GLP-1 Analogues DPP-IV Stability Trp8 Substitution
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current GLP-1 analogues and derivatives face challenges in stability against degradation by DPP-IV and effective binding to the GLP-1 receptor, limiting their metabolic stability and biological activity.
Innovation Solution
Development of GLP-1 analogues with a Trp at position 8 and substituents attached to a Lys residue via a branching group, comprising a Protracting moiety and linker, which enhance stability and receptor binding, allowing for improved metabolic stability and biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If conventional GLP-1 analogues are used, then they can bind to the GLP-1 receptor, but they are rapidly degraded by DPP-IV enzyme, resulting in short duration of action
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of GLP-1 analogues through specific substitutions (e.g., position 8 Trp, position 36 Lys, position 37 Lys) to alter their chemical properties. These sequence modifications change the peptide's resistance to DPP-IV enzymatic cleavage, thereby extending its half-life and duration of action while maintaining receptor binding capability
Solution Approach 2:
The patent employs composite material principles by combining multiple modified amino acid residues within the GLP-1 peptide structure. The synergistic effect of these composite modifications (Trp at position 8, Lys at position 36, Lys at position 37, and other substitutions) creates a peptide with enhanced stability properties that exceed the sum of individual modifications, achieving prolonged duration of action
2Reliability
If GLP-1 analogues are modified to resist DPP-IV degradation, then metabolic stability is improved, but binding affinity to the GLP-1 receptor may be reduced
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific positions (such as position 8, 36, and 37) while leaving other critical regions of the peptide unchanged. This localized modification strategy preserves the essential binding interface structures necessary for high-affinity receptor interaction while conferring DPP-IV resistance at specific cleavage sites, thus maintaining both metabolic stability and binding affinity
3Reliability
If multiple amino acid substitutions are introduced to enhance stability, then metabolic stability is improved, but the complexity of synthesis and manufacturing increases
Solution Approach 1:
The patent applies segmentation by dividing the complex multi-substitution modification process into manageable stages. The amino acid substitutions are introduced through a systematic approach where each position is modified in a controlled manner during solid-phase peptide synthesis, allowing for quality control and simplifying the overall manufacturing process despite the multiple changes required
Data Source
AI summary
The invention relates to GLP-1 analogues and derivatives having a Trp at a position corresponding to position 8 of GLP-1(7-37), and their pharmaceutical use e.g. in the treatment of type 2 diabetes. These Trp8 compounds are very stable against degradation by DPP-IV, while maintaining the capability to bind to and activate the GLP-1 receptor. The derivatives have one or two substituents (P-L) attached to a Lys residue of the GLP-1 analogue via an optional Branching group (B), wherein P is a Protracting moiety such as a fatty diacid, and L is a linker consisting of one or more linker elements such as, for example, 8-amino-3,6-dioxaoctanoic acid. Examples of compounds of the invention include the 8W variants of liraglutide and dulaglutide. The invention also relates to a method for the fully recombinant preparation of 8W GLP-1 analogues and derivatives which is more simple and thereby cheaper as compared to the preparation of known GLP-1 analogues that have been DPP-IV stabilised by inclusion of one or more non-coded amino acids.