NPAR Agonists Reversing Endothelial Dysfunction

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Solution Overview

Problem

Endothelial dysfunction, associated with various diseases such as hypertension, coronary artery disease, and diabetes, is not effectively addressed by existing treatments, as it involves decreased nitric oxide production and increased arginase activity, leading to impaired vascular function.

Innovation Solution

Compounds that stimulate the non-proteolytically activated thrombin receptor (NPAR) agonists, like TP508, are used to block arginase upregulation and promote nitric oxide synthase activation, increasing nitric oxide production and reversing endothelial dysfunction.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If arginase activity is increased, then L-arginine is converted to urea, but nitric oxide production decreases and endothelial function deteriorates

Engineering Contradiction:

Improvenitric oxide productionVSAvoidarginase activity

Core Design Contradiction:

Quantity of substanceVSObject-generated harmful factors

Solution Approach 1:

The patent applies this principle by using NPAR agonists to convert the harmful effect of increased arginase activity into a beneficial outcome. Instead of simply inhibiting arginase, the invention activates the NPAR pathway which indirectly suppresses arginase upregulation while enhancing eNOS phosphorylation and nitric oxide production, thereby transforming the pathological arginase-mediated L-arginine depletion into a therapeutic mechanism that restores endothelial function

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent changes the biochemical parameters of the system by modulating NPAR receptor activity. This triggers a cascade of events including increased eNOS phosphorylation (change in enzyme activation state), altered arginase expression levels (change in gene expression), and shifted L-arginine metabolism (change in substrate availability), collectively restoring the balance between nitric oxide production and arginase activity

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If nitric oxide synthase activity is decreased, then nitric oxide production is reduced, but endothelial dysfunction occurs

Engineering Contradiction:

Improvenitric oxide productionVSAvoidendothelial function

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies preliminary action by activating NPAR receptors before significant endothelial damage occurs. The NPAR agonist treatment preemptively increases eNOS phosphorylation and maintains nitric oxide production levels, preventing the development of endothelial dysfunction rather than treating it after it has manifested

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent introduces NPAR agonists as intermediary substances that mediate between the cellular signaling pathways and the final outcome of nitric oxide production. These compounds act as mediators that bind to NPAR receptors, triggering intracellular cascades including eNOS phosphorylation, thereby indirectly restoring nitric oxide synthesis without directly activating eNOS

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If L-arginine availability is limited, then nitric oxide synthesis is impaired, but vascular function deteriorates

Engineering Contradiction:

ImproveL-arginine availabilityVSAvoidvascular function

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies self-service by enabling the endothelial cells to self-regulate L-arginine availability through NPAR activation. The signaling cascade initiated by NPAR agonists automatically adjusts arginase expression and eNOS phosphorylation to maintain adequate L-arginine levels for nitric oxide synthesis, allowing the system to self-correct without external intervention

Inventive Principle:

Principle #25Self-service

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 use of NPAR agonists effectively reverses endothelial dysfunction by blocking arginase upregulation and enhancing nitric oxide production, improving vascular function and treating conditions like hypertension and diabetes.

Implementation Method 1

blocking the up-regulation of arginase associated with endothelial dysfunction

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Implementation Method 2

promoting the activation or up-regulation of nitric oxide synthase, thereby increasing the production of nitric oxide

Methodology Applied

Scientific EffectPhosphorylation:

Implementation Method 3

activation or up-regulation of nitric oxide synthase

Methodology Applied

Scientific EffectEnzyme activation: Enzyme

Data Source

PatentUS8334259B2Method of treating endothelial dysfunction comprising administration of a thrombin peptide derivative

Publication Date: 2012.12.18 BOARD OF RGT THE UNIV OF TEXAS SYST

AI summary

Endothelial dysfunction (ED) is associated with a number of diseases and disorders. Agonists of the non-proteolytically activated thrombin receptor can be used in methods to treat ED or ED-related diseases and disorders.