Modified Hemoglobin with Allosteric Effector Conjugation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Unmodified hemoglobin solutions used for blood transfusions can lead to renal dysfunction, high blood pressure, and inefficient oxygen release due to dissociation into dimers and interaction with nitric oxide, and existing modifications affect oxygen affinity and transportation efficiency.

Innovation Solution

A modified hemoglobin composition with intra- or inter-crosslinked hemoglobin molecules using polyethylene glycol derivatives, where a peptide with an allosteric effector is conjugated to hemoglobin to regulate oxygen release, and further crosslinked with SPA-PEG-SPA to form a tetramer or polymer, preventing dimer dissociation and enhancing nitric oxide release.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If free hemoglobin is used for blood transfusion, then oxygen carrying capacity is improved, but renal dysfunction and high blood pressure occur due to dimer dissociation and nitric oxide depletion

Engineering Contradiction:

Improveoxygen carrying capacityVSAvoidrenal dysfunction and high blood pressure

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent combines hemoglobin with polyethylene glycol (PEG) through conjugation to form PEG-hemoglobin conjugates. This merging approach increases the molecular size and prevents hemoglobin from dissociating into dimers, thereby eliminating renal toxicity while maintaining oxygen carrying capacity. The PEG-hemoglobin conjugates remain as larger molecules that cannot pass through renal corpuscles.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent creates a composite material by conjugating hemoglobin with polyethylene glycol chains. This composite structure combines the oxygen binding properties of hemoglobin with the hydrophilic and size-increasing properties of PEG, resulting in a material that maintains physiological function while avoiding pathological effects.

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If hemoglobin molecules are crosslinked to prevent dimer dissociation, then renal dysfunction is prevented, but oxygen release efficiency decreases due to conformational changes

Engineering Contradiction:

Improverenal dysfunctionVSAvoidoxygen release efficiency

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The patent uses polyethylene glycol as an intermediary molecule to connect hemoglobin subunits or molecules. The PEG chains act as flexible linkers that prevent close crosslinking of hemoglobin molecules, thereby maintaining the conformational flexibility needed for oxygen binding and release while still preventing dimer dissociation and renal toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the physical parameters of hemoglobin by conjugating with PEG of different molecular weights. This parameter change increases the hydrodynamic radius and prevents renal filtration while maintaining the biochemical properties of hemoglobin for oxygen transport. The PEG chain length can be adjusted to optimize both safety and function.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If unmodified hemoglobin is transfused, then oxygen transportation is provided, but nitric oxide concentration decreases leading to blood vessel contraction and high blood pressure

Engineering Contradiction:

Improveoxygen transportationVSAvoidnitric oxide depletion and blood vessel contraction

Core Design Contradiction:

Quantity of substanceVSObject-generated harmful factors

Solution Approach 1:

The patent effectively extracts or removes the harmful interaction between free hemoglobin and nitric oxide by modifying hemoglobin with PEG. The PEG modification changes the behavior of hemoglobin in circulation, preventing it from depleting nitric oxide while maintaining its oxygen transport function. This separates the beneficial oxygen transport function from the harmful nitric oxide depletion effect.

Inventive Principle:

Principle #2Taking out (Extraction)

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 modified hemoglobin composition effectively prevents renal dysfunction and high blood pressure, enhances oxygen release efficiency, and maintains stable oxygen affinity, making it suitable as a blood plasma substitute with improved oxygen transportation and nitric oxide release.

Implementation Method 1

a peptide with an allosteric effector is conjugated to hemoglobin to regulate oxygen release

Methodology Applied

Scientific EffectAllosteric regulation:

Implementation Method 2

intra- or inter-crosslinked hemoglobin molecules using polyethylene glycol derivatives

Methodology Applied

Scientific EffectCrosslinking:

Data Source

PatentUS7795401B2Modified hemoglobin with allosteric effector conjugated

Publication Date: 2010.09.14 NATIONAL CHUNG CHENG UNIV

AI summary

The present invention relates generally to a modified hemoglobin with an allosteric effector conjugated which is capable of dynamically regulating the efficiency of oxygen release. The hemoglobin composition provided in the present invention is utilizing maleimide-Polyethylene glycol-N-hydroxysuccinimidyl as a linker to crossbridge the peptide comprising SEQ ID NO: 1 to the surface of a hemoglobin, and hence, it is able to decrease the oxygen affinity through the characteristic of the peptide which could enter into the central cavity formed between β- chains of hemoglobin under an appropriate oxygen concentration.