Peptide Complex for Target Molecule Depletion
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Solution Overview
Problem
Many human diseases, such as neurodegenerative disorders and cancer, are associated with the accumulation or over-expression of soluble and cell surface proteins, which are often deemed 'undruggable' due to challenges in targeting them with small molecule therapeutics.
Innovation Solution
A peptide complex comprising a cellular receptor-binding peptide and a target-binding peptide, engineered to have specific affinities that are pH or ionic strength dependent, allowing for selective depletion of target molecules by exploiting endocytic pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If small molecule therapeutics are used to target soluble and cell surface proteins, then the treatment approach is simple, but the proteins are deemed 'undruggable' due to targeting challenges
Solution Approach 1:
The patent uses peptide complexes as intermediary molecules that bridge the gap between small molecule simplicity and antibody effectiveness. These peptide complexes contain a target-binding peptide that specifically binds to the soluble or cell surface protein target, and a receptor-binding peptide that binds to a cellular receptor, enabling targeted delivery and depletion without requiring complex small molecule structures
Solution Approach 2:
The patent employs pH-dependent or ionic strength-dependent binding characteristics of the peptides to enable selective targeting. The peptides are engineered to bind to targets under specific physiological conditions (e.g., pH 7.4 in extracellular environment) and release under different conditions (e.g., pH 5.0-6.0 in endosomes), allowing for condition-specific activation and depletion
2Reliability
If peptides with high affinity for targets are used, then selective depletion is achieved, but the peptides may not be able to release the target for degradation
Solution Approach 1:
The patent creates dynamic binding characteristics where the peptide's affinity for the target is not static but changes in response to environmental conditions. The peptides are engineered to exhibit high affinity under extracellular conditions (pH 7.4, physiological ionic strength) for stable binding and depletion, while automatically reducing affinity under endosomal conditions (pH 5.0-6.0, altered ionic strength) to enable target release for degradation
Solution Approach 2:
The patent utilizes pH and ionic strength as controlling parameters to modulate peptide-target binding affinity. By incorporating amino acid residues that respond to pH changes (e.g., histidine, aspartic acid, glutamic acid) and ionic strength variations, the peptides automatically transition between bound and unbound states based on the local environment, ensuring both stable depletion and effective release
3Productivity
If peptides bind to targets in endosomes, then depletion is enhanced, but the cellular receptor binding may be compromised
Solution Approach 1:
The patent applies different binding characteristics to different parts of the peptide complex. The target-binding peptide is specifically engineered with pH-dependent affinity to bind targets in endosomes, while the receptor-binding peptide is designed with pH-independent or differently pH-responsive binding to maintain receptor association. This spatial and functional differentiation allows the complex to achieve both endosomal target binding and stable receptor interaction
Solution Approach 2:
The patent divides the peptide complex into distinct functional segments: a target-binding peptide domain and a receptor-binding peptide domain. Each segment is independently optimized for its specific function - the target-binding segment responds to endosomal conditions for enhanced target binding, while the receptor-binding segment maintains stable interaction with the cellular receptor across different pH environments, enabling coordinated action
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 peptide complex effectively binds to target molecules and cellular receptors, facilitating endocytosis and subsequent degradation of the target molecules, thereby depleting them and potentially treating associated diseases.
Implementation Method 1
the target-binding peptide is engineered to have an affinity for a target that is lower in an endosome than in an extracellular environment
Implementation Method 2
the cellular receptor-binding peptide is engineered to have an affinity for a cellular receptor is lower in an endosome than in an extracellular environment
Implementation Method 3
facilitating endocytosis and subsequent degradation of the target molecules
Implementation Method 4
subsequent degradation of the target molecules, thereby depleting them
Data Source
AI summary
Described herein are compositions and methods for selective depletion of target molecules using a recyclable CDP-receptor-binding mediated complex to elicit endocytosis and cellular degradation of the target. Exemplary compositions containing a peptide, such as a CDP peptide, that bind a transferrin receptor can be linked to a peptide that binds a target molecule. Such compositions can be used to selectively recruit the target molecule to endosomes via transferrin receptor-mediated endocytosis of the composition and the bound target molecule. Once inside the endosome, the acidic pH can lead to release of the target molecule from the composition due to pH-dependent binding of the composition for the target molecule, and the transferrin receptor portion is recycled back to the cell surface for “reloading”. The target molecule can then be trafficked into lysosomes wherein it is degraded.