Beta-Sheet Peptides for Tight Junction Barrier Modulation
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Solution Overview
Problem
Current methods for transdermal delivery of therapeutic agents and vaccines face challenges due to the intact epithelial barrier, which requires high concentrations of peptides to disrupt tight junctions and lacks effective structural features for low-concentration disruption, and larger or hydrophilic molecules are excluded by the paracellular tight junction barriers.
Innovation Solution
Development of peptides with a self-assembled β-sheet secondary structure, specifically the amino acid sequence SSVSQSTGQIQSKVFDSLLNLSSTLQATR, that transiently disrupt claudin-1 within tight junctions, combined with surfactants like Pluronic® F-127, to facilitate transepithelial drug or vaccine delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high concentrations of peptides are used to disrupt tight junctions, then barrier disruption is achieved, but cytotoxicity and loss of barrier function occur
Solution Approach 1:
The patent modifies the peptide sequence parameters (amino acid composition, length, and structure) to create peptides that disrupt tight junctions at lower concentrations. Specifically, the peptides are designed with specific amino acid sequences that target claudin-1 without requiring high concentrations, thereby reducing cytotoxicity while maintaining barrier disruption effectiveness.
Solution Approach 2:
The patent employs peptides that are rapidly degraded or metabolized after performing their function. The peptides are designed to be transiently active, disrupting the barrier function temporarily to allow drug delivery, and then rapidly cleared from the system to minimize prolonged cytotoxic effects.
2Reliability
If conventional peptides are used to disrupt tight junctions, then some barrier disruption is achieved, but the peptides lack effective structural features for low-concentration disruption
Solution Approach 1:
The patent focuses the peptide disruption mechanism on a specific local target: claudin-1 protein within the tight junctions. By designing peptides that specifically bind to and disrupt claudin-1, the invention achieves localized barrier disruption at the tight junction level without requiring complex peptide structures or high concentrations throughout the entire system.
3Reliability
If the paracellular barrier is intact, then barrier function is maintained, but transdermal delivery of therapeutic agents is impeded
Solution Approach 1:
The patent employs a temporal sequence where the peptide is applied topically, rapidly disrupts the tight junction barrier to enable drug penetration, and then rapidly degraded or cleared. This periodic action allows the barrier to be temporarily opened for drug delivery and then restored, maintaining barrier integrity during storage and application while enabling efficient drug delivery during the brief disruption window.
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
The peptides effectively disrupt tight junctions at lower concentrations than previously reported, allowing for the transdermal delivery of molecules ranging from small compounds to therapeutic antibodies without cytotoxicity, and the barrier function recovers after peptide removal.
Implementation Method 1
The agent comprises a peptide including a self-assembled β-sheet secondary structure
Implementation Method 2
the peptide includes a self-assembled β-sheet secondary structure
Implementation Method 3
Transiently disrupt claudin-1 within tight junctions
Data Source
Figure 1A~1C
Figure 2A~3B
Figure 3C~3E
AI summary
According to aspects illustrated herein, there is provided an agent that transiently disrupts claudin-1 within tight junctions. The agent includes a peptide having at least 40% polar, uncharged amino acid residues and a self-assembled β-sheet secondary structure. According to aspects illustrated herein, there is also provided a transepithelial drug and vaccine formulations, as well as isolated peptides, pharmaceutical compositions, and transdermal delivery devices. Also described herein are methods of disrupting epithelial barrier and methods of administering the transepithelial formulations described herein.