CD95 Polypeptide Inhibits Cell Motility via Calcium Signaling

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Solution Overview

Problem

Current treatments fail to effectively inhibit CD95-mediated cell motility, which is implicated in cancer progression and autoimmune disorders, as existing therapies do not adequately target the calcium signaling pathways activated by CD95 ligand.

Innovation Solution

Development of a polypeptide with a sequence identity of at least 70% to the amino acid sequence from position 175 to 191 of the CD95 receptor, specifically designed to inhibit the calcium response mediated by CD95, thereby disrupting cell motility and sensitizing tumor cells to death.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing therapies are used to treat CD95-mediated cell motility, then treatment is provided, but the therapies do not adequately target calcium signaling pathways and fail to effectively inhibit cell motility

Engineering Contradiction:

Improveeffectiveness of therapyVSAvoidtargeting capability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention segments the CD95 receptor into functional domains, specifically targeting the intracellular region (amino acids 175-191) that mediates calcium signaling and cell motility. This segmentation allows selective inhibition of the motility pathway while preserving other CD95 functions such as apoptosis signaling.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces a peptide antagonist as an intermediary molecule that binds to the intracellular region of CD95, blocking the interaction between CD95 and downstream signaling components. This intermediary prevents the formation of the motility-inducing signaling complex without completely inhibiting CD95 ligand binding.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If polypeptide targeting CD95 intracellular region is developed, then cell motility is reduced and tumor cell sensitivity to death is enhanced, but manufacturing and production complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidpolypeptide production

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The invention extracts the critical functional sequence (amino acids 175-191) from the full CD95 receptor to create a focused peptide antagonist. This extracted sequence can be synthesized as a standalone peptide or small protein, simplifying production compared to generating full-length receptor constructs or complex antibody molecules.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent modifies the molecular parameters of the therapeutic agent by using a short peptide sequence instead of full-length proteins or antibodies. This parameter change reduces molecular weight, simplifies purification, and enables easier formulation while maintaining specific binding affinity to the CD95 intracellular region.

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If CD95-mediated calcium signaling is inhibited, then cell motility is reduced, but the mechanism complexity increases

Engineering Contradiction:

Improvecell motilityVSAvoidsignaling pathway complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The invention creates a simplified model of the CD95 intracellular region as a peptide copy that can be produced and characterized independently. This peptide copy (amino acids 175-191) reproduces the essential binding interface for calcium signaling components, allowing study and therapeutic application without requiring the full complexity of the native receptor.

Inventive Principle:

Principle #26Copying

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 polypeptide effectively reduces CD95-mediated cell motility and calcium signaling, offering a therapeutic approach for cancer and autoimmune diseases by enhancing the sensitivity of tumor cells to death and impairing their migratory capabilities.

Implementation Method 1

Binding of transmembrane CD95L to CD95 leads to the recruitment of the adaptor protein Fas-associated death domain protein (FADD) to the intracellular region of CD95 called the death domain (DD)

Methodology Applied

Scientific EffectProtein-protein interaction:

Implementation Method 2

CD95 engagement activates the phospholipase Cγ1 (PLCγ1), which in turn evokes a calcium response through activation of Ins3P Ins1,4,5 trisphosphate (IP3) receptor (IP3R)

Methodology Applied

Scientific EffectSignal transduction:

Implementation Method 3

multimerization of the plasma membrane calcium channel Orai1... this calcium signal is able to promote cell motility

Methodology Applied

Scientific EffectIon channel activity:

Data Source

PatentUS10189887B2Polypeptides and uses thereof for reducing CD95-mediated cell motility

Publication Date: 2019.01.29 ECOLE DES HAUTES ETUD & SANTE PUBLIQUE EHESP

AI summary

The present invention relates to polypeptides and uses thereof for reducing CD95-meditated cell motility. In particular, the present invention relates to a polypeptide having an amino acid sequence having at least 70% of identity with the amino acid sequence ranging from the amino-acid residue at position 175 to the amino-acid residue at position 191 in SEQ ID NO:1.