Triazole-Bridged Macrocyclic Peptides for Integrin Binding
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Solution Overview
Problem
Current stapled peptides face challenges in achieving consistent cell-permeability due to factors like alpha-helicity, positive charge, and peptide sequence, leading to impermeability or poor permeability across cell membranes, limiting their therapeutic application.
Innovation Solution
Development of chromogranin-A derived peptides with high affinity and bi-selectivity for integrins αvβ6 and αvβ8, specifically designed as intramolecular macrocyclic forms with a triazole-bridged macrocyclic scaffold, enhancing stability and cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If stapled peptides are designed to target intracellular protein-protein interactions, then affinity and specificity for target integrins are improved, but cell-permeability deteriorates due to factors like alpha-helicity, positive charge, and peptide sequence
Solution Approach 1:
The patent modifies key parameters of the peptide structure including the charge distribution (reducing excessive positive charge), hydrophobicity (optimizing hydrophobic content), and alpha-helicity (maintaining appropriate helical content). These parameter changes resolve the contradiction by tuning the peptide properties to achieve both high affinity for integrins and sufficient cell permeability, avoiding membrane lysis while maintaining target engagement.
Solution Approach 2:
The invention creates a composite peptide structure combining hydrocarbon staple moieties with specifically designed peptide sequences that contain RGD motifs and LXXL/I motifs. This composite structure integrates the stability and structural rigidity of stapled peptides with the cell-permeable properties of naturally occurring cell-penetrating sequences, achieving both high affinity and cell permeability simultaneously.
2Ease of operation
If excess hydrophobicity and positive charge are introduced to improve cellular uptake, then cell-permeability is enhanced, but membrane lysis occurs at elevated peptide dosing
Solution Approach 1:
The patent carefully balances the hydrophobicity and positive charge parameters within optimal ranges rather than maximizing them. The peptide design incorporates moderate hydrophobic content and controlled positive charge density, which enables cellular uptake through energy-dependent macropinocytosis without triggering membrane lysis even at elevated dosing levels.
3Loss of information
If many stapled peptides are designed with various sequences to explore cell uptake mechanisms, then understanding of uptake factors is improved, but consistent cell-permeability across designs deteriorates
Solution Approach 1:
The patent establishes specific optimal ranges for key parameters (alpha-helicity, positive charge, hydrophobicity, and staple placement) that consistently produce cell-permeable stapled peptides. By defining these parameter ranges based on comprehensive analysis of numerous peptide variants, the invention provides a reliable design framework that ensures consistent cell permeability while maintaining understanding of the underlying uptake mechanisms.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The peptides demonstrate sub-nanomolar affinity and bi-selectivity for αvβ6/αvβ8 integrins, maintaining receptor-tailored properties upon conjugation, and exhibit stability in biological fluids and microsomes, making them suitable for diagnostic and therapeutic applications.
Implementation Method 1
intramolecular macrocyclic form is obtained by a stapling method or is a head-to-tail cyclic form
Implementation Method 2
chromogranin-A derived compounds, such as (4) and (5), that have high affinity and bi-selectivity for αvβ6 and αvβ8 integrins
Data Source
AI summary
The present invention refers to chromogranin A-derived peptides that are potent dual ligands for integrins αvβ6 and avβ8, their therapeutic and diagnostic uses and relative compositions.