SNAP-25 Polypeptide Constructs for Airway Mucus Dysfunction
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Solution Overview
Problem
Current therapeutic drugs for airway mucus plaques do not effectively target stimulated hypersecretion of mucin mediated by the interaction between Syt2 and SNAP-23.
Innovation Solution
Development of polypeptide constructs comprising a peptide from SNAP-25A or its variant attached to a cell penetrating peptide, forming a hydrocarbon-stapled peptide, and Syt2 expression inhibitors such as shRNAs, ASOs, siRNAs, or miRNAs to inhibit mucin hypersecretion and Ca2+-triggered membrane fusion processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic drugs are used to address mucin production and surface liquid production, then mucus plaques can be treated, but stimulated hypersecretion of mucin mediated by Syt2-SNAP-23 interaction cannot be targeted
Solution Approach 1:
The patent segments the mucin secretion pathway into distinct components (Syt2, SNAP-23, Ca2+) and targets specific interactions rather than treating mucin production as a single unified process. This allows selective inhibition of stimulated hypersecretion while preserving baseline secretion functions.
Solution Approach 2:
The patent introduces Ca2+ as a key intermediary that mediates the interaction between Syt2 and SNAP-23 during stimulated mucin secretion. By targeting Ca2+ channels and the Syt2-Ca2+-SNAP-23 complex, the invention specifically disrupts stimulated hypersecretion without affecting baseline secretion mechanisms.
2Productivity
If SNARE complex components are targeted to inhibit mucin secretion, then stimulated hypersecretion can be reduced, but baseline mucin secretion and other Ca2+-triggered membrane fusion processes may be affected
Solution Approach 1:
The patent applies local quality by targeting specific Ca2+-triggered fusion events in airway epithelial cells rather than broadly inhibiting all membrane fusion. The Syt2-Ca2+-SNAP-23 complex is selectively disrupted in the context of mucin-containing granule secretion, while other Ca2+-triggered fusion processes in different cell types remain unaffected.
Solution Approach 2:
The patent exploits the dynamic nature of Ca2+ signaling to distinguish between baseline and stimulated secretion. Ca2+ channels are activated only during stimulated secretion, creating a dynamic window of opportunity to selectively inhibit mucin hypersecretion without affecting constitutive baseline secretion mechanisms.
Data Source
AI summary
Polypeptide constructs comprising a first peptide attached to a cell penetrating peptide, wherein the first peptide has both homology to a portion of the SNARE protein SNAP-25 and non-natural amino acids comprising one or two macrocyclic crosslinks, are provided herein. These polypeptide constructs are useful for disrupting the primary interface between SNAP-25 or its homolog and Syt1 or its homolog. Methods for treating a subject with mucus hypersecretion-based airway obstruction and/or developed mucus occlusions are also described, as well as methods of inhibiting mucin secretion in an airway epithelial cell.