Mitochondrial Complex IV Subunit Screening for Diabetes Therapy

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Solution Overview

Problem

Current treatments for type II diabetes often rely on metformin, but it is contraindicated in certain conditions and can have side effects, necessitating the identification of alternative agents that target the mitochondrial electron transport complex IV for effective diabetes management.

Innovation Solution

The method involves contacting a sample with a test compound and determining if it binds to or alters the function of mitochondrial electron transport complex IV, specifically targeting subunits like Cox4i1, Cox5a, Cox6b1, Cox7a2, mt-Co2, Cox6c, Cox7c, Cox5b, and Cox6a1, to identify compounds that can treat diabetes without using metformin.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If metformin is used to treat type II diabetes, then diabetes management is effective, but it causes lactic acidosis and is contraindicated in certain conditions

Engineering Contradiction:

Improvediabetes management effectivenessVSAvoidlactic acidosis risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts the beneficial therapeutic effect of metformin (improving insulin sensitivity and glucose metabolism) while removing the harmful side effect (lactic acidosis) by identifying and targeting only the desirable mitochondrial complex IV binding interaction, thereby developing safer alternative compounds that replicate metformin's efficacy without its toxicity

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent uses mitochondrial electron transport complex IV as an intermediary target to achieve metformin's therapeutic effects. By binding to complex IV subunits (particularly Cox4i1, Cox5a, Cox6b1), alternative compounds can modulate mitochondrial function and improve insulin sensitivity without causing the lactic acidosis associated with metformin's broader mechanism

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If metformin is used to treat type II diabetes, then blood glucose control is improved, but it decreases thyroid-stimulating hormone levels in hypothyroidism

Engineering Contradiction:

Improveblood glucose controlVSAvoidthyroid hormone disruption

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with selective binding properties that target specific mitochondrial complex IV subunits in a tissue-specific manner. The compounds aim to achieve glucose control in metabolic tissues (liver, muscle) while avoiding thyroid tissue, thereby maintaining thyroid-stimulating hormone levels and preventing endocrine disruption

Inventive Principle:

Principle #3Local quality

3Object-affected harmful factors

If alternative compounds targeting mitochondrial complex IV are developed, then safety profile is improved, but identification and validation of new compounds requires complex screening methods

Engineering Contradiction:

Improveside effects reductionVSAvoidcompound screening complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent segments the mitochondrial complex IV into individual subunits (Cox4i1, Cox5a, Cox6b1, Cox7a2, mt-Co2, Cox6c, Cox7c, Cox5b, Cox6a1) as separate target entities. This segmentation allows for focused screening assays that test binding to specific subunits, simplifying the identification process compared to testing against the entire complex or using broad metabolic assays

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent replaces complex in vivo metabolic assays with in vitro binding assays that directly measure compound interaction with purified mitochondrial complex IV subunits. This substitution simplifies screening by using direct binding measurements (such as spectroscopic or affinity-based methods) rather than requiring complex cellular or organismal models to assess efficacy and safety

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

This approach allows for the identification and use of compounds that effectively treat type II diabetes by binding to or altering the function of mitochondrial electron transport complex IV, providing alternative therapeutic options beyond metformin, particularly for conditions where metformin is contraindicated.

Implementation Method 1

contacting a sample comprising a mitochondrial electron transport complex IV with a test compound, and determining if the test compound binds a subunit of the mitochondrial electron transport complex IV, and/or alters the function of the mitochondrial electron transport complex IV

Methodology Applied

Scientific EffectMitochondrial electron transport:

Data Source

PatentUS11519913B2Metabolic disorder target

Publication Date: 2022.12.06 UNIV OF PITTSBURGH OF THE COMMONWEALTH SYST OF HIGHER EDUCATION

AI summary

Methods are disclosed herein for identifying a compound of use in treating a condition treatable by metformin. The methods include determining if the test compound binds a subunit of the mitochondrial electron transport complex IV, and/or alters the function of the mitochondrial electron transport complex IV. Methods for treating a subject with a condition treatable by metformin, are also disclosed. In some embodiments, the condition is type II diabetes.