Cyclized Peptides for RHAMM Targeting and Protease Resistance
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Solution Overview
Problem
Current therapies targeting CD44 for inflammatory and cancer-related conditions face challenges due to its ubiquitous expression and complex binding mechanisms, leading to off-target effects and stability issues of short linear peptides against protease hydrolysis.
Innovation Solution
Development of cyclized peptides derived from the hyaluronan-binding region of RHAMM, specifically with amino acid substitutions at positions i, i+4, and/or i+7, forming covalent bonds to enhance stability and specificity, which can be used for diagnosing and treating conditions associated with elevated hyaluronic acid levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If short linear peptides containing only natural L amino acids are used, then the peptide sequence is simple and easy to manufacture, but the peptide has very limited stability against protease hydrolysis in vivo
Solution Approach 1:
The patent introduces non-natural amino acids with specific side chain functionalities (allyl, azide, acetylene groups) to replace natural L amino acids at strategic positions. This parameter change in amino acid composition enables the formation of stable cyclic structures through covalent bonding, dramatically improving protease resistance while maintaining synthetic feasibility through standard Fmoc solid-phase peptide synthesis methods
Solution Approach 2:
The patent creates composite peptide structures by combining natural L amino acids with non-natural amino acid derivatives. The resulting hybrid peptides contain both natural residues (for biological activity) and modified residues (for stability), forming a composite material that achieves both manufacturability and enhanced protease resistance through the incorporation of cyclic constraints
2Reliability
If CD44 is targeted for inflammatory and cancer-related conditions, then the binding mechanism is well-established, but the ubiquitous expression leads to off-target adverse effects
Solution Approach 1:
The patent extracts the hyaluronan-binding functional domain from the full-length RHAMM protein (amino acids 732-767) to create a minimized peptide sequence. This extracted domain retains the specific binding capability to hyaluronan and RHAMM while eliminating other functional regions that could cause off-target effects, thereby improving therapeutic safety while maintaining reliable binding to the intended target
Data Source
AI summary
Cyclized peptides derived from the hyaluronan binding region of RHAMM are provided. Pharmaceutical compositions and methods for using the peptides and pharmaceutical compositions are also provided. The peptides and pharmaceutical compositions can be used for the treatment of cancer, inflammatory disorders, autoimmune disorders, and fibrotic disorders.