Modified Relaxin Polypeptides for Extended Half-Life
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Solution Overview
Problem
Current treatments for heart failure, particularly those involving relaxin peptides, face challenges due to the short pharmacokinetic half-life of relaxin molecules, necessitating continuous intravenous infusion, which is impractical for chronic conditions and limits alternative administration routes.
Innovation Solution
Modified relaxin polypeptides are developed by incorporating non-naturally encoded amino acids and linking them to pharmacokinetic enhancers, such as peptide components and half-life extending moieties, to improve stability, absorption, and therapeutic half-life, allowing for alternative administration methods beyond continuous intravenous infusion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If continuous intravenous infusion is used to maintain therapeutic levels of relaxin, then the therapeutic effect is maintained, but the treatment complexity and burden on patients increases
Solution Approach 1:
The patent modifies the pharmacokinetic parameters of relaxin by conjugating it to albumin-binding peptides and fatty acids, changing its half-life from minutes to days, which eliminates the need for continuous infusion and enables alternative administration routes
Solution Approach 2:
The patent creates composite structures by conjugating relaxin with albumin-binding peptides (such as Angiotensin III, IV, and V) and fatty acids (such as palmitic acid and stearic acid), forming a composite therapeutic agent that combines the therapeutic properties of relaxin with the long circulation half-life of albumin-bound molecules
2Ease of manufacture
If standard relaxin peptides are used, then the therapeutic mechanism is simple and specific, but the pharmacokinetic half-life is too short for practical chronic treatment
Solution Approach 1:
The patent uses albumin-binding peptides as intermediaries that mediate between relaxin and serum albumin, creating a reversible binding interaction that extends the circulation half-life of relaxin without requiring direct fusion to albumin, thus maintaining the simplicity of the therapeutic mechanism while achieving the desired pharmacokinetic improvement
Solution Approach 2:
The patent transforms the short-living relaxin molecule into a long-circulating therapeutic by attaching it to abundant, inexpensive albumin-binding moieties that serve as carriers, effectively converting a rapidly cleared peptide into a sustained-release therapeutic agent
3Ease of operation
If alternative administration routes (such as subcutaneous or oral) are used, then patient convenience is improved, but the bioavailability and therapeutic efficacy may be reduced due to short half-life
Solution Approach 1:
The patent fundamentally changes the pharmacokinetic parameters of relaxin by extending its half-life through albumin binding, which enables the peptide to survive absorption processes and maintain therapeutic levels when administered via subcutaneous, intramuscular, or oral routes, thereby improving patient convenience without sacrificing efficacy
Data Source
AI summary
The present disclosure generally relates to modified relaxin polypeptides, such as modified human relaxin 2 polypeptides, comprising a non-naturally encoded amino acid which is linked to a pharmacokinetic enhancer, and therapeutic uses of such polypeptides, such as for the treatment of cardiovascular conditions (such as heart failure) and/or conditions relating to fibrosis.