Cyclic Cell-Penetrating Peptides for Endosomal Escape
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Solution Overview
Problem
Current cell-penetrating peptides (CPPs) face challenges in efficiently delivering biologics across the plasma membrane, particularly due to the endosomal membrane barrier, with only a negligible fraction escaping into the cell interior, necessitating the development of new CPPs and compositions that can effectively traverse this barrier.
Innovation Solution
The development of compounds comprising cyclic cell-penetrating peptide moieties and cargo moieties, including detectable, therapeutic, and targeting moieties, in various configurations such as endocyclic, exocyclic, and bicyclic systems, to enhance cellular uptake and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cell-penetrating peptides are used to deliver biologics across the plasma membrane, then cellular uptake is achieved, but the endosomal membrane barrier prevents effective delivery into the cell interior
Solution Approach 1:
The delivery system is divided into two functional segments: a cell-penetrating peptide moiety for plasma membrane transduction and an endosomolytic moiety for endosomal membrane disruption. This segmentation allows each component to specialize in overcoming a specific barrier, with the cell-penetrating peptide handling initial cellular uptake and the endosomolytic moiety subsequently breaking down the endosomal barrier to release cargo into the cytoplasm.
Solution Approach 2:
The invention creates composite peptide structures by combining cell-penetrating peptide sequences with endosomolytic sequences (such as histidine-rich motifs or pH-sensitive amino acids). These composite materials exhibit dual functionality: they maintain the cell-penetrating capability of the original peptide while incorporating endosomal escape properties from the endosomolytic component, thereby overcoming both barriers sequentially.
2Reliability
If cyclic cell-penetrating peptide structures are designed to improve stability and uptake, then cellular internalization is enhanced, but the complexity of synthesizing various configurations increases
Solution Approach 1:
The patent develops a universal cyclic peptide platform where a core cyclic structure can accommodate different linear extensions or appended moieties. This universal backbone maintains structural stability and cell-penetrating properties while allowing flexible attachment of various functional groups, cargo molecules, or endosomolytic sequences through standardized coupling methods, thereby reducing overall synthesis complexity.
Solution Approach 2:
The cyclic core structure is synthesized and characterized in advance as a pre-validated building block with known stability and cell-penetrating properties. This preliminary creation of the cyclic framework allows subsequent modular assembly of different configurations (endocyclic, exocyclic, bicyclic) without repeating the complex cyclic synthesis process for each variant, significantly easing manufacturing.
Data Source
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AI summary
Disclosed herein are compounds having activity as cell penetrating peptides. In some examples, the compounds can comprise a cell penetrating peptide moiety and a cargo moiety. The cargo moiety can comprise one or more detectable moieties, one or more therapeutic moieties, one or more targeting moieties, or any combination thereof. In some examples, the cell penetrating peptide moiety is cyclic. In some examples, the cell penetrating peptide moiety and cargo moiety together are cyclic. In some examples, the cell penetrating peptide moiety is cyclic and the cargo moiety is appended to the cyclic cell penetrating peptide moiety structure. In some examples, the cargo moiety is cyclic and the cell penetrating peptide moiety is cyclic, and together they form a fused bicyclic system.