Cleavable Peptides for Conditional Protein Activation
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Solution Overview
Problem
Current therapeutic proteins used in treating diseases like cancer and microbial infections face limitations due to off-target effects, necessitating the development of proteins with conditional activation capabilities to minimize such effects and enhance therapeutic potential.
Innovation Solution
The use of cleavable peptides that are multi-protease cleavable, specifically designed to be activated in tumor environments, serving as linkers between proteins or drug molecules, allowing for selective activation and reduced off-target effects by incorporating protease cleavage sites that are upregulated in tumor microenvironments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic proteins are used to treat diseases, then therapeutic effect is improved, but off-target effects occur
Solution Approach 1:
The therapeutic protein is segmented into two parts: a functional domain and a cleavable peptide linker. The functional domain provides therapeutic activity while the cleavable linker controls localization. Protease cleavage separates these parts at the target site, releasing the functional domain locally while preventing systemic distribution and off-target effects.
Solution Approach 2:
The cleavable peptide acts as an intermediary between the functional protein domain and the targeting system. It mediates the conditional activation of the therapeutic protein by serving as a substrate for proteases that are upregulated in diseased tissues, enabling selective activation only at the target site through proteolytic cleavage.
2Object-affected harmful factors
If conditional activation is implemented using cleavable peptides, then off-target effects are reduced, but protein activity before cleavage is constrained
Solution Approach 1:
The therapeutic protein is pre-assembled in an inactive state with the functional domain masked or inhibited by a blocking element attached via the cleavable peptide. The protein is prepared and administered in this constrained state, and activation occurs automatically when proteases cleave the peptide linker at the target site, releasing the functional domain without requiring additional activation steps.
Solution Approach 2:
The therapeutic protein performs its own activation through proteolytic cleavage of the cleavable peptide linker. The system is self-regulating, using the protease environment at the target site to automatically activate the protein only where needed, eliminating the need for external activation mechanisms or complex control systems.
3Adaptability or versatility
If multi-protease cleavable peptides are used, then selective activation in tumor environment is improved, but peptide sequence complexity increases
Solution Approach 1:
The cleavable peptide is designed with multiple protease cleavage sites that recognize different protease specificities (e.g., MMP-2, MMP-9, cathepsin B sites). This multi-functional peptide can be cleaved by any of several proteases that are upregulated in tumor microenvironments, providing universal activation across different cancer types and reducing the need for disease-specific peptide design.
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
This approach enables targeted activation of therapeutic proteins within tumor environments, reducing off-target effects and enhancing their therapeutic efficacy while maintaining normal tissue integrity.
Implementation Method 1
The cleavable peptide comprises at least two protease cleavage sites, wherein each of the at least two protease cleavage sites is cleaved by a different protease
Data Source
AI summary
The present disclosure relates to cleavable peptides, including multi-protease cleavable peptides, and methods of use thereof. The cleavable peptides are useful in a variety of applications, including as conditional linkers between two groups and as conditional activators of proteins. The present disclosure also relates to a composition of conditionally regulated proteins with cleavable peptides for treatment of diseases including but not limited to cancer. The conditional activation of proteins is based on cleavable polypeptides that regulate the protein activity.