Bicyclic Peptide Ligands for Stable, Specific TfR1 Binding
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Solution Overview
Problem
Existing peptide therapeutics lack specificity and stability for targeting transferrin receptor 1 (TfR1), limiting their efficacy in treating diseases.
Innovation Solution
Development of bicyclic peptide ligands with specific amino acid sequences that form two polypeptide loops covalently bonded to a molecular scaffold, enhancing binding affinity and specificity to TfR1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If linear peptide structures are used, then ease of manufacture is improved, but binding affinity and specificity to TfR1 deteriorate
Solution Approach 1:
The peptide is divided into two separate cyclic structures (first cycle and second cycle) connected by a linker, rather than using a single linear structure. This segmentation allows each cycle to independently contribute to binding while maintaining manufacturability through modular synthesis
Solution Approach 2:
The invention creates a composite structure combining two cyclic peptide domains with a linker, forming a bicyclic peptide that integrates the stability and binding capabilities of cyclic structures while maintaining the flexibility needed for manufacturability
2Reliability
If cyclic peptide structures are used, then binding affinity is improved, but conformational flexibility is reduced
Solution Approach 1:
The bicyclic peptide divides the cyclic constraint into two separate cycles, where each cycle provides localized structural stability for binding while the linker between them preserves overall conformational flexibility, allowing the peptide to adapt to the target binding site
Solution Approach 2:
The linker connecting the two cyclic domains introduces dynamic flexibility to the otherwise rigid cyclic structures, enabling the bicyclic peptide to undergo conformational adjustments during binding while maintaining the stability provided by the cyclic domains
Data Source
AI summary
The present invention relates to peptide ligands, such as bicyclic peptide ligands, specific for transferrin receptor 1 (TfR1). The invention also includes pharmaceutical compositions comprising said peptide ligands and the use of said peptide ligands and pharmaceutical compositions in preventing, suppressing or treating a disease or disorder through TfR1 mediated delivery of a therapeutic agent.