Template-fixed beta-hairpin peptidomimetics for selective FPR1 inhibition
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Solution Overview
Problem
Current treatments lack selective and potent modulators for the Formyl-Peptide Receptor 1 (FPR1), which are essential for addressing various inflammatory and immune-related diseases, as existing ligands often have non-specific effects and limited affinity.
Innovation Solution
Development of β-hairpin peptidomimetics with a specific 14-mer peptide chain attached to a template, stabilizing a β-hairpin conformation to selectively inhibit FPR1, utilizing combinatorial synthesis methods to achieve potent and selective antagonistic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ligands are used to modulate FPR1, then some level of receptor interaction is achieved, but the affinity and selectivity are insufficient leading to non-specific effects
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of ligands through template-induced folding, transforming linear peptides into constrained β-hairpin conformations. This structural parameter change enhances both affinity (through optimized binding geometry) and selectivity (through unique conformational recognition) of the FPR1 modulators
Solution Approach 2:
The invention creates composite structures by combining template molecules with peptide sequences to form template-fixed peptidomimetics. This composite approach integrates the structural stability of templates with the biological activity of peptides, resulting in compounds with improved affinity and selectivity for FPR1
2Quantity of substance
If linear peptide structures are used, then simplicity of design is maintained, but the ability to induce specific conformation and achieve high affinity is limited
Solution Approach 1:
The template acts as an intermediary that mediates between the linear peptide sequence and the desired β-hairpin conformation. The template induces and stabilizes the folded structure without being part of the final active compound, allowing the peptide to achieve high affinity binding through the template-directed conformational organization
Solution Approach 2:
The template performs preliminary action by pre-organizing the peptide chain into the correct β-hairpin conformation before binding to the receptor. This preliminary structural arrangement ensures that the active compound presents the optimal binding geometry for high affinity interaction with FPR1
Data Source
AI summary
Novel template-fixed β-hairpin peptidomimetics of the general formula (I): cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-T1-T2] wherein the single elements T or P are α-amino acid residues connected in either direction which, depending on their positions in the chain, are as defined in the description and the claims, and salts thereof, have the property of antagonizing the biological effect of the receptor FPR1. They can be used as medicaments to treat or prevent diseases or conditions in the areas of inflammatory diseases, allergic conditions, immunological disorders, neuroinflammation, neurological disorders, obstructive airway diseases, infectious diseases, ischemic reperfusion injuries and proliferative disorders such as e.g. cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.