Bat ASC2 Inhibitors Target Adaptor Protein for Inflammasome Suppression
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Solution Overview
Problem
Current inflammasome inhibitors are limited in effectively targeting aberrant inflammasome activation, particularly due to a lack of specific therapies for ASC, which are critical for regulating multiple inflammasome pathways, and existing treatments often have off-target effects or are ineffective in suppressing extracellular ASC specks and other inflammatory factors.
Innovation Solution
Development of ASC antagonists derived from bat ASC2, which inhibit human/mouse inflammasome activation by targeting the adaptor protein ASC, providing a broad-spectrum inhibition of inflammasome-mediated inflammation through specific interaction with ASC and its partners, including NLRP3, AIM2, and pyrin inflammasomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IL-1β targeting therapies (antagonistic proteins or antibodies) are used, then IL-1β inhibition is achieved, but penetration of blood-brain barrier is poor and many other critical pro-inflammatory factors remain ineffective
Solution Approach 1:
The patent segments the inflammasome pathway into multiple components (sensor, adaptor ASC, effector caspase-1) and targets the adaptor ASC level, which controls multiple downstream effectors including IL-1β, IL-18, lipid mediators, and pyroptosis. This segmentation approach allows inhibition of multiple pro-inflammatory factors simultaneously rather than targeting only IL-1β
Solution Approach 2:
The ASC adaptor protein serves as a universal hub that links multiple sensor types (NLRP3, NLRP1, AIM2) to the effector caspase-1. By targeting ASC, the invention achieves multi-functional inhibition of various inflammasome pathways and pro-inflammatory factors, making the therapy applicable to different disease models with diverse inflammasome activations
2Reliability
If caspase-1 inhibitors are used, then inflammasome activity is reduced, but hepatotoxicity occurs and off-target effects on other caspases occur
Solution Approach 1:
The patent applies preliminary action by targeting the adaptor ASC before the effector caspase-1 is activated. By blocking ASC from recruiting caspase-1 to the inflammasome complex, the inhibition occurs upstream of caspase activation, preventing the harmful effects associated with direct caspase-1 inhibition while maintaining inflammasome suppression
Solution Approach 2:
The invention uses ASC as an intermediary target between the sensor and effector components. By blocking the ASC-caspase-1 interaction, the patent creates a selective inhibition point that avoids direct toxicity to liver cells and off-target effects on other caspases, while still achieving effective inflammasome inhibition
3Reliability
If NLRP3 inhibitors are used, then NLRP3-mediated inflammation is suppressed, but NLRP3 is not the predominant sensor in all inflammatory diseases and extracellular ASC speck activity remains unsuppressed
Solution Approach 1:
The ASC adaptor protein is a universal component that functions across multiple inflammasome sensor types (NLRP3, NLRP1, AIM2, IFI16). By targeting ASC, the invention achieves broad-spectrum inhibition that works regardless of which sensor is activated, making it applicable to diverse inflammatory diseases with different primary sensors
Solution Approach 2:
The patent targets ASC as an intermediary that mediates the function of all inflammasome sensors. By blocking ASC from oligomerizing and recruiting caspase-1, the inhibition works downstream of all sensor types, including NLRP3, NLRP1, and AIM2, while also blocking extracellular ASC speck activity that amplifies inflammation independently of sensor activation
Data Source
AI summary
The present disclosure provides ASC inhibitors, compositions comprising said ASC inhibitors, methods of identifying said ASC inhibitors, and therapeutic and prophylactic methods of using said ASC inhibitors.