Protease-Cleavable Moieties for Disease-Specific Polypeptide Activation
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Solution Overview
Problem
There is a need to identify new substrates for proteases that can be used in therapeutic, diagnostic, and prophylactic applications, as existing substrates are not effective in targeting protease activity in diseased tissues while minimizing on-target toxicities in healthy tissues.
Innovation Solution
Development of polypeptides comprising a cleavable moiety (CM) that serves as a substrate for proteases such as MMP and MT-SP1, which are specifically designed to be cleaved in diseased tissues and include an active moiety (AM) for therapeutic, diagnostic, or imaging applications, with enhanced cleavability and stability in healthy tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing substrates are used to target protease activity, then therapeutic effect is achieved, but on-target toxicities occur in healthy tissues
Solution Approach 1:
The patent applies preliminary action by designing substrates with prodrug moieties that are预先 converted to active therapeutic agents only after protease-mediated cleavage. The substrate structure includes a peptide bond that must be cleaved by specific proteases (MMP-2, MMP-9, MT1-MMP) before the therapeutic agent becomes active, ensuring that the therapeutic effect is activated only at the target site and not in healthy tissues during circulation
Solution Approach 2:
The patent implements local quality by creating substrates with tissue-specific protease recognition sequences that are selectively cleaved only in diseased tissues where specific proteases (MMP-2, MMP-9, MT1-MMP) are overexpressed. This ensures the therapeutic agent is activated locally at the tumor site rather than systemically, reducing off-target toxicities while maintaining therapeutic efficacy
2Productivity
If substrates are designed for high cleavability in diseased tissues, then therapeutic activation is improved, but stability in healthy tissues decreases
Solution Approach 1:
The patent applies parameter changes by modifying the peptide sequence parameters of the substrate to match the specific substrate specificity of disease-associated proteases (MMP-2, MMP-9, MT1-MMP). The substrate contains optimized peptide bonds with specific amino acid sequences that have high cleavage rates (kcat/KM ratios) for these proteases, while being resistant to cleavage by proteases in healthy tissues, thus achieving high therapeutic activation in diseased tissues while maintaining stability in healthy tissues
Solution Approach 2:
The patent converts the harmful overexpression of proteases in diseased tissues into a beneficial activation mechanism. The substrates are specifically designed to be recognized and cleaved by the overexpressed proteases (MMP-2, MMP-9, MT1-MMP) in diseased tissues, transforming what would normally be a source of tissue degradation into a selective activation switch for therapeutic agents only where needed
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 polypeptides provide targeted activation in diseased tissues with reduced systemic toxicities, offering a broader therapeutic window and improved safety profile by leveraging protease activity in disease-specific microenvironments.
Implementation Method 1
Proteases are enzymes that catalyze the hydrolysis of peptide bonds between amino acid residues
Implementation Method 2
Proteases are enzymes that catalyze the hydrolysis of peptide bonds between amino acid residues
Data Source
AI summary
Isolated polypeptides that include a cleavable moiety that is a substrate for at least one protease (e.g., MMP) are disclosed. Activatable molecules including the isolated polypeptides are disclosed. Methods of making and using the isolated polypeptides and activatable molecules including the isolated polypeptides in a variety of therapeutic, diagnostic, and prophylactic applications are disclosed.