Cyclic Cell-Penetrating Peptides for Cytosolic Cargo Delivery

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Solution Overview

Problem

Traversing the plasma membrane presents a significant challenge for delivering biologics such as peptides, proteins, and nucleic acids into cells, with endosomal membranes acting as a barrier to cytoplasmic delivery by cell-penetrating peptides (CPPs).

Innovation Solution

Development of cyclic peptides comprising at least two arginines and either one non-aromatic hydrophobic or one hydrophobic side chain, which can efficiently deliver agents into various cell types by overcoming the endosomal membrane barrier.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CPPs use hydrophobic aromatic side chains to penetrate plasma membranes, then cellular uptake is achieved, but endosomal membrane barrier prevents cytoplasmic delivery

Engineering Contradiction:

Improvecytoplasmic delivery efficiencyVSAvoidendosomal membrane barrier

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical parameters of the peptide by replacing hydrophobic aromatic side chains with non-aromatic hydrophobic side chains and incorporating cyclic structures. This parameter change allows the peptide to overcome the endosomal membrane barrier while maintaining plasma membrane penetration capability, achieving reliable cytoplasmic delivery.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite peptide structures combining multiple functional elements: arginine residues for charge interaction, non-aromatic hydrophobic side chains for membrane interaction, and cyclic configurations for structural stability. This composite approach enables simultaneous penetration of plasma membrane and endosomal membrane barriers.

Inventive Principle:

Principle #40Composite materials

2Productivity

If CPPs rely on hydrophobic aromatic side chains for membrane penetration, then plasma membrane traversal is achieved, but cytosolic delivery is blocked by endosomal barrier

Engineering Contradiction:

Improvecellular uptake efficiencyVSAvoidcytosol access

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent modifies the hydrophobicity parameters by substituting aromatic side chains with non-aromatic hydrophobic side chains. This parameter change maintains membrane penetration efficiency while enabling escape from endosomal vesicles, achieving reliable cytosolic access and improved productivity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Instead of using the conventional hydrophobic aromatic side chains that get trapped in endosomes, the patent inverts the approach by using non-aromatic hydrophobic side chains that facilitate endosomal escape. This inversion enables the peptide to achieve both plasma membrane penetration and cytosolic delivery.

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If cyclic peptides are designed with specific amino acid compositions, then cytosolic delivery is enhanced, but peptide structure complexity increases

Engineering Contradiction:

Improvecytosolic delivery efficiencyVSAvoidpeptide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies local quality by concentrating specific functional amino acid residues (arginine, non-aromatic hydrophobic side chains) at critical positions within the cyclic structure. This localized optimization achieves enhanced cytosolic delivery without requiring complex peptide sequences throughout the entire structure.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent optimizes peptide structure by changing compositional parameters - specifically the ratio and arrangement of arginine residues, non-aromatic hydrophobic side chains, and cyclic configurations. These parameter changes enhance delivery efficiency while maintaining manageable structural complexity through systematic design.

Inventive Principle:

Principle #35Parameter changes

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 cyclic peptides achieve high cytosolic delivery efficiency, surpassing previous CPPs by effectively entering the cytosol without relying on hydrophobic aromatic side chains, thus enhancing cellular uptake.

Implementation Method 1

at least one of the amino acids is an amino acid having a non-aromatic hydrophobic side chain

Methodology Applied

Scientific EffectHydrophobic interaction: Hydrophobe

Implementation Method 2

One potential strategy to subvert the membrane barrier and deliver the biologics into cells is to attach them to 'cell-penetrating peptides (CPPs)'

Methodology Applied

Scientific EffectCell-penetrating peptide mechanism:

Data Source

PatentUS20260001916A1Cyclic cell-penetrating peptide compounds

Publication Date: 2026.01.01 OHIO STATE INNOVATION FOUND

AI summary

Disclosed are cell penetrating peptides and compositions comprising such peptides that can be used to deliver agents to various cell types.