Pre-fused PROTAC Lipid Nanoparticles for Degradation Efficiency

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current PROTACs face challenges with low cell permeability due to increased molecular weight and the presence of multiple hydrogen bond donors and acceptors, and the 'hook effect' of the three-component system, which decreases degradation efficiency at high concentrations.

Innovation Solution

The development of pre-fused PROTACs, where the PROTAC and E3 ligase are pre-complexed before encapsulation into lipid nanoparticles, forming a two-component system that enhances intracellular delivery and protein degradation efficiency by simplifying the ternary complex formation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If PROTAC molecular weight is increased to improve degradation efficiency, then degradation ability improves, but cell permeability decreases

Engineering Contradiction:

Improvedegradation efficiencyVSAvoidcell permeability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The PROTAC molecule is divided into separate components: a ligand portion and an E3 ligase binding portion, which are administered separately but work together to achieve protein degradation, avoiding the cell permeability issues of high molecular weight PROTACs

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses an intermediary approach where the ligand and E3 ligase binding portion are administered separately but coordinate through a shared binding mechanism to achieve the degradation function without requiring a single large PROTAC molecule

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If PROTAC concentration is increased to improve degradation efficiency, then degradation ability improves, but the hook effect decreases degradation efficiency

Engineering Contradiction:

Improvedegradation efficiencyVSAvoiddegradation stability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

By separating the PROTAC into ligand and E3 ligase binding portions that are administered separately, the system avoids the hook effect associated with high concentrations of intact PROTAC while maintaining degradation efficiency through coordinated action of the separate components

Inventive Principle:

Principle #1Segmentation

3Productivity

If traditional three-component PROTAC system is used, then protein degradation function is achieved, but system complexity increases

Engineering Contradiction:

Improveprotein degradation functionVSAvoidsystem complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The E3 ligase component is extracted from the traditional three-component PROTAC system and administered separately, simplifying the system while maintaining the protein degradation function through the remaining ligand and E3 ligase binding portion

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS20230414723A1Enhanced hyt-induced protein degradation using lipid nanoparticle delivery

Publication Date: 2023.12.28 TRUSTEES OF TUFTS COLLEGE

AI summary

Disclosed are conjugates, comprising a PROTAC and a protein. Also disclosed are nanoparticles, comprising the conjugates disclosed herein and a membrane. The present disclosure further relates to therapeutic methods of using the conjugates and nanoparticles.