Biosynthetic Proline-Alanine Random Coil Polypeptides for Therapeutic Half-Life Extension
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Solution Overview
Problem
Current methods for extending the plasma half-life of therapeutic proteins, such as PEGylation, are costly, require additional processing steps, and can cause side effects due to non-biodegradability, while natural amino acid sequences often fold or aggregate, leading to immunogenicity and reduced bioactivity.
Innovation Solution
Development of biosynthetic random coil polypeptides composed solely of proline and alanine amino acid residues, which form a stable random coil conformation, increasing hydrodynamic volume and solubility, and are biodegradable, thereby extending plasma half-life without interfering with bioactivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If PEGylation is used to extend plasma half-life, then plasma half-life is improved, but manufacturing complexity and cost increase
Solution Approach 1:
The patent uses short, simple amino acid sequences (e.g., 5-20 residues) that are biodegradable and can be easily synthesized or expressed, replacing complex PEGylation processes. These short peptides serve as temporary, disposable extensions that are naturally metabolized, avoiding the need for complex manufacturing and purification procedures required for PEG conjugates.
Solution Approach 2:
The patent changes the chemical parameters by using natural amino acid sequences with specific properties (hydrophilicity, charge, flexibility) instead of synthetic PEG polymers. By varying the amino acid composition and sequence length, the patent optimizes plasma half-life extension while maintaining simplicity in manufacturing and expression systems.
2Duration of action of moving object
If PEGylation is used to extend plasma half-life, then plasma half-life is improved, but additional processing steps are required
Solution Approach 1:
The patent merges the therapeutic protein with a short amino acid sequence extension through genetic fusion, creating a single polypeptide chain. This eliminates the need for separate chemical conjugation steps required in PEGylation, as the extension is co-expressed and co-purified with the therapeutic protein in a single manufacturing process.
Solution Approach 2:
The short amino acid sequences are designed to be self-sufficient in extending plasma half-life without requiring additional chemical modification steps. The sequences naturally interact with plasma proteins or resist renal filtration through their intrinsic physical-chemical properties, eliminating the need for external PEG reagents and complex conjugation chemistry.
3Duration of action of moving object
If non-biodegradable materials are used to extend plasma half-life, then plasma half-life is improved, but harmful side effects occur
Solution Approach 1:
The patent employs short, biodegradable amino acid sequences that are naturally metabolized by the body through standard proteolytic pathways. These sequences serve as temporary extensions that are gradually broken down and eliminated, avoiding the accumulation and long-term toxicity associated with non-biodegradable PEG materials.
Solution Approach 2:
The patent changes the biodegradability parameter by using natural amino acid sequences that are substrates for cellular proteases, in contrast to the non-biodegradable PEG polymers. This ensures the extension material can be safely metabolized and eliminated, preventing the harmful side effects of PEG accumulation in tissues.
4Stability of the object's composition
If natural amino acid sequences are used to extend plasma half-life, then biodegradability is improved, but folding and aggregation occur leading to immunogenicity
Solution Approach 1:
The patent applies local quality control by using short amino acid sequences (5-20 residues) rather than long natural protein sequences. These short segments are too short to form stable folded structures or aggregates that trigger immune responses, while still providing the desired plasma half-life extension. The local sequence composition is optimized to remain soluble and resistant to aggregation.
Solution Approach 2:
The patent changes the stability parameters by using short sequences that inherently resist folding into immunogenic structures. The amino acid composition is specifically selected to maintain solubility and prevent aggregation, while the short length ensures rapid metabolic degradation before immune recognition can occur, thus maintaining biodegradability without inducing immunogenicity.
Data Source
AI summary
The present invention relates to a biosynthetic random coil polypeptide or a biosynthetic random coil polypeptide segment or biosynthetic conjugate, in which the biosynthetic random coil polypeptide, the biosynthetic random coil polypeptide segment, or the biosynthetic conjugate comprises an amino acid sequence consisting solely of proline and alanine amino acid residues, wherein the amino acid sequence consists of at least about 50 proline (Pro) and alanine (Ala) amino acid residues. The at least about 50 proline (Pro) and alanine (Ala) amino acid residues may be (a) fconstituent(s) of a heterologous polypeptide or an heterologous polypeptide construct. Also uses and methods of use of these biosynthetic random coil polypeptides or polypeptide segments or conjugates are described.