that constrain the peptide backbone into stable alpha-helical conformations. This structural parameter change increases the peptide's rigidity and protease resistance. Additionally, the patent conjugates cholesterol or PEG-cholesterol to the C-terminus, further modifying physical parameters such as membrane affinity and pharmacokinetic properties, thereby enhancing overall stability and reliability.
2Reliability
If peptide length is increased to improve binding affinity, then affinity increases, but protease susceptibility and structural flexibility increase
Solution Approach 1:
The patent uses hydrocarbon staples as composite structural elements that are incorporated into the peptide sequence at specific positions (e.g., i, i+3 or i, i+4 relationships). These staples create rigid hydrophobic bridges that lock the peptide into an alpha-helical conformation, providing protease resistance while maintaining the length necessary for high binding affinity to viral proteins such as GP2.
Solution Approach 2:
The patent applies local quality by placing hydrocarbon staples at specific local positions within the peptide sequence rather than uniformly throughout. The staples are strategically positioned to stabilize critical helical regions involved in viral binding while leaving other regions flexible enough for binding interactions. This localized stabilization allows the peptide to maintain both high affinity and protease resistance.
3Reliability
If peptides are modified to enhance stability, then protease resistance improves, but complexity of synthesis and structure increases
Solution Approach 1:
The patent applies segmentation by dividing the peptide synthesis into distinct modules: (1) selection of amino acid sequence from viral protein, (2) identification of staple positions based on i, i+3 or i, i+4 relationships, (3) introduction of non-natural amino acid precursors with olefinic side chains, and (4) catalytic cyclooligomerization to form hydrocarbon staples. This segmented approach simplifies the overall synthesis process by breaking down the complex task of creating stable stapled peptides into manageable, sequential steps.
Solution Approach 2:
The patent changes the chemical parameter of the amino acid sequence by incorporating non-natural amino acids with specific olefinic side chains (e.g., 4-pentenyl or 6-heptenyl groups) at predetermined positions. These parameter changes enable subsequent cyclooligomerization reactions that form the hydrocarbon staples. The use of standardized non-natural amino acid building blocks simplifies synthesis while achieving the desired protease resistance and structural stability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The peptides effectively inhibit Ebola virus infection by stabilizing the helical structure, conferring protease resistance and preventing membrane fusion, offering potential therapeutic and prophylactic benefits.
Implementation Method 1
peptide stabilizing technology (e.g., stapling, e.g., hydrocarbon stapling) that recapitulates and fortifies the structure of bioactive helices
Implementation Method 2
conjugated with PEG and/or cholesterol (or a variant of cholesterol, e.g., thiocholesterol)
Implementation Method 3
peptides...mimic and reinforce the bioactive helices of Ebola virus glycoprotein GP2 to inhibit membrane fusion
Data Source
AI summary
This disclosure relates to structurally-stabilized (e.g., stapled, e.g., hydrocarbon stapled) Ebolavirus peptides and variants thereof, and structurally-stabilized (e.g., stapled, e.g., hydrocarbon stapled) Ebolavirus peptides and variants thereof, conjugated with polyethylene glycol (PEG) and/or cholesterol (or a variant thereof, e.g., thiocholesterol), e.g., a generated PEG(n)-cholesterol or PEG(n)-thiocholesterol derivatization to further optimize activity, and methods for using such structurally-stabilized peptide conjugates in the prevention and treatment of an Ebolavirus infection or disease in a subject (e.g., human, non-human primate, or fruit bat). The disclosure also relates to methods of using such structurally-stabilized peptides and conjugates in the prevention and treatment of a Marburg virus infection, a Bombali ebolavirus infection, or a Mengla dianlovirus infection in a subject.