Retro-Inverse Angiotensin-(1-9) Peptide Stability
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Solution Overview
Problem
Angiotensin-(1-9) peptides are short-lived due to rapid enzymatic degradation, limiting their therapeutic potential despite their high bioactivity and specificity, necessitating the development of stable analogues that maintain biological activity.
Innovation Solution
Development of retro-inverse angiotensin-(1-9) peptides using D-amino acids in an inverted sequence to enhance stability and plasma half-life while retaining biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If angiotensin-(1-9) peptide is used for therapeutic purposes, then high bioactivity and specificity are achieved, but the peptide is rapidly degraded by enzymes resulting in short half-life
Solution Approach 1:
The patent applies retro-inverse methodology by inverting the amino acid sequence of angiotensin-(1-9) and replacing L-amino acids with their D-enantiomers. This creates a mirror-image peptide structure (DHDFDPDHDIDYDVDRDD) that maintains the three-dimensional conformation and receptor binding capability while becoming resistant to enzymatic degradation by proteases that specifically recognize and cleave L-amino acid sequences. The inverted structure allows the peptide to evade metabolic breakdown while retaining biological activity.
Solution Approach 2:
The patent changes the stereochemical parameter of the amino acid residues from L-configuration to D-configuration. This fundamental parameter change transforms the peptide's interaction with enzymatic systems while preserving its ability to bind to angiotensin receptors. The D-amino acid configuration alters the peptide's spatial arrangement in a way that maintains functional activity but confers resistance to proteolytic enzymes.
2Duration of action of stationary object
If stable analogues are developed to extend plasma half-life, then duration of action is improved, but structural modification may reduce biological activity
Solution Approach 1:
By inverting both the sequence order and the stereochemical configuration of all amino acids, the patent creates a retro-inverse analog that preserves the essential three-dimensional pharmacophore features required for receptor binding. The mirror-image structure maintains the spatial relationships between key functional groups while becoming metabolically stable, thus achieving both extended half-life and retained biological activity.
Solution Approach 2:
The patent creates a composite molecular structure combining D-amino acid residues in an inverted sequence configuration. This composite approach integrates multiple stabilizing features (stereochemical inversion + sequence reversal) to achieve metabolic stability while maintaining the peptide's ability to interact with its biological target, effectively creating a hybrid structure with enhanced properties.
Data Source
AI summary
The present invention provides an angiotensin-(1-9) analog, particularly an angiotensin-(1-9) peptide synthesized from D-amino acids. This invention further involves the inversion of the original sequence of angiotensin-(1-9). This analog possesses an increased stability and maintains the biological activity of angiotensin-(1-9). Another embodiment of this invention comprises pharmaceutical compositions containing said analog and their use in the treatment of cardiovascular diseases, tissue remodeling in kidney, brain, and also the induction of cardioprotection.