GLP-1 Polypeptide Conjugates with Albumin-Binding Moieties
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Solution Overview
Problem
Current treatments for metabolic disorders, particularly those involving Glucagon-Like Peptide-1 (GLP-1) compounds, face challenges such as short half-life and low efficacy, requiring frequent injections and posing discomfort for patients due to their administration method.
Innovation Solution
Development of polypeptide conjugates comprising a biologically active GLP-1 receptor agonist attached to a peptide linker with a clearance-reducing moiety (CRM) conjugated at a specific distance from the C-terminal amino acid residue, enhancing half-life and activity while maintaining therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 compounds are administered by frequent injection to maintain therapeutic levels, then glucose control efficacy is improved, but patient compliance and ease of operation deteriorate due to fear of injection and dosing frequency
Solution Approach 1:
The patent changes the pharmacokinetic parameters of GLP-1 by conjugating it with albumin-binding moieties, extending the half-life from minutes to days. This parameter change allows transition from frequent dosing to once-weekly or less frequent dosing, resolving the contradiction between maintaining efficacy and improving patient compliance
Solution Approach 2:
The patent creates composite structures by chemically conjugating GLP-1 peptides with albumin-binding moieties (such as fatty acid chains). This composite material combines the glucose-lowering effect of GLP-1 with the long circulation time of albumin, achieving both efficacy and reduced dosing frequency
2Duration of action of moving object
If GLP-1 compounds are modified to extend half-life, then dosing frequency is reduced, but biological activity and therapeutic efficacy may deteriorate
Solution Approach 1:
The patent segments the modification strategy by placing the albumin-binding moiety at the C-terminus of GLP-1 while preserving the N-terminal active region. This segmentation allows the C-terminal extension to extend half-life without interfering with the N-terminal glucose-dependent insulinotropic activity
Solution Approach 2:
The patent applies local quality modification by specifically modifying the C-terminal region of GLP-1 with albumin-binding moieties while leaving the N-terminal active site unchanged. This localized modification ensures that half-life is extended without compromising the critical biological activity at the N-terminus
Data Source
AI summary
The present disclosure provides a polypeptide conjugates comprising GLP-1 receptor agonist and a peptide linker, and pharmaceutical compositions comprising the same. Methods of using such for treating diseases are also provided.