Thioamide-Modified Peptides for Proteolytic Stability
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Solution Overview
Problem
Peptide biologics, such as GLP-1, undergo rapid proteolysis in vivo, leading to unfavorable pharmacokinetics and requiring extensive modification to stabilize them while maintaining biological activity, which is time-consuming and often unsuccessful.
Innovation Solution
Thioamide modifications are introduced at specific peptide bonds, particularly between the second and third amino acid residues from the N-terminus, to stabilize peptides against proteolytic degradation, increasing their half-life and maintaining biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptides are used as biologic drugs, then biological activity is maintained, but rapid proteolysis occurs leading to unfavorable pharmacokinetics
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of peptide bonds from standard amide bonds to thioamide bonds. This chemical modification changes the bond type from -C(=O)NH- to -C(=S)NH-, which fundamentally alters the peptide's susceptibility to proteolytic degradation while preserving its biological activity, thereby resolving the contradiction between maintaining biological activity and extending half-life
Solution Approach 2:
The patent creates composite peptide structures by incorporating thioamide modifications at specific positions within the peptide sequence. These thioamide-modified peptides function as hybrid molecules that combine the biological activity of natural peptides with the proteolytic resistance of chemically modified structures, achieving both prolonged half-life and maintained functionality
2Stability of the object's composition
If peptides are modified to reduce proteolysis, then stability improves, but the modification process is time-consuming and often fails
Solution Approach 1:
The patent identifies that changing the fundamental chemical parameter of peptide bonds to thioamides provides a straightforward and reliable pathway to proteolytic stability. This single parameter change (amide to thioamide) avoids the need for complex multi-step modifications and identifies a modification strategy that is both time-efficient and reliably successful
Solution Approach 2:
The patent segments the peptide modification approach by targeting specific bond positions for thioamide conversion rather than requiring comprehensive structural changes. By focusing modifications at specific locations (particularly at positions susceptible to DPP-4 cleavage), the process becomes more efficient and less time-consuming while achieving the desired stability
3Duration of action of stationary object
If DPP-4 inhibitors are used to stabilize GLP-1, then half-life increases, but the mechanism is indirect and requires enzyme inhibition
Solution Approach 1:
The patent extracts the vulnerability of GLP-1 to DPP-4 cleavage by modifying the peptide bonds at the specific positions where DPP-4 acts. By converting these vulnerable amide bonds to thioamide bonds, the patent removes the substrate for DPP-4, thereby preventing enzyme action rather than merely inhibiting it, which simplifies the overall mechanism
Solution Approach 2:
Instead of using DPP-4 inhibitors to indirectly protect GLP-1 degradation, the patent inverts the approach by directly modifying the peptide structure to become resistant to DPP-4 cleavage. This inversion transforms the problem from enzymatic inhibition to structural resistance, simplifying the mechanism from indirect enzyme blocking to direct proteolytic resistance
Data Source
AI summary
The invention includes a thioamide-modified peptide, wherein the thioamide modification increases the in vivo half-life of the peptide. The invention further includes methods of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a thioamide-modified peptide of the invention.