Peptide Inhibitor Targeting TRPM2 Channel for Stroke Treatment
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Solution Overview
Problem
Current treatments for stroke and neurological injuries lack effective inhibitors for TRPM2 ion channels, which are implicated in ischemic neuronal damage, with existing inhibitors being non-specific and not effective in females.
Innovation Solution
Development of specific peptide inhibitors, such as tat-M2NX, that target the ADPribose binding pocket of TRPM2 channels, inhibiting channel activity and reducing neuronal damage in both males and females.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-specific TRPM2 inhibitors such as clotrimazole are used, then neuronal death is reduced in male animals, but the inhibitors lack specificity and are not effective in female animals
Solution Approach 1:
The peptide inhibitor is designed to specifically target the ADP-ribose binding pocket within the NUDT9-H domain of TRPM2 channels. By focusing inhibition at this specific local site rather than using non-specific inhibitors, the patent achieves both high reliability in reducing neuronal death and improved adaptability across different genders through precise molecular recognition
Solution Approach 2:
The invention changes the molecular parameters of TRPM2 inhibition by using a peptide sequence (GSREPGEMLPRKLKRVLRQEFWV) that specifically binds to the ADP-ribose binding pocket. This parameter change from non-specific inhibition to specific pocket binding enables the inhibitor to work effectively in both male and female animals, resolving the gender-specific efficacy problem
2Object-affected harmful factors
If TRPM2 channels are inhibited to reduce infarct size, then neurological damage is reduced, but lack of specific inhibitors limits therapeutic potential
Solution Approach 1:
The patent introduces a peptide intermediary (tat-M2NX) that mediates inhibition of TRPM2 channels by binding to the ADP-ribose binding pocket. This specific intermediary molecule serves as a therapeutic agent that reduces ischemic neuronal damage while being manufacturable through peptide synthesis, resolving the limitation of lacking specific inhibitors
Solution Approach 2:
The peptide inhibitor is designed to copy or mimic the binding interaction of ADP-ribose with the TRPM2 channel, but in an inhibitory manner. By creating a peptide copy that interacts with the same binding pocket, the invention enables specific inhibition that can be synthesized and manufactured, overcoming the limitation of unavailable specific inhibitors
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
tat-M2NX effectively reduces infarct volume and improves functional recovery in stroke, traumatic brain injury, and neurodegenerative diseases, demonstrating a broader therapeutic window and gender-neutral efficacy.
Implementation Method 1
TRPM2 channels are non-selective cation channels activated by ADP ribose (ADPr). The inventors targeted the ADP-ribose binding pocket as a strategy to inhibit TRPM2 channel activation.
Implementation Method 2
The inventors generated peptides, including GSREPGEMLPRKLKRVLRQEFWV (SEQ ID NO: 1; 'M2NX'), fused to the cell permeable TAT sequence, YGRKKRRQRRR (SEQ ID NO:2; 'tat 47-57') to form the 34-mer, YGRKKRRQRRRGSREPGEMLPRKLKRVLRQEFWV (SEQ ID NO:3; 'tat-M2NX'), which specifically inhibits TRPM2 channel activity via interaction with the ADP-ribose binding pocket of the NUDT9-H domain of the channel.
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 2A~3B
AI summary
Methods for treating and preventing neurodegenerative disease, neurological injury, including stroke, via administration of Transient receptor potential M2 (TRPM2)- inhibitors. The inhibitors may be administered in conjunction with another therapeutic agent or therapeutic regimen. The peptides may be administered to a human male. The peptides may be administered within eight hours of a neurological injury, such as a stroke.