Tie2-Activating Peptide-PEG Multimer for Vascular Leak Reduction

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Solution Overview

Problem

Current therapeutic approaches for treating coronavirus-induced acute lung injury and related conditions like ARDS are limited, and there is a need for effective agents that can modulate the Tie2/Angiopoietin signaling pathway to address vascular leak without rapid development of resistance.

Innovation Solution

Development of a simpler vasculotide analog (Mpa-Br) that links a T7 peptide to a PEG tetramer through a linear sulfane moiety, providing a stable compound that activates the Tie2 receptor, reducing vascular leak and stimulating endothelial cell functions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Vasculotide is used to activate Tie2 receptor and reduce vascular leak, then therapeutic effect is achieved, but the compound structure is complex and manufacturing is difficult

Engineering Contradiction:

Improvetherapeutic effectVSAvoidcompound structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The Vasculotide compound is segmented into distinct functional modules: a T7 peptide sequence (His-His-His-Arg-His-Ser-Phe) that binds to the Tie2 receptor, a PEG tetramer core structure that provides structural stability, and linker moieties that connect these elements. This segmentation allows for simplified manufacturing of each component separately while maintaining the overall therapeutic effect through controlled assembly.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The essential active component (T7 peptide sequence) is extracted and isolated from the complex Vasculotide structure. This extracted peptide can be synthesized independently using standard peptide synthesis methods, then attached to the PEG core, thereby simplifying the manufacturing process while preserving the therapeutic function of Tie2 receptor activation.

Inventive Principle:

Principle #2Taking out (Extraction)

2Reliability

If complex recombinant proteins are engineered to bind and cluster Tie2 receptors, then agonistic action is achieved, but the manufacturing process becomes more difficult and costly

Engineering Contradiction:

Improveagonistic actionVSAvoidmanufacturing process simplicity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

Instead of engineering complex recombinant proteins to mimic Ang1's agonistic action, the invention uses a simplified T7 peptide sequence that copies only the essential receptor-binding function. This peptide sequence is designed to bind to Tie2 and induce receptor clustering, achieving the agonistic effect without requiring the complex protein structure of natural Ang1, thereby greatly simplifying manufacturing.

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The invention changes the molecular parameters from large recombinant proteins to a compact peptide-PEG conjugate. The T7 peptide (7 amino acids) combined with a PEG tetramer creates a molecule with appropriate molecular weight, charge distribution, and structural flexibility to activate Tie2 receptors, while being much easier to manufacture through chemical synthesis rather than recombinant protein expression.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If natural Ang1 is used to activate Tie2 receptor, then physiological function is maintained, but the protein is complex and difficult to purify for therapeutic application

Engineering Contradiction:

Improvephysiological functionVSAvoidpurification difficulty

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The invention replaces the complex, difficult-to-purify natural Ang1 protein with a synthetic peptide-PEG conjugate that can be manufactured through chemical synthesis. The T7 peptide sequence retains the essential physiological function of activating Tie2 receptors, while the synthetic nature and modular PEG structure enable straightforward purification and consistent quality control, making it suitable for therapeutic application.

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

Mpa-Br effectively activates the Tie2 receptor, reducing vascular permeability, treating lung injury, and preventing conditions associated with coronavirus infections by stabilizing endothelial cell function and reducing cytokine storms.

Implementation Method 1

Mpa-Br effectively activates the Tie2 receptor, reducing vascular permeability

Methodology Applied

Scientific EffectReceptor binding and activation:

Implementation Method 2

Activation of this pathway, marked by Tie2 receptor phosphorylation serves as a transdominant signal; opposing the induction of vascular leak following exposure to a myriad of inflammatory factors

Methodology Applied

Scientific EffectVascular permeability regulation:

Implementation Method 3

This receptor has been found to activate a number of intracellular pathways that regulate proliferation and endothelial cell survival (MAPK and AKT)

Methodology Applied

Scientific EffectCell survival signaling:

Data Source

PatentUS20250345387A1Coronavirus therapeutics and treatment methods

Publication Date: 2025.11.13 VASOMUNE THERAPEUTICS INC

AI summary

The present disclosure relates to compounds of Formula (I) which are multimeric forms of a monomeric binding peptide linearly bonded to PEG moieties to form the multimers and their use in treating or preventing coronavirus infections and Acute Respiratory Distress Syndrome