Double-Acylated GLP-1 Peptides for Extended Half-Life
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Solution Overview
Problem
Current GLP-1 derivatives have limitations in terms of half-life and administration frequency, with existing options requiring daily or weekly administration, and there is a need for compounds with longer duration of action and improved potency for effective diabetes management and other therapeutic uses.
Innovation Solution
Development of double-acylated GLP-1 like peptides with specific amino acid changes and long fatty diacid acylation sites, including one at the C-terminus and internally, to enhance stability and receptor binding, allowing for once-monthly administration while maintaining potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If GLP-1 derivatives are developed for longer half-life, then administration frequency can be reduced, but potency may be compromised
Solution Approach 1:
The molecule is segmented into two distinct acylation sites: one at the C-terminus (position 42) and another internally (positions 18, 23, 27, 31, 36, or 38). This dual-site acylation strategy allows independent optimization of half-life extension and potency maintenance, resolving the contradiction between prolonged duration and sustained efficacy
Solution Approach 2:
The patent creates a composite molecular structure by combining GLP-1 peptide backbone with long fatty diacid chains (C12-C22) at two strategic locations. This composite approach integrates the peptide's biological activity with the lipid's membrane-interaction properties, achieving both extended half-life through albumin binding and maintained potency through dual receptor engagement
2Duration of action of moving object
If double-acylated derivatives are created with long fatty diacids, then half-life is extended, but molecular complexity increases
Solution Approach 1:
The patent systematically varies parameters including fatty diacid chain length (C12-C22), acylation positions (C-terminal position 42 and internal positions 18, 23, 27, 31, 36, or 38), and amino acid substitutions to optimize the balance between half-life extension and molecular complexity. This parameter optimization reduces unnecessary complexity while maintaining therapeutic benefits
Solution Approach 2:
The double-acylation strategy applies different functional qualities to different parts of the molecule: the C-terminal acylation primarily extends half-life through albumin binding, while the internal acylation maintains potency through GLP-1 receptor interaction. This localized functional differentiation manages overall molecular complexity by assigning specific roles to each modification site
3Ease of operation
If once-monthly administration is achieved, then patient compliance improves, but dosage precision may be affected
Solution Approach 1:
The patent creates highly stable molecular copies of GLP-1 with extended half-life through double-acylation, allowing the same therapeutic effect to be delivered at less frequent intervals. This molecular copying approach maintains precise dosing control while enabling once-monthly administration, thus improving compliance without sacrificing dosage precision
Data Source
AI summary
The invention relates to derivatives of GLP-1 like peptides which are C-terminally extended analogues of native GLP-1. The derivatives comprise two side chains, one at a position corresponding to position 42, and one at a position corresponding to position 18, 23, 27, 31, 36, or 38, wherein both positions are when compared to GLP-1(7-37). The side chains comprise a C19, C20, or C22 diacid protracting moiety and optionally a linker. The invention also relates to intermediate products in the form of novel GLP-1 analogues incorporated in the derivatives of the invention, as well as pharmaceutical compositions and medical uses of the derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.