PROTAC Protein Intracellular Delivery via Cell-Penetrating Peptide

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Solution Overview

Problem

Conventional PROTAC technologies face challenges with low solubility and decreased intracellular penetration, leading to reduced efficiency in degrading target proteins within cells, necessitating the development of a PROTAC protein with enhanced delivery and degradation capabilities.

Innovation Solution

A PROTAC protein structure comprising a target protein binding sequence linked via a glycine linker to a von Hippel-Lindau protein sequence, combined with a cell-penetrating peptide or antibody, facilitates efficient intracellular delivery and degradation of target proteins by binding to a ubiquitin ligase, overcoming solubility and penetration issues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small-molecule PROTAC compounds are used, then structural binding to target protein and E3 ligase is achieved, but intracellular penetration and solubility are reduced

Engineering Contradiction:

Improvetarget protein degradation efficiencyVSAvoidintracellular penetration

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent changes the molecular form parameter from small-molecule compound to protein-based structure, improving solubility and intracellular penetration while maintaining the dual-binding capability through engineered protein domains

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The PROTAC protein is constructed as a composite structure combining E3 ligase binding domain, target protein binding domain, and cell-penetrating peptide domain, integrating multiple functions into a single protein molecule to overcome the limitations of small-molecule compounds

Inventive Principle:

Principle #40Composite materials

2Reliability

If small-molecule PROTAC compounds are used, then dual binding capability is achieved, but solubility is reduced

Engineering Contradiction:

Improvedual binding capabilityVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the chemical composition parameter from hydrophobic small-molecule structure to hydrophilic protein structure, fundamentally improving solubility while maintaining binding functionality through specific domain design

Inventive Principle:

Principle #35Parameter changes

3Reliability

If conventional PROTAC technology is used, then protein degradation mechanism is established, but intracellular delivery function is reduced

Engineering Contradiction:

Improveproteasome degradation mechanismVSAvoidintracellular delivery function

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The cell-penetrating peptide domain is incorporated into the PROTAC protein structure in advance, enabling the molecule to actively penetrate cell membranes and deliver the degradation mechanism into the cell interior before target engagement occurs

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The cell-penetrating peptide acts as an intermediary component that facilitates entry into the cell, bridging the gap between extracellular administration and intracellular target protein degradation

Inventive Principle:

Principle #24Intermediary (Mediator)

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 PROTAC protein achieves high target protein degradation efficiency and improved intracellular delivery, effectively addressing limitations of conventional PROTAC technologies, particularly in treating cancer and inflammatory diseases.

Implementation Method 1

PROTAC is composed of two protein-binding molecules, one for binding to an E3 ubiquitin ligase and the remaining one for binding to a target protein. By binding to both proteins, PROTAC delivers the target protein to the E3 ligase

Methodology Applied

Scientific EffectProtein-protein binding:

Implementation Method 2

Ubiquitination involves three steps: activation, conjugation, and ligation performed by ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). As a result of this sequential cascade, ubiquitin is covalently attached to the target protein

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 3

The ubiquitinated protein is eventually degraded by the proteasome

Methodology Applied

Scientific EffectProteolysis:

Data Source

PatentUS20240287206A1Bio protac protein having intracellular delivery function, and pharmaceutical composition comprising same

Publication Date: 2024.08.29 NIBEC

AI summary

The present invention relates to a proteolysis targeting chimera (PROTAC) protein having an intracellular delivery function, and a pharmaceutical composition comprising same. The PROTAC protein according to the present invention has higher solubility than a PROTAC prepared by a conventional method and efficiently degrades intrinsic disease proteins when applied to cells, and thus is effective in the treatment of cancer or inflammatory diseases.