Stapled Peptide Delivery via Cyclic Cell-Penetrating Peptides
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Solution Overview
Problem
Designing stapled peptides with consistent cell-permeability remains a major challenge due to factors like α-helicity, positive charge, peptide sequence, and staple composition, leading to many stapled peptides being either impermeable or poorly permeable across the cell membrane, limiting their therapeutic application.
Innovation Solution
The development of polypeptide conjugates that combine stapled peptides with cyclic cell-penetrating peptides (cCPPs), where the cCPPs are conjugated directly or indirectly to the stapled peptides, enhancing cellular uptake by facilitating entry into the cytosol and nucleus.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If stapled peptides are designed with optimal hydrophobicity, positive charge, and helical content to improve cellular uptake, then cell permeability is enhanced, but membrane lysis occurs at elevated peptide dosing
Solution Approach 1:
The patent introduces cell-penetrating peptides (CPPs) as intermediary carriers that facilitate the delivery of stapled peptides into cells. The CPPs handle the challenging task of membrane penetration, allowing the stapled peptides to follow along without directly interacting with the membrane at high concentrations. This mediator approach enables efficient cellular uptake while avoiding the membrane lysis that would occur if high concentrations of stapled peptides alone were used.
2Adaptability or versatility
If many stapled peptides are designed to target intracellular protein-protein interactions, then therapeutic potential is expanded, but most remain impermeable or poorly permeable to the cell membrane
Solution Approach 1:
The patent combines two previously separate entities into a single conjugate: the cell-penetrating peptide (CPP) responsible for membrane translocation and the stapled peptide responsible for target binding. This merged structure integrates the membrane-crossing capability of CPPs with the target-specific binding of stapled peptides, creating a unified therapeutic agent that can both enter cells efficiently and engage intracellular targets.
Solution Approach 2:
The invention creates a composite molecular structure consisting of a CPP-stapled peptide conjugate. This composite material combines the functional properties of two distinct peptide types: the amphipathic and cell-penetrating properties of CPPs with the structured, target-binding properties of stapled peptides. The composite nature allows the molecule to exhibit both high membrane permeability and high target affinity.
3Reliability
If stapled peptides are designed with various modifications to improve permeability, then cellular uptake may increase, but the complexity of design and optimization increases significantly
Solution Approach 1:
The patent divides the therapeutic agent into two functional segments: a well-characterized CPP segment that handles membrane penetration and a stapled peptide segment that handles target binding. This segmentation allows each component to be optimized independently using established protocols, rather than attempting to optimize all properties simultaneously in a single molecule. The modular nature reduces design complexity while maintaining high performance.
Data Source
AI summary
The present disclosure provides novel polypeptide conjugates. The polypeptide conjugates disclosed herein comprise a stapled peptide comprising a peptide and at least one staple which holds the peptide in an α-helical conformation, and a cyclic cell-penetrating peptide (cCPP) conjugated, directly or indirectly, to the stapled peptide. The present disclosure demonstrates that cCPPs can be used to confer consistent cell-permeability to stapled peptides.