Stapled Peptide Modules for Intracellular Cargo Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Many therapeutic and diagnostic agents struggle to cross cell membranes efficiently, limiting their ability to reach intracellular targets within cells.
Innovation Solution
Development of cell-permeable stapled peptides that are structurally stabilized through internal cross-linking, allowing them to transport various cargoes, including therapeutic agents and diagnostic molecules, into cells by maintaining a constrained structure and enhancing hydrophobicity and protease resistance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If therapeutic and diagnostic agents are designed to bind with strong affinity to intracellular disease targets, then binding strength is improved, but cell membrane permeability deteriorates
Solution Approach 1:
The invention segments the delivery system into two functional components: a cell-permeable carrier peptide and a cargo molecule with disease-target binding activity. The carrier peptide (e.g., stapled peptides like ATSP-7041 or CPSP modules) handles membrane traversal, while the cargo (e.g., stapled BCL-2 family peptides) provides specific target binding. This segmentation allows each component to be optimized for its specific function without compromise.
Solution Approach 2:
The cell-permeable carrier peptide acts as an intermediary that ferries the cargo across the cell membrane barrier. The carrier peptide temporarily associates with the cargo, mediates its transport through the membrane, and facilitates intracellular delivery. This intermediary approach resolves the contradiction by decoupling the membrane traversal function from the target binding function.
2Object-affected harmful factors
If peptides are made more hydrophobic to enhance cell membrane permeability, then cell permeability is improved, but protease resistance deteriorates
Solution Approach 1:
The invention changes the structural parameters of the peptide through stapling modifications, which alter the conformational ensemble and physical properties. Stapled peptides exhibit modified hydrophobicity, increased rigidity, and enhanced protease resistance simultaneously. The cyclic constraint introduced by stapling changes the peptide's parameters in a way that improves multiple properties at once, including membrane permeability and stability.
Solution Approach 2:
The invention creates composite peptide structures by combining natural amino acid sequences with non-natural staple modifications. These composite molecules integrate the cell-permeable properties of hydrophobic sequences with the stability provided by the cyclic staple structure. The composite nature allows simultaneous optimization of permeability and protease resistance.
Data Source
AI summary
The disclosure relates to cell-permeable stabilized peptide modules and methods of use for e.g., cellular delivery of cargoes.