Macrocyclic Peptides Inhibit PD-L1 Interactions
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Solution Overview
Problem
Current therapies for cancer and infectious diseases often fail to effectively inhibit the PD-1/PD-L1 and CD80/PD-L1 interactions, leading to immune evasion and suppression, which limits the efficacy of treatments for various diseases, including cancer and chronic infections.
Innovation Solution
Development of macrocyclic peptides that specifically bind to PD-L1, inhibiting its interaction with PD-1 and CD80, thereby enhancing T cell functional activity and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used to treat cancer and infectious diseases, then treatment is administered, but the PD-1/PD-L1 and CD80/PD-L1 interactions are not effectively inhibited, leading to immune evasion and suppression
Solution Approach 1:
The patent employs macrocyclic peptides as intermediary molecules that specifically bind to PD-L1, blocking its interaction with PD-1 and CD80. These peptides act as mediators between the therapeutic agent and the immune checkpoint proteins, preventing the harmful immune evasion mechanism while enhancing T cell functional activity.
Solution Approach 2:
The invention changes the binding parameters by developing macrocyclic peptides with optimized affinity and specificity for PD-L1. The cyclic structure and specific amino acid composition (including conserved residues at positions 1, 3, 6, 8, 9, 10, and 13) create high-affinity binding that effectively competes with PD-1 and CD80, altering the interaction dynamics to favor immune activation.
2Reliability
If macrocyclic peptides are developed to specifically bind PD-L1, then inhibition of PD-1/PD-L1 and CD80/PD-L1 interactions is achieved, but this requires high specificity and affinity binding
Solution Approach 1:
The macrocyclic peptides incorporate specific local quality features through conserved amino acid residues at critical positions (1, 3, 6, 8, 9, 10, and 13) that are essential for PD-L1 binding. These localized conserved regions ensure high specificity and affinity, while other regions can be varied to optimize pharmacological properties without compromising binding precision.
Solution Approach 2:
The invention creates composite molecular structures by combining multiple amino acid residues with specific properties (conserved and variable regions) into a macrocyclic peptide framework. This composite structure integrates high-affinity binding capabilities with enhanced stability and selectivity, achieving reliable inhibition of the PD-1/PD-L1 and CD80/PD-L1 interactions.
3Reliability
If the interaction between PD-1 and PD-L1 is blocked, then T cell activation is restored, but this requires effective competition with the natural ligand-receptor binding
Solution Approach 1:
The macrocyclic peptides are designed to copy the binding interface of natural T cell receptors by incorporating conserved amino acid residues that mimic the natural binding pattern. This copying strategy allows the peptides to effectively compete with PD-1 for binding to PD-L1, restoring T cell activation without requiring entirely novel binding mechanisms.
Data Source
AI summary
The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-L1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.