Double-acylated GLP-1 Derivatives for Oral Bioavailability
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Solution Overview
Problem
Current GLP-1 derivatives have limitations in terms of pharmacokinetic profile, oral bioavailability, and receptor binding affinity, particularly in the presence of albumin, which affects their therapeutic efficacy and administration routes.
Innovation Solution
Development of double-acylated GLP-1 derivatives at positions K26 and K34 with specific protracting moieties and linkers, enhancing their pharmacokinetic profile, bioavailability, and receptor binding affinity, allowing for subcutaneous, intravenous, and oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 derivatives are administered to achieve therapeutic effects, then diabetes treatment efficacy is improved, but pharmacokinetic profile is limited and oral bioavailability is poor
Solution Approach 1:
The patent applies composite material principles by creating double-acylated GLP-1 derivatives that combine the GLP-1 peptide with two fatty acid chains attached at specific lysine residues (K26 and K34). This composite structure integrates the bioactive peptide core with lipophilic fatty acid moieties, creating a molecule with improved pharmacokinetic properties including extended half-life and enhanced oral bioavailability while maintaining therapeutic efficacy for diabetes treatment
Solution Approach 2:
The patent employs parameter changes by systematically varying the fatty acid chain lengths, linker types, and acylation positions on the GLP-1 peptide. By optimizing these molecular parameters—such as using fatty acids with specific carbon chain lengths and incorporating different linker structures—the patent achieves derivatives with enhanced stability, prolonged duration of action, and improved absorption characteristics
2Ease of operation
If GLP-1 derivatives are designed for once-daily or once-weekly administration, then administration frequency is reduced, but receptor binding affinity is compromised
Solution Approach 1:
The patent applies segmentation by separating the functional elements of the GLP-1 derivative into distinct modules: the bioactive GLP-1(7-37) peptide core, the fatty acid protracting moieties, and the linker structures. This modular segmentation allows independent optimization of each component—the peptide core maintains receptor binding affinity while the fatty acid moieties and linkers are designed to extend circulation half-life, enabling reduced administration frequency without compromising efficacy
Solution Approach 2:
The patent uses linker structures as intermediaries connecting the GLP-1 peptide core to the fatty acid protracting moieties. These linker intermediaries mediate between the conflicting requirements of maintaining peptide-receptor interaction while attaching extended half-life moieties, allowing the derivative to achieve both prolonged circulation and sustained receptor binding capability
3Duration of action of moving object
If double-acylation is performed at K26 and K34 positions, then pharmacokinetic profile is enhanced, but structural complexity increases
Solution Approach 1:
The patent applies local quality by selectively modifying specific lysine residues (K26 and K34) on the GLP-1 peptide chain while leaving other regions unchanged. This localized modification strategy enhances pharmacokinetic properties through double-acylation at strategic positions without unnecessarily complicating the entire molecular structure, maintaining simplicity in non-critical regions while achieving the desired pharmacokinetic enhancement
Data Source
AI summary
The invention relates to a derivative of a GLP-1 peptide, which peptide comprises a first K residue and a second K residue, at positions corresponding to position 26, and 34, respectively, of GLP-1(7-37) (SEQ ID NO:1), and a maximum of eight amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is Chem. 2: HOOC—C6H4—O—(CH2)y—CO—*, in which y is an integer in the range of 6-13; and the linker comprises Chem. 3a: *—NH—(CH2)q—CH[(CH2)w—NR1R2]—CO—*, wherein q is an integer in the range of 0-5, R1 and R2 independently represent *—H or *—CH3, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.