Isolated Polypeptides Inhibit Wnt Signaling to Treat CDI
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Solution Overview
Problem
Current treatments for Clostridium difficile infections (CDI) are ineffective and have a high recurrence rate due to the lack of targeted therapies, with Clostridium difficile toxin B (TcdB) being a critical virulence factor that inhibits Wnt signaling by binding to Frizzled receptors, leading to epithelial damage and disease progression.
Innovation Solution
Development of isolated polypeptides and fusion proteins with specific amino acid sequences that mimic the TcdB binding domain, competing with TcdB for Frizzled receptor binding, thereby inhibiting Wnt signaling and blocking toxin entry into cells, including recombinant FZD2-CRD fragments and fusion proteins with an Fc portion of human IgG1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotics are used to treat CDI, then bacterial infection is targeted, but treatment effectiveness is low and recurrence rate is high
Solution Approach 1:
The patent converts the harmful mechanism of TcdB (inhibiting Wnt signaling by binding to Frizzled receptors) into a beneficial therapeutic approach. By developing polypeptides that mimic the TcdB binding domain, the invention uses the toxin's own mechanism against it, allowing these polypeptides to compete for Frizzled receptor binding and block toxin entry into cells, thereby treating CDI with high effectiveness and reducing recurrence
Solution Approach 2:
The patent introduces isolated polypeptides and fusion proteins as intermediary substances that mediate between the toxin and the Frizzled receptors. These polypeptides contain amino acid sequences (SEQ ID NO: 18, 19, or 20) that bind to Frizzled receptors, preventing TcdB from binding and thereby blocking the harmful signaling pathway without requiring direct elimination of the bacteria
2Ease of operation
If TcdB binds to Frizzled receptors, then toxin entry into cells is enabled, but Wnt signaling is inhibited causing epithelial damage
Solution Approach 1:
The patent applies preliminary anti-action by introducing polypeptides that pre-bind to Frizzled receptors before TcdB can attach. These polypeptides with sequences SEQ ID NO: 18, 19, or 20 are designed to compete for the same binding site on Frizzled receptors, thereby preventing toxin entry into cells and blocking the subsequent inhibition of Wnt signaling that causes epithelial damage
Solution Approach 2:
The patent creates simplified copies of the TcdB binding domain through isolated polypeptides containing specific amino acid sequences (SEQ ID NO: 18, 19, or 20). These polypeptide copies mimic the toxin's binding capabilities but lack its harmful enzymatic functions, allowing them to bind Frizzled receptors and block TcdB entry without causing epithelial damage
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 proposed solution significantly reduces TcdB entry into cells, offering a therapeutic approach to treat CDI by blocking Wnt signaling and potentially addressing the high recurrence rates of the infection.
Implementation Method 1
TcdB competes with Wnt for binding to the conserved cysteine-rich domain (CRD) in FZDs... A recombinant FZD2-CRD fragment protected cells from TcdB... Triple FZD1/2/7 knockout (KO) cells were dramatically resistant to toxin entry
Data Source
AI summary
The present disclosure relates to isolated polypeptides that inhibit Wnt signaling, pharmaceutical compositions comprising the isolated polypeptides, and methods of use thereof. Nucleic acids, cells, and methods of production related to the isolated polypeptides and compositions are also disclosed.