Cyclic Beta-Hairpin CPPs for Endosomal Escape of Larger Cargos
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Solution Overview
Problem
Existing cell-penetrating peptides (CPPs) face challenges in efficiently delivering biologics across the plasma membrane and overcoming endosomal entrapment, resulting in low cytosolic delivery efficiencies, especially for larger cargos.
Innovation Solution
Development of cyclic beta-hairpin peptides with a D-Pro-L-Pro motif that promotes beta-hairpin structures and efficient cellular uptake, allowing for both endocyclic and exocyclic delivery of larger peptide cargos by forming structured motifs for cellular entry and target binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional linear CPPs are used, then cellular uptake can occur, but cytosolic delivery efficiency is low due to endosomal entrapment
Solution Approach 1:
The CPP is divided into functional segments: a cell-penetrating peptide moiety for membrane translocation, a beta-hairpin turn creating moiety for structural stabilization, and a cargo moiety for target binding. This segmentation allows each component to optimize its specific function, with the beta-hairpin segment specifically addressing endosomal escape issues.
Solution Approach 2:
The patent changes the structural parameters of the CPP by introducing cyclic beta-hairpin configurations with D-Pro-L-Pro motifs. This structural parameter change transforms the peptide from a linear to a cyclic conformation, which significantly improves endosomal escape and cytosolic delivery efficiency while maintaining cellular uptake capability.
2Quantity of substance
If larger peptide cargos are delivered, then therapeutic potential increases, but delivery efficiency decreases
Solution Approach 1:
The cargo moiety is nested within the structured beta-hairpin framework of the CPP. The cyclic beta-hairpin structure acts as a protective scaffold that accommodates larger peptide cargos while maintaining efficient cellular uptake and endosomal escape, effectively nesting the cargo within a functional delivery vehicle.
Solution Approach 2:
The patent creates a composite peptide structure combining the cell-penetrating peptide moiety, beta-hairpin turn creating moiety, and cargo moiety into a single integrated cyclic peptide. This composite structure leverages the advantages of each component to achieve efficient delivery of larger cargos that would otherwise be difficult to deliver across the plasma membrane and endosomal barriers.
3Reliability
If cyclic beta-hairpin structure is introduced, then endosomal escape improves, but peptide stability may be affected
Solution Approach 1:
The cyclic beta-hairpin structure is introduced locally at specific positions within the peptide sequence where it is most effective for endosomal escape. The D-Pro-L-Pro motifs are strategically placed to create the beta-hairpin turn without compromising the overall stability of the peptide structure, allowing localized functional enhancement while maintaining global structural integrity.
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 cyclic beta-hairpin peptides enhance cytosolic delivery efficiency, enabling effective delivery of larger cargos into cells and targeting intracellular proteins, with applications in treating diseases such as cancer, metabolic disorders, and immune disorders.
Implementation Method 1
cyclic beta-hairpin peptides with a D-Pro-L-Pro motif that promotes beta-hairpin structures and efficient cellular uptake
Implementation Method 2
efficient cellular uptake, allowing for both endocyclic and exocyclic delivery of larger peptide cargos
Implementation Method 3
The plasma membrane presents a major challenge in drug discovery, especially for biologics such as peptides, proteins and nucleic acids. One potential strategy to subvert the membrane barrier and deliver the biologics into cells is to attach them to 'cell-penetrating peptides' (CPPs).
Implementation Method 4
Existing cell-penetrating peptides (CPPs) face challenges in efficiently delivering biologics across the plasma membrane and overcoming endosomal entrapment, resulting in low cytosolic delivery efficiencies
Data Source
AI summary
Disclosed herein are peptides having activity as cell penetrating peptides. In some embodiments, the peptides can comprise a cell penetrating peptide moiety and beta-haripin turn creating moiety. In other embodiments, the peptides also comprise a cargo moiety.