SxIP Peptides Targeting EB Proteins for Neuroprotection

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Solution Overview

Problem

Current technologies lack effective solutions for promoting cell survival and inhibiting cell death, particularly in neuronal cells, and for enhancing synaptic plasticity, which are crucial for addressing neurodegenerative disorders and mental health conditions.

Innovation Solution

Development of novel peptides, such as those containing the core sequences SKIP, SGIP, SRIP, or NAPVSxIPQ, which interact with microtubule End Binding proteins like EB3, promoting cell survival, inhibiting apoptosis, and enhancing synaptic vitality.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional technologies are used for promoting cell survival and inhibiting cell death, then existing therapeutic options are limited, but effective treatment of neurodegenerative disorders and mental health conditions cannot be achieved

Engineering Contradiction:

Improvecell survival promotion efficacyVSAvoidtherapeutic applicability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent uses EB proteins as intermediary targets to mediate the effect of peptides on cell survival and synaptic plasticity. The peptides (containing SxIP motifs) bind to EB proteins, which then interact with microtubules and other cellular components to promote cell survival and inhibit apoptosis, providing a reliable and versatile therapeutic mechanism for treating neurodegenerative disorders and mental health conditions.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If peptides containing core sequences SKIP, SGIP, SRIP, or NAPVSxIPQ are developed to interact with EB proteins, then cell survival is promoted and apoptosis is inhibited, but the complexity of identifying and optimizing effective peptide sequences increases

Engineering Contradiction:

Improvecell protection efficacyVSAvoidpeptide sequence optimization complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the peptide structure into a conserved core sequence (SxIP motif: Ser-x-Ile-Pro) and variable flanking regions. This segmentation allows identification of the essential binding element (SxIP) that interacts with EB proteins, while allowing flexibility in the variable regions for optimizing stability and activity. This reduces the complexity of sequence optimization by focusing on the critical conserved segment.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent systematically varies parameters such as the x-position in the SxIP motif (allowing Ser-Gly-Ile-Pro, Ser-Lys-Ile-Pro, etc.), the length of flanking regions (up to 40 amino acids at N- and C-termini), and the presence of lipophilic moieties to optimize peptide efficacy, stability, and binding affinity while maintaining the core SxIP binding motif.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If current technologies are used for enhancing synaptic plasticity, then existing methods are insufficient, but effective treatment of synaptic disruption and death cannot be achieved

Engineering Contradiction:

Improvesynaptic plasticity enhancementVSAvoidsynaptic disruption and death

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs peptides that preemptively bind to EB proteins and stabilize microtubule dynamics before synaptic disruption occurs. The peptides promote cell survival and maintain synaptic integrity by modulating EB protein function in advance, preventing the harmful effects of synaptic disruption and death rather than treating them after they occur.

Inventive Principle:

Principle #10Preliminary action

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

These peptides effectively protect neuronal cells from toxic agents, promote synaptic plasticity, and offer therapeutic potential for neurodegenerative disorders and mental health conditions by modulating cell susceptibility to apoptosis and enhancing EB protein expression.

Implementation Method 1

EB1 was shown to interact with a conserved binding site in +TIPS—namely, SxIP

Methodology Applied

Scientific EffectProtein-protein binding:

Implementation Method 2

EB proteins mediate interactions between the ends of MTs, organelles, and protein complexes as well as altering MT stability

Methodology Applied

Scientific EffectMicrotubule-associated protein interaction:

Implementation Method 3

EB3 is associated with cellular differentiation, and it may form a dimer with EB1 and act also in neuroprotection

Methodology Applied

Scientific EffectCell protection mechanism:

Data Source

PatentUS10822375B2Method for identifying a modulator of cell survival or plasticity

Publication Date: 2020.11.03 RAMOT AT TEL AVIV UNIVERSITY LTD

AI summary

This invention provides novel compounds and methods for promoting cell survival and/or plasticity, especially in neuronal cells, by targeting the microtubule End Binding (EB) proteins and other associated proteins (e.g., drebrin). Methods for identifying potential modulators of cell death/plasticity are also described.