Draxin Peptides Disrupt Netrin1 Receptor Binding
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Solution Overview
Problem
Current decoy Netrin receptor fragments used to disrupt Netrin/Netrin receptor interactions in cancer cells interfere late in the signaling cascade and fail to prevent residual binding of Netrin to full-length receptors, even at high concentrations.
Innovation Solution
Development of specific γ-Netrin-binding peptides and antibodies that bind with high affinity to Netrins, particularly Netrin1, to interfere with Netrin/Netrin receptor binding, and inhibit the binding of Draxin to Netrins, thereby disrupting the interaction and inducing pro-apoptotic signaling in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If decoy Netrin receptor fragments are used to disrupt Netrin/Netrin receptor interactions, then Netrin/Netrin receptor binding is interfered with, but residual binding of Netrin to full-length receptors cannot be prevented even at high concentrations
Solution Approach 1:
The patent introduces Draxin as an intermediary molecule that binds to Netrin1 with high affinity, acting as a mediator to sequester Netrin1 and prevent its interaction with Netrin receptors. This intermediary approach is more effective than using decoy receptor fragments because Draxin directly competes for Netrin1 binding at the source, rather than attempting to block receptor binding sites downstream.
Solution Approach 2:
The patent employs preliminary action by using Draxin to bind and sequester Netrin1 before it can interact with Netrin receptors. This preemptive binding approach prevents the formation of the Netrin1-receptor complex in the first place, rather than attempting to disrupt it after formation. The Draxin-Netrin1 complex is formed upstream in the signaling cascade, blocking Netrin1 availability to receptors.
2Reliability
If high concentrations of decoy receptor fragments are used, then Netrin/Netrin receptor binding is more effectively interfered with, but the complexity and dosage requirements increase
Solution Approach 1:
The patent changes the binding affinity parameter by utilizing Draxin's naturally high affinity for Netrin1 (KD in the low nM range). This high affinity allows Draxin to effectively compete for Netrin1 binding at physiological concentrations, eliminating the need for high dosages required by decoy receptor fragments. The parameter change from low to high binding affinity directly addresses the dosage issue.
3Ease of operation
If decoy Netrin receptor fragments are used, then the signaling cascade is interrupted at a late stage, but this results in less effective disruption compared to earlier intervention
Solution Approach 1:
The patent applies preliminary action by intervening at the earliest possible stage in the Netrin signaling cascade - the binding of Netrin1 to its receptor. By using Draxin to sequester Netrin1 before it reaches the receptor, the patent achieves maximum disruption effectiveness. This upstream intervention point is more effective than late-stage interference with decoy receptors, which only block signaling after the complex has already formed.
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 γ-Netrin-binding peptides and antibodies effectively compete with Netrin receptors for binding to Netrin1, significantly reducing Netrin receptor activation and inducing cancer cell death, offering a more effective approach than existing decoy receptor fragments.
Implementation Method 1
The γ-Netrin-binding peptides and antibodies effectively compete with Netrin receptors for binding to Netrin1, significantly reducing Netrin receptor activation
Implementation Method 2
an antibody against Draxin inhibiting binding of Draxin to γ-Netrins
Data Source
Figure 1A~1B
Figure 2A~2B
Figure 3
AI summary
This invention relates to extracellular protein-protein interactions and their possible therapeutic uses. More particularly, this invention describes the interaction between Draxin, particularly fragments binding to γ-Netrins comprising SEQ ID NO.: 1, 2 or 3, and variants thereof, with γ-Netrins, and the use of this interaction to disrupt γ-Netrin/Netrin receptor interactions. The invention also relates to diagnostic and/or therapeutic uses of Draxin or fragments or variants thereof, as well as to an antibody against Draxin inhibiting binding of Draxin to γ-Netrins. Further, the invention relates to fragments of γ-Netrins, in particular Draxin-binding Netrin1-fragments comprising SEQ ID NO.: 51 and variants thereof, as well as to an antibody against γ-Netrins inhibiting binding of γ-Netrins to Netrin receptors.