Amphiphilic Peptides for Antimicrobial Activity

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Solution Overview

Problem

Current antimicrobial peptides face challenges such as high systemic toxicity, poor stability, and high manufacturing costs due to long peptide sequences, as well as the risk of triggering resistance and immunogenicity, limiting their clinical application in addressing antibiotic-resistant infections.

Innovation Solution

Development of short synthetic amphiphilic peptides with β-sheet folding structures, comprising hydrophobic and cationic amino acids, designed to self-assemble into β-sheet structures upon contact with microbial membranes, minimizing hemolysis and maximizing antimicrobial activity while being resistant to proteases and maintaining stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If long peptide sequences are used to enhance antimicrobial activity, then antimicrobial efficacy is improved, but manufacturing cost increases and stability decreases

Engineering Contradiction:

Improveantimicrobial efficacyVSAvoidmanufacturing cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The peptide sequence is divided into short repeating units of 4 amino acids ((X1Y1X2Y2)n where n≥1). This segmentation maintains antimicrobial activity while reducing the total length and manufacturing complexity compared to long peptide sequences (20+ amino acids), directly addressing the contradiction between efficacy and manufacturability

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention changes the parameter of peptide length from long (20+ amino acids) to short (repeating 4-amino acid units), and modifies the chemical structure by C-terminal amidation. These parameter changes reduce manufacturing cost and improve stability while preserving antimicrobial efficacy through optimized hydrophobic-cationic patterns

Inventive Principle:

Principle #35Parameter changes

2Reliability

If long peptide sequences are used to enhance antimicrobial activity, then antimicrobial efficacy is improved, but peptide stability decreases

Engineering Contradiction:

Improveantimicrobial efficacyVSAvoidpeptide stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

Segmenting the peptide into short repeating units (X1Y1X2Y2)n protects against proteolytic degradation by creating multiple potential cleavage sites while maintaining overall structure, thereby improving stability without sacrificing antimicrobial efficacy

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

C-terminal amidation and optimization of amino acid composition (hydrophobic X1, X2 and cationic Y1, Y2) enhance peptide stability by reducing susceptibility to proteases while maintaining the amphiphilic structure necessary for antimicrobial activity

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If peptide sequences similar to host defence peptides are used to maintain natural immunity function, then immune compatibility is improved, but resistance development is triggered

Engineering Contradiction:

Improveimmune compatibilityVSAvoidresistance development

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The peptide maintains local quality features (amphiphilic structure with hydrophobic and cationic regions) necessary for membrane disruption while using non-natural repeating patterns that differ from host defence peptides, achieving both immune compatibility and resistance prevention

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of using sequences similar to host defence peptides, the invention inverts the approach by using completely synthetic repeating units with optimized properties, thereby avoiding resistance triggers while maintaining the necessary membrane-active functionality

Inventive Principle:

Principle #13The other way round (Inversion)

4Ease of manufacture

If peptide length is reduced to lower manufacturing cost and improve stability, then manufacturability is improved, but antimicrobial activity may be compromised

Engineering Contradiction:

ImprovemanufacturabilityVSAvoidantimicrobial activity

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

Optimization of the repeating unit composition (hydrophobic X1, X2 and cationic Y1, Y2) and C-terminal amidation compensates for the reduced length, maintaining antimicrobial activity while enabling easier manufacturing and improved stability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The peptide combines hydrophobic and cationic amino acids in a specific repeating pattern to create an amphiphilic structure that achieves high antimicrobial activity despite short length, resolving the contradiction between manufacturability and efficacy

Inventive Principle:

Principle #40Composite materials

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 demonstrate broad-spectrum antimicrobial activity with high selectivity for microbial membranes, reducing the likelihood of resistance development and toxicity to mammalian cells, effectively killing bacteria, including those in biofilms, and neutralizing endotoxins without significant cytotoxicity.

Implementation Method 1

designed to self-assemble into β-sheet structures upon contact with microbial membranes

Methodology Applied

Scientific EffectSelf-assembly: Self-Assembly

Implementation Method 2

short synthetic amphiphilic peptides with β-sheet folding structures

Methodology Applied

Scientific Effectβ-sheet folding: Folding

Implementation Method 3

the majority of the cationic antimicrobial peptides exert their activities via physical disruption of the more negatively charged microbial membrane lipid bilayers

Methodology Applied

Scientific EffectElectrostatic interaction: Electrostatics

Implementation Method 4

X1 and X2 is independently of each other a hydrophobic amino acid; physical disruption of the more negatively charged microbial membrane lipid bilayers to induce leakage of cytoplasmic components

Methodology Applied

Scientific EffectHydrophobic interaction: Hydrophobe

Data Source

PatentUS9273096B2Amphiphilic peptides comprising the formula I: (X1Y1X2Y2)n, and uses thereof

Publication Date: 2016.03.01 AGENCY FOR SCI TECH & RES

AI summary

Disclosed are amphiphilic peptides. Also disclosed are methods of treating proliferative disease, bacterial infection, viral infection and fungal infection, endotoxin neutralization and a method of removing biofilm. Also disclosed is the use of the amphiphilic peptides.