Cyclic CAL-PDZ Peptides for Mutant CFTR Stabilization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for cystic fibrosis, such as potentiators and correctors, fail to fully restore CFTR function due to increased susceptibility of mutant CFTR to lysosomal degradation, necessitating the development of therapeutic agents that protect CFTR from degradation.
Innovation Solution
Development of cyclic peptides comprising a cell-penetrating peptide sequence (cCPP) conjugated with a CAL-PDZ binding sequence, which synergistically improve binding to the CAL-PDZ domain and stabilize mutant CFTR at the plasma membrane, thereby inhibiting lysosomal degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If potentiators and correctors are used to improve chloride ion channel function, then CFTR function is partially restored, but mutant CFTR remains susceptible to lysosomal degradation
Solution Approach 1:
The patent introduces a cyclic peptide as an intermediary molecule that binds to the CAL-PDZ domain, preventing CFTR from interacting with this degradation pathway. The peptide acts as a mediator that blocks the harmful interaction between CFTR and the lysosomal degradation system, thereby stabilizing CFTR without directly modifying CFTR itself.
Solution Approach 2:
The cyclic peptide preemptively blocks the CAL-PDZ binding site before CFTR can be targeted for lysosomal degradation. By occupying this binding domain in advance, the peptide prevents the subsequent degradation process, providing preliminary protection against the harmful effect.
2Stability of the object's composition
If cyclic peptides with cCPP sequence are designed to protect CFTR from degradation, then CFTR stability is improved, but peptide design complexity increases
Solution Approach 1:
The patent combines two functional sequences into a single cyclic peptide structure: the cell-penetrating peptide (cCPP) sequence for cellular uptake and the CAL-PDZ binding sequence for stabilization. This merging allows the single molecule to perform multiple functions - entering cells and simultaneously protecting CFTR - thereby managing complexity through functional integration rather than separate components.
Solution Approach 2:
The cyclic peptide is designed with multi-functionality: it serves as both a cell delivery vehicle (via cCPP) and a stabilizing agent (via CAL-PDZ binding sequence). This universal design allows one molecule to fulfill multiple therapeutic roles, reducing the need for separate administration of multiple agents and simplifying the overall treatment approach despite the molecular complexity.
Data Source
AI summary
Described herein, in various embodiments, are peptides comprising: (i) a cyclic cell-penetrating peptide sequence (cCPP) and (ii) a CAL-PDZ binding sequence, which is conjugated, directly or indirectly, to an N-terminus of an amino acid in the cCPP, to a C-terminus of an amino acid on the cCPP, or on a side chain of an amino acid in the cCPP. In other embodiments, the peptides further comprise a physiologically cleavable group, wherein after entering the cell, the physiologically cleavable group is reduced, thereby providing a linear peptide. Without being bound by theory, the inventors discovered that the amino acid sequence in the cCPP, which facilities cytosolic delivery of the CAL-PDZ binding sequence also, surprisingly and unexpectedly, synergistically improves binding of CAL-PDZ binding sequence to the CAL-PDZ binding domain. Additionally, the cCPP sequence may also improve selectivity of the CAL-PDZ binding sequence for the CAL-PDZ domain relative to other PDZ binding domains.