REST Phosphomimetic Peptides Targeting CTDSP1 for Gene Derepression

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Solution Overview

Problem

Current methods fail to effectively target and regulate the RE1 silencing transcription factor (REST) for treating conditions such as traumatic brain injury, epilepsy, dementia, Huntington's Disease, chronic pain, brain cancer, diabetes, and peripheral nerve injury, as they do not adequately address the transcriptional and post-transcriptional regulation of REST, which is crucial for neuronal differentiation and gene expression.

Innovation Solution

Development of peptides with high affinity to C-terminal domain small phosphatase 1 (CTDSP1) to inhibit REST activity, using REST phosphomimetic peptides that bind to CTDSP1, enhance intracellular transport, and promote the degradation or expression of REST target genes, thereby increasing the expression of BDNF and other neural genes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current methods are used to target REST, then treatment of REST-related conditions is attempted, but the methods fail to effectively regulate REST due to inadequate address of transcriptional and post-transcriptional regulation

Engineering Contradiction:

Improveeffectiveness of REST regulationVSAvoidcomplexity of regulation mechanism

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention segments the regulation of REST into two distinct components: transcriptional regulation (controlling REST gene expression) and post-transcriptional regulation (controlling REST protein stability through CTDSP1-mediated dephosphorylation). By targeting both segments independently with different molecular agents, the patent achieves comprehensive and effective REST regulation that overcomes the limitations of previous single-mechanism approaches.

Inventive Principle:

Principle #1Segmentation

2Reliability

If peptides with high affinity to CTDSP1 are developed, then REST activity is inhibited and neural gene expression is increased, but the complexity of peptide design and synthesis increases

Engineering Contradiction:

Improveinhibition of REST activityVSAvoidease of peptide synthesis

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs parameter changes in peptide design by systematically varying amino acid sequences to optimize CTDSP1 binding affinity. Specific modifications include incorporating phosphomimetic residues (glutamate or aspartate at positions corresponding to phosphorylated serines), adjusting peptide length, and modifying flanking regions to enhance stability and affinity. These parameter optimizations enable effective REST inhibition while maintaining feasibility of synthesis.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If REST protein levels are reduced through peptide treatment, then neuronal differentiation is promoted, but the stability and half-life of the therapeutic peptide may be compromised

Engineering Contradiction:

Improvepromotion of neuronal differentiationVSAvoidhalf-life of therapeutic peptide

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The invention extracts the critical functional elements required for CTDSP1 binding and REST inhibition from the full-length REST protein sequence. By isolating and synthesizing only the essential phosphomimetic peptide region that interacts with CTDSP1, the patent creates a minimized therapeutic agent that maintains high binding affinity and effectiveness while improving pharmacokinetic properties including stability and half-life compared to larger protein constructs.

Inventive Principle:

Principle #2Taking out (Extraction)

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 peptides effectively reduce REST protein levels, increase expression of neural genes, and promote neuronal differentiation, offering therapeutic potential for conditions associated with REST dysregulation, including traumatic brain injury, chronic pain, and brain cancer.

Implementation Method 1

REST phosphomimetic peptides, TEDLEPPEPPLPKEN (SEQ ID NO: 1), EDLEPPEPPLPK (SEQ. ID NO: 15), nekplppeppeldet (SEQ ID NO: 16) and kplppeppelde (SEQ ID NO: 17), which bind CTDSP1 to inhibit REST activity

Methodology Applied

Scientific EffectProtein-protein binding:

Implementation Method 2

The lowercase letters represent D-amino acids, which are resistant to degradation and therefore increase peptide half-life, without compromising binding affinity

Methodology Applied

Scientific EffectProteolytic resistance:

Implementation Method 3

enhance intracellular transport, and promote the degradation or expression of REST target genes

Methodology Applied

Scientific EffectIntracellular transport:

Data Source

PatentUS20250206790A1Compositions and methods for derepressing re1 silencing transcription factor target genes

Publication Date: 2025.06.26 ALCAMENA STEM CELL THERAPEUTICS LLC

AI summary

The invention relates to compounds, compositions, and methods for derepressing RE1 silencing transcription factor (REST) target genes are provided. In particular, a peptide having the sequence TEDLEPPEPPLPKEN (SEQ. ID NO: 1) and EDLEPPEPPLPK (SEQ. ID NO: 15), or the reversed sequences made of D-amino acids (retro inverted, RI) nekplppeppeldet (SEQ ID NO: 16) and kplppeppelde (SEQ ID NO: 17), are disclosed for inhibiting REST activity. The peptides are useful to treat, prevent, or ameliorate conditions such as traumatic brain injury, epilepsy, dementia, Huntington's Disease (HD), chronic pain, brain cancer (including glioblastoma multiforme), pancreatic cancer; diabetes, and peripheral nerve injury.