Macrocyclic Immunomodulators for Dual PD-L1/PD-1 and CD80/PD-L1 Blockade
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Solution Overview
Problem
The interaction between PD-L1 and PD-1 or CD80 leads to immune suppression and T cell exhaustion, which is a challenge in treating diseases like cancer and infectious diseases, as it reduces immune responses and promotes tumor evasion and chronic infections.
Innovation Solution
Development of macrocyclic compounds that inhibit the PD-L1/PD-1 and CD80/PD-L1 protein interactions, enhancing immune responses by blocking these interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-L1/PD-1 and CD80/PD-L1 interactions are blocked using macrocyclic compounds, then immune response is enhanced and T cell activation is restored, but the complexity of the therapeutic approach increases
Solution Approach 1:
The macrocyclic compounds combine multiple functional groups and amino acid residues within a single cyclic structure to simultaneously block both PD-L1/PD-1 and CD80/PD-L1 interactions. This merging of multiple binding functionalities into one compound achieves dual inhibition without requiring combination therapy, thereby enhancing immune response while managing therapeutic complexity.
Solution Approach 2:
The compounds are composed of composite structures incorporating natural amino acids, non-natural amino acids, and modified peptide backbones arranged in a macrocyclic framework. This composite design enables simultaneous engagement with multiple protein targets (PD-L1, PD-1, CD80) through different regions of the macrocycle, achieving multi-target inhibition with a single agent.
2Reliability
If monoclonal antibodies are used to block PD-L1/PD-1 interaction, then T cell activation is restored, but the treatment does not effectively block CD80/PD-L1 interaction
Solution Approach 1:
The macrocyclic compounds are designed with multiple binding interfaces that can simultaneously or sequentially interact with PD-L1, PD-1, and CD80. This multi-functional design allows a single compound to inhibit both PD-L1/PD-1 and CD80/PD-L1 interactions, providing universal blockade of multiple immune checkpoint pathways that monoclonal antibodies targeting a single epitope cannot achieve.
Solution Approach 2:
The macrocyclic structure is divided into distinct functional regions or domains, each capable of binding to different targets (PD-L1, PD-1, or CD80). This segmentation allows different portions of the macrocycle to engage different proteins independently, enabling simultaneous multi-target inhibition without requiring multiple separate antibody molecules.
Data Source
AI summary
In accordance with the present disclosure, 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.