Photoactivatable Gasdermin Linker for Reversible Pore Control
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Solution Overview
Problem
Current understanding of gasdermin-mediated pyroptosis is limited by the irreversible nature of gasdermin pores and the lack of control over their dynamic conformations and interaction with cell signaling, which complicates their regulation and therapeutic applications.
Innovation Solution
A modified gasdermin protein with a photoactivatable linker inserted between the N-terminal and C-terminal domains, allowing for controlled pore formation through illumination, enabling modulation of pore size and dynamics without cell death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If gasdermin pores are formed to enable therapeutic agent transport, then cell permeability is improved, but cell lysis and loss of homeostasis occur
Solution Approach 1:
The patent introduces a photoactivatable linker that enables dynamic control of gasdermin pore formation. The linker remains intact in the dark, preventing pore formation and maintaining cell homeostasis. Upon light activation, the linker undergoes conformational change or cleavage, enabling controlled pore formation for therapeutic agent transport. This dynamic switching mechanism resolves the contradiction by making pore formation reversible and controllable rather than permanent and uncontrolled.
Solution Approach 2:
The patent utilizes light wavelength as a controllable parameter to regulate gasdermin activity. By changing the illumination parameter (light exposure), the gasdermin protein transitions between inactive and active states, controlling pore formation on demand. This parameter-based control allows therapeutic agent transport when needed while preventing cell lysis when light is not applied.
2Productivity
If gasdermin pores are made large to facilitate agent transport, then transport efficiency is improved, but cell homeostasis damage increases
Solution Approach 1:
The photoactivatable linker enables dynamic modulation of pore size and duration. By controlling light exposure time and intensity, the pore dimensions can be adjusted to match the size requirements of therapeutic agents while limiting excessive damage. The reversible nature allows pores to close after transport, restoring homeostasis.
3Ease of operation
If gasdermin activation is made irreversible to ensure cell death, then therapeutic efficacy is improved, but control over timing and location is lost
Solution Approach 1:
The patent transforms the irreversible cell death process into a reversible, dynamically controllable system. The photoactivatable linker allows researchers to control exactly when and where gasdermin pores form by applying light at specific times and locations. The process can be reversed by removing light, allowing cells to recover if desired, thus providing precise spatiotemporal control while maintaining therapeutic reliability through controlled activation.
Solution Approach 2:
The gasdermin protein with the photoactivatable linker is pre-installed in cells before therapy. The system is prepared in an inactive state, and activation occurs only when light is applied at the desired time and location. This preliminary preparation enables precise control over when the therapeutic effect is triggered.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach allows for precise control over gasdermin pore formation, facilitating therapeutic agent transport and treatment of diseases by modulating pore size and dynamics, and demonstrating reversible optogenetic activation, enhancing therapeutic efficacy and safety.
Implementation Method 1
a photoactivatable linker inserted between the N-terminal domain and C-terminal domain of a gasdermin protein... wherein the photoactivatable linker dimerizes or dissociates upon illumination
Implementation Method 2
the photoactivatable linker is a photocleavable protein that dissociates into at least two fragments or releases one end of a loop insertion upon illumination
Data Source
AI summary
This invention relates to a modified gasdermin protein having a photoactivatable linker inserted between the C-terminal domain and N-terminal domain a gasdermin protein, nucleic acids and vectors encoding the modified gasdermin protein, and methods of using the modified gasdermin protein to introduce agents into cells and facilitate the treatment of diseases or conditions.