Modified eIF4G1 Peptide Stabilizes Alpha-Helix for High-Affinity eIF4E Binding

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Solution Overview

Problem

Current therapies lack effective, targeted approaches to inhibit the eIF4E:7-methylguanosine cap interaction, which is elevated in various cancers and associated with disease progression, and there is a need for specific small molecule inhibitors or alternative methods to disrupt the eIF4E-eIF4G interaction to treat cancer and potentially autism.

Innovation Solution

Development of a modified eIF4G1 peptide that stabilizes the α-helix structure, enhancing its binding affinity to eIF4E, and its use in pharmaceutical compositions or methods for treating cancer and autism by administering a pharmaceutically effective amount to inhibit eIF4E activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional eIF4G1 peptide is used to inhibit eIF4E, then the eIF4E-eIF4G interaction is disrupted, but the binding affinity is insufficient for effective therapeutic inhibition

Engineering Contradiction:

Improvebinding affinityVSAvoidpeptide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The peptide sequence is modified by substituting specific amino acid residues (e.g., position 631 with Aib, position 628 with Cα-methyl-L-phenylalanine) to enhance α-helix stability and binding affinity to eIF4E, transforming the conventional peptide into a high-affinity inhibitor

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The peptide incorporates non-natural amino acids including Aib (α-aminoisobutyric acid) and Cα-methylated phenylalanine residues alongside natural amino acids, creating a composite structure that combines the benefits of natural peptide recognition with enhanced structural stability and helix formation

Inventive Principle:

Principle #40Composite materials

2Productivity

If eIF4E expression is elevated in cancer to promote weak mRNA translation, then cell growth and survival are enhanced, but targeted inhibition is lacking

Engineering Contradiction:

Improvetranslation efficiencyVSAvoidcancer progression

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The invention extracts and targets the specific eIF4E-eIF4G interaction interface, using a modified eIF4G1 peptide that selectively disrupts this interaction to inhibit cap-dependent translation of weak mRNAs involved in cancer progression, without affecting strong mRNA translation

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The modified eIF4G1 peptide acts as an intermediary that competes with endogenous eIF4E for binding to the peptide, thereby disrupting the eIF4E-eIF4G interaction and inhibiting the translation initiation complex formation that drives cancer cell growth

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS9533023B2EIF4E binding peptides

Publication Date: 2017.01.03 AGENCY FOR SCI TECH & RES

AI summary

The present invention relates to modified eIF4G1 peptides, uses thereof and pharmaceutical compositions comprising the modified eIF4G1 peptides.