Stapled RSV Peptide Conjugates for Protease-Resistant Viral Entry Blocking
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Solution Overview
Problem
Current strategies for the prophylaxis and treatment of Respiratory Syncytial Virus (RSV) infections are inadequate, particularly against drug-resistant strains, necessitating new approaches to prevent and treat RSV infections effectively.
Innovation Solution
The development of structurally-stabilized RSV peptides, stabilized through hydrocarbon stapling and conjugated with PEG and/or cholesterol derivatives, which inhibit RSV infection by binding to the RSV 5-helix bundle protein and preventing cellular infection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional peptide structures are used to target RSV, then they can bind to viral proteins, but they are rapidly degraded by proteases in the body
Solution Approach 1:
The patent applies composite materials by combining peptides with hydrocarbon staples and PEG-cholesterol conjugates to create a hybrid structure that maintains protease resistance while enhancing structural stability. The hydrocarbon staples create a rigid scaffold that protects the peptide backbone from proteolytic cleavage, while the PEG-cholesterol moiety adds membrane affinity and structural rigidity, solving the contradiction between protease resistance and structural stability.
Solution Approach 2:
The patent changes the physical and chemical parameters of the peptide by introducing hydrocarbon crosslinks that alter the conformational flexibility and structural rigidity. This parameter change transforms the peptide from a flexible, protease-susceptible structure to a rigid, protease-resistant helical structure that maintains its bioactive conformation in physiological conditions.
2Strength
If peptide length is increased to improve binding affinity to RSV proteins, then binding strength increases, but peptide susceptibility to proteolysis increases
Solution Approach 1:
The patent uses composite materials by incorporating hydrocarbon staples within the peptide sequence to create a protected core structure. This composite approach allows longer peptide sequences to maintain binding affinity while the hydrocarbon scaffold shields the extended peptide backbone from protease access, resolving the contradiction between binding strength and protease resistance.
Solution Approach 2:
The patent applies segmentation by dividing the peptide into distinct functional regions: hydrocarbon-stapled core segments that provide structural protection and protease resistance, and terminal regions that maintain binding functionality. This segmentation allows the peptide to achieve both long binding interfaces and protease resistance through spatial organization of protective and functional elements.
3Reliability
If hydrocarbon staples are introduced to stabilize peptide structure, then protease resistance improves, but manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-installing olefin-containing side chains on amino acid residues before peptide assembly. These pre-positioned reactive groups are then crosslinked via ring-closing metathesis in a single subsequent step, allowing the hydrocarbon stapling to be achieved efficiently without requiring complex multi-step synthesis procedures, thus reducing manufacturing complexity while maintaining protease resistance.
Solution Approach 2:
The patent changes the chemical reactivity parameters by using ring-closing metathesis, a well-established organic reaction with predictable outcomes. This parameter change in the crosslinking chemistry allows for reliable and scalable manufacturing of hydrocarbon-stapled peptides, reducing the complexity barrier despite the introduction of structural stabilization features.
4Ease of operation
If PEG-cholesterol conjugates are added to enhance membrane interaction, then cellular uptake improves, but molecular weight and structural complexity increase
Solution Approach 1:
The patent uses PEG-cholesterol as an intermediary moiety that mediates between the hydrophobic peptide core and the aqueous cellular environment. The cholesterol portion provides membrane affinity and facilitates cellular uptake, while the PEG linker provides solubility and spacing, acting as a bridge that enhances cellular interaction without requiring complex multi-component systems.
Solution Approach 2:
The patent applies composite materials by creating a tri-component conjugate system (peptide-PEG-cholesterol) where each component contributes a specific function: the peptide provides viral binding, PEG provides solubility and spacing, and cholesterol provides membrane affinity. This composite approach enhances cellular uptake through functional complementarity rather than structural complexity.
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
These peptides confer remarkable protease resistance and target RSV, effectively preventing and treating RSV infections by stabilizing the bioactive helical structure and inhibiting viral penetration into host cells.
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
remarkable protease resistance can be conferred by burying the otherwise labile amide bonds at the core of the helical structure and/or restraining amide bonds in a manner that precludes their recognition and proteolysis by the body's proteases
Implementation Method 3
combined with a method for cholesterol or a cholesterol variant (e.g., thiocholesterol) (e.g., PEG(n)-cholesterol or PEG(n)thiocholesterol) derivatization
Implementation Method 4
generate an optimized and targeted prophylactic and therapeutic agent for prevention and/or treatment of RSV infection
Implementation Method 5
the conjugate binds to an RSV 5-helix bundle protein and/or wherein the conjugate inhibits infection of a cell by RSV
Data Source
AI summary
This disclosure relates to structurally-stabilized (e.g., stapled, e.g., hydrocarbon stapled) respiratory syncytial virus (RSV) peptides and variants thereof, and structurally-stabilized (e.g., stapled, e.g., hydrocarbon stapled) RSV peptides and variants thereof, conjugated with polyethylene glycol (PEG) and/or cholesterol (or a variant thereof, e.g., thiocholesterol), e.g., a PEG(n)-cholesterol or PEG(n)-thiocholesterol derivatization, and methods for using such structurally-stabilized peptides and conjugates in the prevention and treatment of an RSV infection in a subject (e.g., human).