Celastrol Targets Multidrug-Resistant Synovial Fibroblasts

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Solution Overview

Problem

Refractory rheumatoid arthritis, characterized by drug resistance due to intrinsic or acquired mechanisms, including apoptosis-resistance and overexpression of ABC transporter proteins like P-glycoprotein, poses a significant challenge in treatment, as conventional therapies are ineffective against multidrug-resistant synovial fibroblasts.

Innovation Solution

Administration of a quinonemethide triterpenoid, specifically celastrol, which acts as a P-glycoprotein inhibitor and calcium mobilizer, inducing autophagy and apoptosis in synovial fibroblasts, thereby overcoming drug resistance and reducing inflammation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional therapeutic agents are used to treat rheumatoid arthritis, then general anti-inflammatory effect is achieved, but drug resistance develops due to intrinsic mechanisms including apoptosis-resistance and ABC transporter protein overexpression

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddrug resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the chemical parameter by using a quinonemethide triterpenoid with specific chemical structure (Formula I) rather than conventional agents. This chemical parameter change enables the compound to bypass ABC transporter-mediated efflux and directly induce apoptosis in RASFs, overcoming the drug resistance problem while maintaining treatment effectiveness

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent converts the harmful apoptosis-resistant phenotype of RASFs into a beneficial target. By designing a compound that specifically triggers apoptosis pathways in these resistant cells, the invention transforms the previously protective mechanism (apoptosis resistance) into the very vulnerability that enables selective destruction of pathological cells

Inventive Principle:

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

2Object-affected harmful factors

If ABC transporter proteins are overexpressed to protect cells, then drug efflux is enhanced, but intracellular drug concentration decreases to sub-optimal levels

Engineering Contradiction:

Improvedrug effluxVSAvoidintracellular drug concentration

Core Design Contradiction:

Object-affected harmful factorsVSQuantity of substance

Solution Approach 1:

The quinonemethide triterpenoid acts as an intermediary that disrupts the ABC transporter-mediated efflux process. The compound accumulates in RASFs by interfering with the normal function of P-glycoprotein and other ABC transporters, thereby serving as a mediator that reverses the harmful efflux mechanism and restores intracellular drug concentration to therapeutic levels

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The compound exploits the overexpressed ABC transporters against the cells themselves. By designing a molecule that is recognized by these transporters but cannot be efficiently effluxed, the invention enables the cells' own protective mechanisms to become the pathway for drug accumulation, achieving self-service in overcoming resistance

Inventive Principle:

Principle #25Self-service

3Object-generated harmful factors

If p53 mutations occur in synovial fibroblasts, then apoptosis inhibition is enhanced, but inflammatory cytokine production increases

Engineering Contradiction:

Improveinflammatory cytokine productionVSAvoidapoptosis function

Core Design Contradiction:

Object-generated harmful factorsVSReliability

Solution Approach 1:

The patent segments the apoptotic pathway into multiple targetable components. Rather than relying solely on p53-dependent apoptosis, the quinonemethide triterpenoid activates alternative apoptotic pathways (including mitochondrial and death receptor pathways) that can function independently of p53 status, thereby overcoming the apoptosis inhibition caused by p53 mutations while still achieving cell death in inflammatory cells

Inventive Principle:

Principle #1Segmentation

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

Celastrol effectively targets multidrug-resistant rheumatoid arthritis synovial fibroblasts, enhancing the accumulation of cytotoxic compounds and inducing cell death, thereby providing a novel treatment approach for refractory rheumatoid arthritis.

Implementation Method 1

Celastrol effectively targets multidrug-resistant rheumatoid arthritis synovial fibroblasts, enhancing the accumulation of cytotoxic compounds

Methodology Applied

Scientific EffectP-glycoprotein inhibition:

Implementation Method 2

Administration of a quinonemethide triterpenoid, specifically celastrol, which acts as a P-glycoprotein inhibitor and calcium mobilizer, inducing autophagy and apoptosis in synovial fibroblasts

Methodology Applied

Scientific EffectCalcium mobilization:

Data Source

PatentUS10688105B2Method of treating refractory rheumatoid arthritis associated with p53 mutation

Publication Date: 2020.06.23 MACAU UNIV OF SCI & TECH

AI summary

A method for treating a subject suffering from refractory rheumatoid arthritis includes the step of administering an effective amount of a quinonemethide triterpenoid or a pharmaceutically tolerable salt, solvate or anhydrate thereof to the subject. Also is a method for inducing autophagy in a synovial fibroblast, and a method of inducing calcium mobilization in a synovial fibroblast. Further a pharmaceutical composition includes an effective dose of a quinonemethide triterpenoid and an anti-arthritis compound. The quinonemethide triterpenoid is suitable to treat refractory rheumatoid arthritis (RA) in particular ABC-protein-dependent RA and apoptosis-deficient RA. The quinonemethide triterpenoid also possesses significant inhibitory effects on the growth of synovial fibroblasts, in particular modulating the calcium homeostasis in multidrug-resistant rheumatoid arthritis synovial fibroblasts.