Macrocyclic Peptides Inhibit PD-1/PD-L1 Interactions
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Solution Overview
Problem
Current therapies for cancer and infectious diseases, such as cancer immunotherapy using PD-1/PD-L1 blockade, face limitations in effectively inhibiting the PD-1/PD-L1 and PD-1/CD80 protein-protein interactions, which are crucial for immune evasion and exhaustion, particularly in chronic infections and tumors.
Innovation Solution
Development of novel macrocyclic peptides that specifically inhibit the interaction between PD-L1 and PD-1 or CD80, enhancing T cell functional activity and immune response by blocking these interactions, thereby offering therapeutic potential for cancer and infectious diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to block PD-1/PD-L1 interaction, then immune response is enhanced, but therapy cost and complexity increase
Solution Approach 1:
The patent employs small molecule compounds instead of expensive monoclonal antibodies to block PD-1/PD-L1 interaction. These small molecules are cheaper to produce and administer, providing a cost-effective alternative while maintaining therapeutic efficacy in enhancing immune response against tumors and chronic infections.
Solution Approach 2:
The invention changes the molecular parameters by using small molecule compounds with specific chemical structures (as defined in the patent's formula I) rather than large protein-based antibodies. This parameter change enables simpler administration and reduced manufacturing complexity while achieving the desired immunomodulatory effect.
2Reliability
If PD-1/PD-L1 blockade is used to treat cancer, then tumor growth is inhibited, but immune evasion mechanisms may develop resistance
Solution Approach 1:
The patent uses small molecule compounds as intermediaries that bind to PD-1 or PD-L1 to prevent their interaction. These small molecules act as mediators that can be optimized for better penetration and sustained binding, providing a different mechanism of action compared to antibodies and potentially overcoming resistance developed against antibody-based therapies.
3Reliability
If macrocyclic peptides are designed to inhibit PD-L1/CD80 interaction, then T cell functional activity is enhanced, but molecular design complexity increases
Solution Approach 1:
The patent segments the complex immunomodulatory function into specific molecular interactions by designing macrocyclic peptides that target either PD-1/PD-L1 or PD-L1/CD80 interactions separately. This segmentation allows for optimized design of each peptide's binding specificity while maintaining overall therapeutic effectiveness through enhanced T cell functional activity.
Solution Approach 2:
The invention employs macrocyclic peptides with composite molecular structures combining specific amino acid sequences and cyclic conformations. These composite structures provide both stability and specific binding affinity for their targets, achieving enhanced T cell functional activity while the macrocyclic framework simplifies the overall molecular design compared to linear peptides or protein-based therapeutics.
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.