Beta-Hairpin Cyclic Peptides for Cytosolic Cargo Delivery
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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 peptides with beta-hairpin structures incorporating a D-Pro-L-Pro motif to promote both cellular uptake and target binding, allowing efficient delivery of larger peptide cargos through endocyclic and exocyclic mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional cell-penetrating peptides are used to deliver biologics across the plasma membrane, then cellular uptake is achieved, but cytosolic delivery efficiency remains low due to endosomal entrapment
Solution Approach 1:
The peptide is divided into distinct functional segments: a cell-penetrating peptide moiety for plasma membrane crossing, 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 while working together to overcome endosomal entrapment and achieve efficient cytosolic delivery.
Solution Approach 2:
The invention changes the structural parameters of the peptide by incorporating a beta-hairpin turn creating moiety (such as D-Pro-L-Pro or L-Pro-D-Pro) that induces a specific folded conformation. This structural parameter change enhances the peptide's ability to escape endosomes and deliver cargo to the cytosol, directly addressing the endosomal entrapment problem.
2Productivity
If cyclic peptides with beta-hairpin structures are developed to improve cellular uptake, then cytosolic delivery efficiency increases, but peptide structure complexity increases
Solution Approach 1:
The invention merges multiple functional elements into a single integrated cyclic peptide structure. The cell-penetrating peptide moiety, beta-hairpin turn creating moiety, and cargo moiety are combined in one continuous sequence that forms a cyclic structure with a beta-hairpin fold. This merging achieves efficient cytosolic delivery while managing structural complexity through a unified design.
Solution Approach 2:
The cyclic peptide structure serves multiple functions simultaneously: the cell-penetrating peptide moiety mediates plasma membrane crossing, the beta-hairpin turn creating moiety provides structural stability and promotes endosomal escape, and the cargo moiety enables target binding. This multi-functionality in a single structure maximizes delivery efficiency while consolidating complexity into one versatile molecule.
3Quantity of substance
If larger peptide cargos are delivered using conventional CPPs, then therapeutic applications are enabled, but delivery efficiency decreases due to endosomal entrapment
Solution Approach 1:
The beta-hairpin turn creating moiety performs preliminary structural organization that facilitates subsequent endosomal escape and cytosolic delivery. By pre-forming the beta-hairpin structure, the peptide is better positioned to withstand endosomal conditions and release its cargo, enabling efficient delivery of larger peptide cargos that would otherwise be trapped.
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.