GLP-1 Polypeptide Conjugates With Linkers for Longer Half-Life
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Solution Overview
Problem
Existing GLP-1 compounds have short in vivo half-lives due to N-terminal cleavage and inactivation by dipeptidyl peptidase DPP-IV, leading to suboptimal efficacy and dosing frequency for treating metabolic disorders like diabetes.
Innovation Solution
Development of polypeptide conjugates comprising a GLP-1 receptor agonist attached to a peptide linker with a clearance-reducing moiety (CRM) to enhance stability and prolong the half-life of GLP-1 compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If native GLP-1 or truncated GLP-1 peptides are used, then biological activity is maintained, but in vivo half-life is extremely short due to DPP-IV cleavage
Solution Approach 1:
The GLP-1 peptide is divided into two functional segments: the biologically active peptide portion (residues 7-36 or 7-37) that binds to GLP-1 receptors, and a peptide linker portion that provides structural flexibility and conjugation sites. This segmentation allows the active segment to maintain biological function while the linker segment provides protection against enzymatic degradation.
Solution Approach 2:
A peptide linker acts as an intermediary between the GLP-1 receptor agonist and the clearance-reducing moiety. This linker is designed to be resistant to DPP-IV cleavage while maintaining proper spatial arrangement of functional groups, thereby protecting the active peptide from enzymatic degradation and extending half-life.
2Duration of action of moving object
If clearance-reducing moieties are conjugated to GLP-1 compounds, then half-life is extended, but structural complexity increases
Solution Approach 1:
The invention merges the GLP-1 receptor agonist, peptide linker, and clearance-reducing moiety into a single integrated polypeptide conjugate structure. This merging approach ensures that all functional elements work together synergistically to extend half-life while maintaining a manageable overall structure through covalent bonding.
Solution Approach 2:
The polypeptide conjugate functions as a composite molecular structure combining different functional domains: the biologically active peptide segment, the flexible peptide linker, and the clearance-reducing moiety. This composite structure leverages the advantages of each component while distributing structural complexity across functional regions.
3Productivity
If peptide linkers are used to attach CRMs, then pharmacokinetic properties are improved, but manufacturing precision requirements increase
Solution Approach 1:
The peptide linker is designed with specific local properties: it contains designated conjugation sites with particular amino acid residues (such as lysine or cysteine) that provide controlled attachment points for clearance-reducing moieties. This local quality approach ensures consistent conjugation while maintaining overall molecular flexibility and function.
Data Source
AI summary
The present disclosure provides polypeptide conjugates comprising GLP-1 receptor agonist and a peptide linker, and liquid pharmaceutical compositions comprising the same. Methods of using such for treating diseases are also provided.