Macrocyclic Peptides Inhibit PD-1/PD-L1 Interaction
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Solution Overview
Problem
Current therapies for treating cancer and infectious diseases, such as cancer and chronic infections, are limited in their ability to effectively inhibit the interaction between PD-1 and PD-L1, leading to immune evasion by cancer cells and persistent infections.
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 potentially treating various diseases, including 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 treatment complexity and cost increase
Solution Approach 1:
The patent employs small molecule compounds instead of expensive monoclonal antibodies. These small molecules are less complex, more cost-effective, and can be administered as short-acting agents that achieve therapeutic effect without the complexity of antibody-based therapies.
Solution Approach 2:
The invention changes the molecular parameters from large protein-based antibodies to small molecule compounds. This parameter change reduces treatment complexity while maintaining the ability to block PD-1/PD-L1 interaction and enhance immune response.
2Reliability
If PD-L1 interaction with PD-1 is blocked, then T cell activation is restored, but cancer cells may develop resistance through alternative mechanisms
Solution Approach 1:
The small molecule compounds are designed to interact with multiple targets in the PD-1 pathway simultaneously. This multi-functionality approach prevents cancer cells from developing resistance through single mechanism evasion, as the compounds can block multiple interaction points.
Solution Approach 2:
The patent utilizes composite chemical structures that combine multiple pharmacophores capable of binding to different components of the PD-1/PD-L1 pathway. This composite approach creates a more robust immunomodulatory effect that is harder for cancer cells to resist.
3Device complexity
If small molecule compounds are used instead of antibodies, then treatment cost and complexity are reduced, but binding specificity and affinity may be limited
Solution Approach 1:
The small molecule compounds are designed with specific local chemical features and functional groups that target precise epitopes on PD-L1. This local quality optimization ensures high binding specificity despite the smaller overall molecular size compared to antibodies.
Solution Approach 2:
The invention optimizes molecular parameters such as hydrophobicity, hydrogen bonding capacity, and steric fit to enhance binding affinity. By carefully adjusting these parameters, the small molecules achieve specificity comparable to antibodies while maintaining treatment simplicity.
Data Source
AI summary
The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PDL1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.