GLP-1 Analogue Acylation for Extended Action and Oral Administration
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Solution Overview
Problem
Existing GLP-1 analogs have short half-lives and require frequent administration, leading to suboptimal patient compliance and stability issues due to susceptibility to enzymatic cleavage.
Innovation Solution
Development of GLP-1 analogs with an additional Leu or Ile at the C-terminal and acylation of the Lys side chain with specific protracting moieties, enhancing stability and duration of action, allowing for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If GLP-1 analogs are developed with improved half-life, then duration of action is extended, but structural complexity increases
Solution Approach 1:
The patent modifies the amino acid sequence parameters by incorporating Leu or Ile at the C-terminal position and acylating Lys side chains with specific protracting moieties (fatty acids with 14-20 carbons), which changes the chemical and physical parameters of the GLP-1 analogue to extend half-life and duration of action
Solution Approach 2:
The patent creates composite molecular structures by combining GLP-1 core sequence with C-terminal Leu/Ile extensions and Lys acylation moieties, forming a composite peptide structure that integrates multiple functional elements to achieve extended duration of action
2Reliability
If GLP-1 analogs are made more stable against enzymatic cleavage, then reliability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent modifies specific amino acid parameters at critical positions (C-terminal Leu/Ile, Lys acylation) to change the peptide's susceptibility to enzymatic cleavage, thereby improving stability while maintaining manufacturability through defined modification patterns
3Ease of operation
If frequency of administration is reduced, then patient compliance is improved, but duration of action must be extended
Solution Approach 1:
The patent changes the pharmacokinetic parameters of GLP-1 analogues by incorporating C-terminal Leu/Ile and Lys acylation, which extends the duration of action to enable once-weekly or less frequent administration, thereby improving patient compliance
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified GLP-1 analogs exhibit improved potency and prolonged action, reducing the frequency of administration and enhancing patient compliance by minimizing enzymatic cleavage.
Implementation Method 1
The analogs disclosed herein are acylated with protracting moieties, which increase the duration of activity of the compounds
Implementation Method 2
The new analogs are potent GLP-1 agonists with reduced adverse effect and improved duration of action... minimizing enzymatic cleavage
Data Source
AI summary
The present disclosure pertains to novel Glucagon like Peptide-1 (GLP-1) (7-37) analogs having an amino acid sequence with Leu or Ile at the C-terminal. The new analogs are potent GLP-1 agonists with reduced adverse effect and improved duration of action. The present disclosure further relates to acylated derivatives of the new analogs which have further improved potency and duration of action and are suitable for oral administration. The analogs of present disclosure may be useful in treatment of diabetes and obesity.