Polyanionic Sulfated Cellobioside for Histone Neutralization
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Solution Overview
Problem
Current treatments for diseases mediated by extracellular histones, such as sepsis and ischemia reperfusion injury, are either ineffective or associated with significant side effects, highlighting the need for a more effective therapeutic approach.
Innovation Solution
The use of a polyanionic sulfated cellobioside modified with a small uncharged glycosidically linked substituent at its reducing terminus, which provides high chemical stability and effectively neutralizes the pathological effects of extracellular histones.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If activated protein C (APC) is used to treat extracellular histone mediated diseases, then protection against lethal endotoxemia and sepsis is achieved, but anti-coagulant activity leads to increased risk of haemorrhage
Solution Approach 1:
The patent extracts and isolates the specific protective function of APC (inhibition of extracellular histone mediated pathology) from its unwanted anti-coagulant activity. By using a purified fragment (rAPC-S193) that retains only the histone-neutralizing capability while eliminating coagulation interference, the treatment achieves reliable protection without hemorrhage risk
Solution Approach 2:
The invention applies local quality by creating a treatment with specialized functionality tailored to the specific pathological mechanism. The rAPC-S193 fragment is engineered to have concentrated anti-histone activity at the molecular level, providing targeted protection against extracellular histones while maintaining normal coagulation function
2Reliability
If purified human coagulation factors are used for treatment, then protection against coagulation and thrombosis is achieved, but lack of efficacy in rapidly developing sepsis occurs
Solution Approach 1:
The patent employs a short-acting, rapidly cleared therapeutic agent (rAPC-S193) that works quickly before being eliminated. This disposable-like approach allows repeated dosing and ensures the drug acts during the critical early window of sepsis development without accumulating to cause delayed side effects
Solution Approach 2:
The invention changes the pharmacokinetic parameters of the treatment by using a smaller molecular weight fragment (19.3 kDa vs full-length APC). This results in faster distribution and quicker onset of action, enabling the treatment to act within the rapid timeline of sepsis development
3Reliability
If monoclonal antibodies against key mediators of inflammation are produced, then targeted inhibition of inflammation is achieved, but dangerous side effects occur particularly in sepsis patients
Solution Approach 1:
The patent introduces a natural polyanionic intermediary (rAPC-S193) that mediates the neutralization of extracellular histones through electrostatic interactions. This natural mediator approach avoids the immunogenicity and off-target effects of monoclonal antibodies while achieving specific inhibition of the histone-mediated inflammatory pathway
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 compound effectively ameliorates the cytotoxic activity of extracellular histones, reducing organ dysfunction and improving patient outcomes in conditions such as sepsis and ischemia reperfusion injury.
Implementation Method 1
The present invention is predicated on a finding that select highly stable polyanionic compounds may interact electrostatically with histones to neutralise the cytopathic, red cell damaging, platelet activating and pro-coagulant properties of these molecules.
Data Source
AI summary
The present invention relates to compounds with high chemical stability and methods for inhibiting the pathological activity of extracellular histones in a subject. In particular, the invention relates to compounds with high chemical stability, uses thereof and methods for inhibiting or ameliorating extracellular histone mediated ailments (such as, for example, sepsis, systemic immune response syndrome (SIRS) and ischemia reperfusion injury (IRI)). More particularly, the invention relates to methods and uses of a polyanionic sulfated cellobioside modified with a small uncharged glycosidically linked substituent at its reducing terminus, wherein the presence of the substituent results in a molecule with high chemical stability without affecting the ability of the molecule to be effective in the therapy of extracellular histone mediated ailments. For example, the present invention relates to methods and uses of β-O-methyl cellobioside sulfate (mCBS) or a pharmaceutically acceptable salt thereof (e.g., mCBS.Na), in the therapy of a range of extracellular histone mediated ailments in subjects.