Amylin Receptor Agonist Peptides for Weekly Dosing and Selectivity
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Solution Overview
Problem
Current amylin-based therapies, such as pramlintide, have short plasma half-lives, require frequent dosing, and lack selectivity for the amylin receptor over the calcitonin receptor, leading to potential off-target toxicity and formulation challenges, particularly when combined with insulin or GLP-1 analogs.
Innovation Solution
Development of novel amylin receptor agonist peptides with specific modifications, including albumin binding moieties and extended half-life features, such as thioacetal bridges and fatty acid linkers, to enhance stability and selectivity, allowing for once-weekly dosing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pramlintide is used as an amylin agonist, then diabetes treatment efficacy is achieved, but plasma half-life is short requiring frequent dosing
Solution Approach 1:
The patent modifies the amino acid sequence of pramlintide by substituting specific residues (e.g., position 25, 28, 29 with proline; position 37 with pyroglutamic acid) to change the molecular properties and extend plasma half-life while maintaining amylin receptor agonist activity
Solution Approach 2:
The patent creates hybrid molecules by fusing amylin agonist sequences with albumin binding domains, forming composite structures that combine the pharmacological activity of amylin with the long circulation time of albumin, achieving extended half-life
2Reliability
If amylin-based therapies are administered, then glucose control is improved, but off-target toxicity occurs due to lack of selectivity for calcitonin receptor
Solution Approach 1:
The patent introduces specific local modifications at key positions in the amylin sequence (e.g., position 25, 28, 29, 37) to enhance selectivity for the amylin receptor over the calcitonin receptor, reducing off-target effects while maintaining therapeutic activity
3Stability of the object's composition
If pramlintide is formulated in acidic solution, then chemical stability is improved, but compatibility with neutral pH formulations is lost
Solution Approach 1:
The patent modifies the molecular structure to change its physicochemical properties, enabling the amylin agonist to remain stable at neutral pH unlike native amylin and pramlintide which require acidic formulations, thereby allowing compatibility with insulin and GLP-1 analog formulations
4Reliability
If frequent dosing is required, then therapeutic efficacy is maintained, but patient compliance deteriorates
Solution Approach 1:
The patent creates dynamic formulations including liposomal encapsulation and albumin-binding constructs that provide sustained release and extended circulation, transforming the dosing regimen from frequent injections to less frequent administrations while maintaining therapeutic levels
Data Source
AI summary
The present disclosure relates to the field of medicine. More particularly, the disclosure is in the field of treatment of diabetes, obesity and/or chronic weight management, dyslipidemia and/or NASH. The disclosure relates to compounds that agonize the amylin receptor and can lower food intake, body weight, glucose and/or triglycerides, so can be used to treat diabetes, obesity, and/or dyslipidemia. The present disclosure also includes pharmaceutical compositions containing such compounds and therapeutic uses of such compounds and compositions.