Macrocyclic Compounds Inhibiting 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 PD-L1/CD80 interactions, leading to immune evasion and suppression, which limits the efficacy of treatments for chronic infections and tumors.
Innovation Solution
Development of macrocyclic compounds that specifically bind to PD-L1, inhibiting its interaction with PD-1 and CD80, thereby enhancing immune responses and stimulating antigen-specific T cell functions.
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 PD-L1/CD80 interactions are not effectively inhibited, leading to immune evasion and suppression
Solution Approach 1:
The patent introduces macrocyclic compounds as intermediary substances that specifically bind to PD-L1, blocking its interaction with PD-1 and CD80. These compounds act as mediators that interfere with the harmful protein-protein interactions, preventing immune evasion without requiring direct modification of the immune cells or pathogens.
Solution Approach 2:
The invention changes the binding parameters of the PD-L1 protein by introducing macrocyclic compounds with specific molecular structures (formulas I and II) that have high affinity and selectivity for PD-L1. This alters the interaction dynamics between PD-L1 and its partners PD-1/CD80, effectively blocking the suppressive signaling pathway.
2Reliability
If macrocyclic compounds are developed to specifically bind to PD-L1, then inhibition of PD-1/PD-L1 and PD-L1/CD80 interactions is achieved, but this requires novel compound design and synthesis
Solution Approach 1:
The macrocyclic compounds are designed with segmented modular structures containing specific functional groups (amino acid side chains, peptide bonds, and macrocyclic rings) that can be independently optimized. This segmentation allows for systematic structure-activity relationship studies and facilitates synthetic planning by dividing the complex molecule into manageable building blocks.
Solution Approach 2:
The invention employs composite molecular structures combining natural amino acid side chains with unnatural modifications within a macrocyclic framework. This composite approach leverages the biological recognition capabilities of natural amino acids while incorporating synthetic elements to enhance stability, affinity, and selectivity for PD-L1 binding.
Data Source
AI summary
In accordance with the present disclosure, macrocyclic compounds have been discovered that bind to PD-L1 and are capable of inhibiting the interaction of PD-L1 with PD-1 and CD80. These macrocyclic compounds exhibit in vitro immunomodulatory efficacy thus making them therapeutic candidates for the treatment of various diseases including cancer and infectious diseases.