CRY1 Secondary-Pocket Agents for Precise Circadian Resetting
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Solution Overview
Problem
Current methods to regulate circadian rhythms with drug-like molecules have not yielded viable candidates due to off-target effects, as they target proteins involved in multiple signaling pathways, and there is a need for agents that can rapidly and precisely reset the circadian clock to address disorders like shift-work sleep disorder and jet lag.
Innovation Solution
Development of agents that bind to the secondary pocket of CRY1 and inhibit interaction with the CLOCK PAS-B domain, disrupting the CRY1-CLOCK-BMAL1 ternary complex, allowing for precise control of circadian rhythms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current methods target proteins involved in multiple signaling pathways to regulate circadian rhythms, then circadian rhythm regulation is achieved, but off-target effects occur reducing reliability
Solution Approach 1:
The patent segments the circadian clock system by identifying and targeting a specific protein-protein interaction interface (CRY1-CLOCK) rather than the entire pathway. By focusing on the secondary pocket of CRY1 as a discrete target, the invention achieves specificity while avoiding off-target effects on other signaling pathways that share common circadian proteins.
Solution Approach 2:
The invention applies local quality by designing agents that bind specifically to the secondary pocket of CRY1, a localized structural feature. This targeted approach allows precise modulation of the CRY1-CLOCK interaction without affecting other functional domains of CRY1 or unrelated proteins, thereby improving reliability while minimizing harmful off-target effects.
2Measurement precision
If agents are designed to bind to the secondary pocket of CRY1 to disrupt CRY1-CLOCK-BMAL1 complex, then precision in resetting circadian clock is improved, but complexity of agent design increases
Solution Approach 1:
The patent extracts the critical functional element (secondary pocket of CRY1) from the complex CRY1-CLOCK-BMAL1 ternary complex. By isolating and targeting this specific binding pocket, the invention achieves precise circadian clock resetting without requiring complex multi-component agents, thereby improving precision while managing design complexity.
Solution Approach 2:
The secondary pocket of CRY1 serves as an intermediary target that mediates the disruption of the CRY1-CLOCK-BMAL1 complex. Agents designed to bind this pocket act as intermediaries that specifically interfere with clock protein interactions, achieving precise circadian modulation through a focused molecular mechanism rather than complex multi-target approaches.
3Speed
If CRY1-CLOCK-BMAL1 complex is disrupted to reset circadian rhythms, then rapid resetting capability is achieved, but stability of circadian complex formation is reduced
Solution Approach 1:
The patent applies preliminary anti-action by designing agents that preemptively bind to the secondary pocket of CRY1, preventing the formation or stabilizing the disruption of the CRY1-CLOCK-BMAL1 complex. This preemptive interference with protein-protein interactions enables rapid circadian clock resetting by blocking complex assembly before it can stabilize, thereby achieving speed while managing complex stability.
Data Source
AI summary
Provided are agents that disrupt CRY1-CLOCK-BMAL1 ternary complexes. In certain aspects, the agents bind to the secondary pocket of CRY1 and inhibit interaction between the secondary pocket and the PAS-B domain of CLOCK, to disrupt CRY1-CLOCK-BMAL1 ternary complexes. Also provided are methods for identifying such agents, compositions including such agents, and therapeutic methods employing such agents.