Polypeptide Scaffold Stability and Synthesis Optimization
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Solution Overview
Problem
Existing protein pharmaceuticals face challenges such as alkali instability, high antigenicity, structural instability, and difficulties in chemical synthesis due to amino acid residues that affect solubility and yield, as well as immunogenicity issues that can lead to unwanted immune responses.
Innovation Solution
Development of novel polypeptide variants based on modified scaffolds with improved alkaline stability, reduced antigenicity, enhanced structural stability, and optimized amino acid sequences for chemical synthesis, including the use of pseudoprolines to facilitate peptide synthesis and the introduction of hydrophilic residues to enhance solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If protein pharmaceuticals are produced using conventional methods, then production is achieved, but alkali stability is poor and purification requires multiple steps
Solution Approach 1:
The patent modifies amino acid parameters in the protein sequence, specifically replacing residues prone to deamidation (Asn, Gln) with more stable alternatives (Ala, Ser, Thr, Val, Leu, Ile, Met, Lys, Arg, His, Asp, Glu, Cys, Phe, Trp, Tyr). This parameter change at the molecular level directly improves alkali stability and reduces purification complexity by eliminating the need for multiple purification steps to remove degradation products
2Reliability
If protein pharmaceuticals are produced with conventional sequences, then production is achieved, but structural stability is insufficient
Solution Approach 1:
The patent applies parameter changes by systematically replacing amino acid residues to optimize structural stability. Specific replacements include Asn→Ala/Ser/Thr, Gln→Ala/Ser/Thr, and other substitutions that enhance structural integrity while maintaining production feasibility through standardized biochemical processes
3Object-affected harmful factors
If protein pharmaceuticals are produced with conventional sequences, then production is achieved, but antigenicity is high leading to immune responses
Solution Approach 1:
The patent reduces antigenicity through parameter changes that eliminate immunogenic epitopes. By replacing residues like Asn and Gln that can form immunogenic degradation products, and optimizing the overall amino acid composition, the patent produces proteins with reduced immune response potential while maintaining straightforward production protocols
4Productivity
If amino acid residues affecting solubility are present, then protein synthesis is achieved, but chemical synthesis yield is reduced
Solution Approach 1:
The patent improves chemical synthesis yield through parameter changes in amino acid selection. By choosing residues with favorable solubility characteristics and avoiding those that cause aggregation or poor coupling efficiency, the patent achieves higher synthesis yields while simplifying the chemical synthesis process
Data Source
AI summary
Populations of polypeptide variants based on a common scaffold, each polypeptide in the population comprising the scaffold amino acid sequence EXXXAXXEIX XLPNLTXXQX XAFIXKLXDD PSQSSELLSE AKKLNDSQ (SEQ ID NO: 1) or AKYAKEXXXAXX EIXXLPNLTX XQXXAFIXKL XDDPSQSSEL LSEAKKLNDS Q (SEQ ID NO: 2), wherein each X individually corresponds to an amino acid residue which is varied in the population are disclosed. Also populations of polynucleotides, wherein each member encodes a member of a polypeptide population are disclosed. Furthermore, combinations of such polypeptide populations and such polynucleotide populations are disclosed, wherein each member of polypeptide population is physically or spatially associated with the polynucleotide encoding that member via means for genotype-phenotype coupling.