Peptidic PKCζ Inhibitors for Transient Tight Junction Modulation
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Solution Overview
Problem
Current tight junction modulating agents for enhancing drug absorption suffer from a narrow therapeutic window, unspecific mode of action, and toxicity, leading to inefficacy in cancer treatment due to restricted drug penetration through tight junctions in epithelial cells, and hinder mucosal vaccine delivery by restricting passage of macromolecules.
Innovation Solution
Development of novel peptides that inhibit protein kinase C zeta (PKCζ) type, inducing transient redistribution of occludin and ZO-1, thereby causing a transient opening of tight junctions for enhanced tissue permeability, allowing larger therapeutic molecules to penetrate tissues, including cancer drugs and mucosal vaccines.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tight junction modulating agents are used to enhance drug absorption, then drug permeability is improved, but toxicity and narrow therapeutic window occur
Solution Approach 1:
The patent uses peptidic PKCζ inhibitors to specifically modulate tight junction permeability through a defined molecular mechanism, changing the physiological parameter of paracellular transport in a controlled manner that avoids the toxicity of non-specific TJ openers
Solution Approach 2:
The patent introduces PKCζ inhibition as an intermediary mechanism to achieve tight junction modulation. Rather than directly opening TJs, the peptides inhibit PKCζ activity, which indirectly and reversibly increases permeability, thereby reducing direct toxicity while maintaining therapeutic effect
2Reliability
If tight junction modulating agents are used to increase drug permeability, then absorption is enhanced, but irreversible opening of tight junctions occurs
Solution Approach 1:
The patent achieves transient and reversible tight junction opening through periodic or controlled administration of peptidic PKCζ inhibitors. The effect is temporary rather than permanent, allowing tight junctions to return to their original state, thus maintaining structural integrity while enhancing drug absorption during the treatment window
Solution Approach 2:
The patent temporarily changes the permeability parameter of tight junctions through reversible PKCζ inhibition, rather than causing permanent structural alteration. This controlled parameter change enhances absorption temporarily while preserving the stability and integrity of the tight junction structure
3Adaptability or versatility
If conventional PKC inhibitors are used, then broad PKC isoform inhibition occurs, but lack of selectivity leads to off-target effects
Solution Approach 1:
The patent applies local quality by designing peptidic inhibitors with specific sequences that selectively target PKCζ isoform. The pseudosubstrate region of the peptide is engineered to match the specific binding requirements of PKCζ, providing localized and selective inhibition without affecting other PKC isoforms, thereby avoiding off-target effects
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 significantly increase the efficacy of anti-cancer drugs by improving tissue penetration and enhance immune responses to mucosal vaccines, offering a safe and reversible method for transmucosal drug delivery, including nasal penetration of high molecular weight drugs.
Implementation Method 1
Peptidic protein kinase c inhibitors and uses thereof... novel peptides, which once inside a cell, act as inhibitors of protein kinase C zeta type (PKCζ), which unexpectedly induce a transient redistribution of occludin and ZO-1 inside the intracellular compartment and a transient opening of the tight junctions
Data Source
AI summary
The present invention relates to novel peptides, compositions and uses thereof useful in tissue permeabilization, in particular in the context of treatment of cancer prevention and/or treatment or induction of an immune response, in particular via mucosal vaccination.