Stapled Peptides Disrupt WASF3 Complex to Suppress Cancer Metastasis

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Solution Overview

Problem

Current therapies lack effective methods to specifically target and inhibit the metastasis-promoting WASF3 protein, which is crucial for cancer cell invasion and metastasis, particularly in breast and prostate cancers.

Innovation Solution

Development of stapled peptides that mimic alpha-helical structures to inhibit the protein-protein interactions between WASF3 and its interacting proteins CYFIP1 and NCKAP1, disrupting the stability and activation of WASF3, thereby suppressing cancer cell invasion and metastasis without affecting cellular proliferation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If stapled peptides are designed to target the WASF3-CYFIP1 or CYFIP1-NCKAP1 protein-protein interfaces, then the binding of CYFIP1 to WASF3 or NCKAP1 is inhibited, leading to suppression of invasion and metastasis, but the complexity of the therapeutic approach increases due to the need for specialized peptide design and delivery

Engineering Contradiction:

Improvesuppression of invasion and metastasisVSAvoidpeptide design and delivery complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs stapled peptides as intermediary molecules that bind to the protein-protein interfaces of WASF3-CYFIP1 or CYFIP1-NCKAP1 complexes. These peptides act as mediators to disrupt the stabilizing interactions between these proteins, leading to WASF3 degradation and suppression of metastasis without requiring direct genetic manipulation or complex small molecule designs

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention utilizes chemical modification of peptide backbones through stapling to alter the physical and chemical parameters of the peptides. This includes changing the conformational stability, cellular permeability, and binding affinity of the peptides to their target protein interfaces, thereby optimizing their therapeutic efficacy while managing delivery complexity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If stapled peptides are used to disrupt WASF3 stability by targeting its interaction with CYFIP1 and NCKAP1, then WASF3 protein levels are reduced and invasion is suppressed, but the manufacturing complexity increases due to the need for precise peptide synthesis and stabilization

Engineering Contradiction:

Improvereduction of WASF3 protein levelsVSAvoidpeptide synthesis complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies chemical stapling to peptide backbones to modify their physical parameters, including increased conformational stability and resistance to proteolytic degradation. This chemical modification approach simplifies manufacturing by improving peptide half-life and reducing the need for continuous synthesis, while maintaining specific binding to target protein interfaces

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention utilizes relatively simple peptide sequences that can be synthesized using standard solid-phase peptide synthesis methods. The stapled peptides are designed to be sufficiently stable for therapeutic use but can be easily replaced through repeated administration, avoiding the need for complex manufacturing processes required for more stable protein-based therapies

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 stapled peptides effectively reduce WASF3 protein levels and activity, leading to significant suppression of cancer cell invasion and metastasis, as demonstrated by reduced invasion potential and phosphoactivation of WASF3 in breast and prostate cancer cells, without impacting cell proliferation.

Implementation Method 1

these proteins interact via large, elongated binding surface that is largely mediated by alpha-helical structures

Methodology Applied

Scientific EffectProtein-protein interaction:

Implementation Method 2

stapled peptides that target the protein-protein interface (PPI) between WASF3 and CYFIP1, or CYFIP1 and NCKAP1

Methodology Applied

Scientific EffectAlpha-helical structure mimicry:

Implementation Method 3

disrupting the stability and activation of WASF3, thereby suppressing cancer cell invasion and metastasis

Methodology Applied

Scientific EffectProtein complex disruption:

Data Source

PatentEP3280431B1Disruption of the wave3 protein complex for suppression of invasion and metastasis

Publication Date: 2023.11.08 UNIVERSITY OF GEORGIA RESEARCH FOUNDATION INC

Figure 1A~1D
Figure 2A~2B
Figure 2C

AI summary

As disclosed herein, stapled peptides targeting the interaction interface between proteins that maintain the integrity of Wiskott-Aldrich syndrome protein family member 3 (WASF3) leads to destabilization of WASF3 and suppression of invasion. Disclosed are stapled peptides that inhibit the binding of Cytoplasmic FMR1-interacting protein 1 (CYFIP1) to either WASF3 or NCK-associated protein (NCKAP1). Also disclosed are methods for treating or suppressing invasion and metastasis of a cancer in a subject that involve administering to the subject a therapeutically effective amount of a stapled peptide disclosed herein.