Microprotein Scaffolded Polypeptides for Protease Resistance
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Solution Overview
Problem
Current methods for producing di- or multimeric peptide effector molecules face challenges such as short plasma half-lives due to proteolytic degradation, difficulty in recombinant production, and the need for chemical synthesis, which results in unwanted side products and limited bioavailability.
Innovation Solution
The development of polypeptides comprising at least two microproteins, which are designed to provide improved in vivo characteristics like increased stability and bioavailability by forming a framework that enhances conformational fixation and reduces conformational entropy, allowing for polyvalency and heterofunctionality, and can be produced recombinantly.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dimeric peptide effector molecules are designed to activate receptors, then agonistic activity is improved, but plasma half-life is reduced due to proteolytic degradation
Solution Approach 1:
The patent combines a functional peptide sequence with a stable microprotein scaffold to create a hybrid polypeptide. The microprotein provides structural stability and protease resistance, while the peptide sequence retains receptor binding and agonistic activity. This composite structure resolves the contradiction by maintaining biological activity while extending plasma half-life through enhanced stability.
Solution Approach 2:
The patent modifies the physical and chemical parameters of the peptide by incorporating it into a microprotein framework. This changes the peptide's susceptibility to proteolysis, its conformational flexibility, and its overall stability profile, thereby extending duration of action while preserving agonistic function.
2Reliability
If peptides are designed for high receptor affinity, then binding activity is improved, but recombinant production becomes difficult
Solution Approach 1:
The patent extracts the essential binding function from the full-length peptide and incorporates it into a microprotein scaffold. This allows the critical receptor-interacting residues to be preserved while eliminating sequences that cause production problems, enabling successful recombinant expression.
Solution Approach 2:
By changing the structural parameters of the peptide through microprotein incorporation, the patent creates a molecule that maintains high affinity for the target receptor while becoming amenable to recombinant production in microbial systems.
3Adaptability or versatility
If chemical synthesis is used to produce peptides, then production flexibility is improved, but unwanted side products and limited bioavailability occur
Solution Approach 1:
The patent replaces chemical synthesis with biological synthesis through recombinant DNA technology. This substitution eliminates the side reactions and impurities inherent in chemical peptide synthesis while maintaining the ability to produce complex sequences with high precision and purity.
Data Source
AI summary
Disclosed is a polypeptide comprising at least two microproteins, which preferably comprise an amino acid sequence having a specific binding activity to a target protein. Furthermore, disclosed are polynucleotides encoding such a polypeptide as well as pharmaceutical compositions and kits comprising said polypeptide or polynucleotide. Also disclosed herein are methods of treatments and second medical uses applying the disclosed polypeptide or polynucleotide. Additionally, the disclosure of the present application relates to a method for forming a covalent bond in a microprotein which can be used for producing the disclosed polypeptides.