Modified Polypeptides with Beta-Amino Acids for Receptor Selectivity
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Solution Overview
Problem
Naturally occurring vasoactive intestinal peptide (VIP) has a short half-life and limited receptor selectivity, making it challenging to effectively target specific biological pathways for therapeutic applications without disrupting other receptor functions.
Innovation Solution
Development of modified polypeptide sequences with increased degradation resistance and receptor selectivity by incorporating β-amino acids, which enhance the polypeptide's conformational rigidity and stability, allowing for selective modulation of VIP receptor subtypes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If naturally occurring VIP polypeptide is used, then it can bind to VIP receptors, but it has short half-life and limited receptor selectivity
Solution Approach 1:
The patent applies parameter changes by substituting natural amino acids with non-natural amino acids (specifically β-amino acids and N-methylated amino acids) to modify the polypeptide's physical and chemical properties. This changes the degradation resistance and conformational stability parameters, resulting in prolonged half-life while maintaining or enhancing receptor selectivity through preserved binding interface characteristics
Solution Approach 2:
The patent creates composite polypeptide structures by combining natural amino acids with non-natural amino acids (β-amino acids, N-methylated amino acids) within the same polypeptide sequence. This composite approach allows different regions of the polypeptide to have different properties: enhanced stability and degradation resistance from non-natural amino acids while maintaining natural binding interfaces for receptor selectivity
2Duration of action of moving object
If non-natural amino acids are incorporated to increase degradation resistance, then half-life is prolonged, but manufacturing complexity increases
Solution Approach 1:
The patent uses parameter changes by systematically substituting specific natural amino acids with non-natural variants at defined positions in the sequence. This controlled substitution approach, rather than random modification, simplifies manufacturing by providing clear design rules for incorporating β-amino acids and N-methylated amino acids while achieving the desired half-life extension
3Stability of the object's composition
If conformational rigidity is increased to enhance stability, then half-life is prolonged, but flexibility for receptor binding may be reduced
Solution Approach 1:
The patent applies local quality by differentiating the functional roles of different regions within the polypeptide. Non-natural amino acids (β-amino acids, N-methylated variants) are strategically positioned in regions where conformational stability is needed, while natural amino acids are retained at binding interface positions where flexibility and adaptability are required for receptor interaction
Solution Approach 2:
The patent segments the polypeptide into distinct functional regions: stable structural regions enriched with non-natural amino acids for conformational rigidity, and flexible binding regions with natural amino acids for receptor interaction. This segmentation allows simultaneous optimization of stability and binding adaptability in different parts of the molecule
Data Source
AI summary
This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.