Macrocyclic Peptides Block PD-L1 Interactions
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Solution Overview
Problem
Current treatments for cancer and infectious diseases, such as cancer and chronic infections, face challenges due to immune evasion mediated by the PD-1/PD-L1 and PD-L1/CD80 interactions, which inhibit immune responses and lead to T-cell exhaustion.
Innovation Solution
Development of macrocyclic compounds that inhibit the PD-1/PD-L1 and PD-L1/CD80 protein-protein interactions, enhancing immune responses by blocking these interactions, thereby stimulating immune activation and reducing T-cell exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to block PD-1/PD-L1 interactions, then immune response is enhanced, but treatment cost and administration complexity increase
Solution Approach 1:
The patent employs small molecule compounds instead of expensive monoclonal antibodies. These small molecules are cheaper to produce and administer while achieving the same therapeutic effect of blocking PD-1/PD-L1 interactions to enhance immune response against cancer and infectious diseases.
Solution Approach 2:
The invention changes the molecular parameters from large protein-based monoclonal antibodies to smaller small molecule compounds. This parameter change enables easier administration, reduced cost, and improved bioavailability while maintaining the ability to block immune checkpoint interactions.
2Reliability
If PD-1/PD-L1 pathway is blocked to restore T cell activity, then tumor rejection is achieved, but off-target immune suppression may occur
Solution Approach 1:
The small molecule compounds are designed to specifically target the PD-1/PD-L1 interaction interface with high local precision. By focusing the blocking action exactly where needed (the protein-protein interaction interface), the treatment achieves tumor rejection while minimizing off-target effects on other immune pathways.
Solution Approach 2:
The small molecule compounds act as intermediary molecules that bind to either PD-1 or PD-L1 and prevent their interaction. This intermediary approach allows controlled disruption of the immune checkpoint pathway without directly activating or suppressing broader immune responses, reducing off-target effects.
3Reliability
If existing PD-1 inhibitors are used, then T cell exhaustion is reduced, but resistance develops over time
Solution Approach 1:
The patent develops multiple distinct small molecule compounds with different molecular structures and binding modes. By segmenting the therapeutic approach into multiple mechanisms of action (different compounds targeting different aspects of the PD-1/PD-L1 pathway), the treatment can maintain effectiveness longer and reduce the development of resistance compared to single-agent therapy.
Solution Approach 2:
The invention employs composite therapeutic strategies using small molecule compounds that may be used in combination or sequence. This composite approach, analogous to using multiple drugs with different mechanisms, prevents tumor cells from developing resistance through single mutations and extends the duration of effective immune response.
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.