Compounds for treating and preventing extracellular histone mediated pathologies
Inventors
Parish, Christopher • O'MEARA, CONNOR • COUPLAND, LUCY • QUAH, BENJAMIN JU CHYE • KORDBACHEH, FARZANEH • Orlov, Anna • BROWNE, ANNA • Stephens, Ross • Tredwell, Gregory David • Philip, Lee Andrew • KNOX, KAREN • Von Itzstein, Laurence Mark • Chang, Chih-Wei • BRÜSTLE, ANNE • DAVIS, DAVID ANAK SIMON
Assignees
Australian National University • Griffith University
Publication Number
US-12295966-B2
Publication Date
2025-05-13
Expiration Date
2038-12-14
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Abstract
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.
Core Innovation
The invention relates to compounds with high chemical stability and methods for inhibiting the pathological activity of extracellular histones in a subject. Particularly, it concerns polyanionic sulfated cellobiosides modified with a small uncharged glycosidically linked substituent at their reducing terminus, which enhances chemical stability without compromising therapeutic efficacy. Specifically exemplified compounds include β-O-methyl cellobioside sulfate (mCBS) and its pharmaceutically acceptable salts (e.g., mCBS.Na). These compounds neutralize the cytopathic, red blood cell damaging, platelet activating, and pro-coagulant properties of extracellular histones and are useful in treating or preventing extracellular histone mediated ailments such as sepsis, systemic immune response syndrome (SIRS), and ischemia reperfusion injury (IRI).
The problem addressed is the pathological activity of extracellular histones released during inflammatory processes, which mediate endothelial dysfunction, organ failure, systemic inflammatory and toxic responses, and contribute to progression of various diseases including autoimmune, inflammatory diseases, and cancer. Existing therapeutics such as monoclonal antibodies, activated protein C, recombinant thrombomodulin, and heparin have limited clinical utility due to inefficacy or serious side effects, including anticoagulant activity causing bleeding risks. Thus, diseases mediated by extracellular histones remain largely untreated and represent a significant clinical concern.
The invention is predicated on the discovery that certain highly stable polyanionic sulfated disaccharides, modified with a small uncharged glycosidically linked substituent at the reducing terminus, have improved chemical stability and effectively neutralize pathological effects of extracellular histones. This modification confers a new principle of treatment and prevention of histone-mediated pathologies. Specifically, mCBS has higher stability compared to CBS, has minimal anticoagulant effects, is well tolerated at high concentrations, and reduces histone-induced coagulation perturbations. Thus, mCBS and related compounds offer promising therapeutic methods and pharmaceutical compositions for extracellular histone associated diseases.
Claims Coverage
The patent contains one independent claim defining a pharmaceutical composition with specific compound and formulation features.
Pharmaceutical composition containing a stable modified sulfated cellobioside
A pharmaceutical composition comprising a polyanionic sulfated cellobioside modified with a small uncharged glycosidically linked substituent at its reducing terminus or a pharmaceutically acceptable salt thereof, having a specific general structure.
Specific substituent selection
The substituent R1 is methoxy or ethoxy group, improving chemical stability compared to a sulfate at the reducing terminus.
Preferred compound identity
The compound is sulfated β-O-methyl cellobioside disaccharide or a pharmaceutically acceptable salt thereof, especially sodium β-O-methyl cellobioside sulfate.
Buffer system and formulation features
The pharmaceutical composition further comprises a buffer system selected from disodium hydrogen phosphate-monobasic sodium phosphate or sodium citrate dihydrate-citric acid, buffered at pH 7.5, and may include pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
Dosing and administration
The composition includes formulations for single or multi-dose administration by continuous infusion and can be administered at the same time or concomitantly with a second active agent such as anti-inflammatory, antibiotic, antiviral, antifungal agents or other adjunct treatments.
Routes of administration
The composition can be formulated for oral, intravenous, intramuscular, subcutaneous, transdermal, or transmucosal administration.
The independent claim covers a pharmaceutical composition containing a chemically stable polyanionic sulfated cellobioside with a small uncharged substituent at the reducing terminus, preferably mCBS or its sodium salt, formulated with specific buffers and excipients for treatment of extracellular histone mediated ailments via various administration routes.
Stated Advantages
The compounds exhibit high chemical stability compared to unsubstituted analogues, enhancing shelf-life and usability.
They effectively neutralize extracellular histone-mediated cytotoxicity, red blood cell damage, platelet activation, and procoagulant effects.
The compounds have minimal anticoagulant activity, reducing bleeding risk compared to existing treatments like heparin or activated protein C.
They are well tolerated at high doses, allowing for effective therapeutic concentrations.
The compounds provide a new general principle for treatment and prevention of histone-mediated pathologies such as sepsis, SIRS, IRI, thrombosis, and autoimmunity.
Documented Applications
Treatment or prevention of extracellular histone mediated ailments including sepsis, systemic immune response syndrome (SIRS), and ischemia reperfusion injury (IRI).
Use in ameliorating trauma including surgical trauma and traumatic haemorrhage.
Treatment of burns and acute pancreatitis related to extracellular histone toxicity.
Management of coagulation and thrombosis disorders mediated by extracellular histones.
Therapy for autoimmune and inflammatory diseases such as multiple sclerosis and rheumatoid arthritis.
Treatment of acute respiratory distress syndrome (ARDS) associated with histone-mediated pathology.
Use in treatment of cardiovascular diseases associated with extracellular histones.
Treatment of retinal detachment, fibrosis, diabetes, and complications from chemotherapy, radiotherapy, and cytokine therapy.
Use in wound healing by ameliorating histone-induced cytotoxicity.
Therapy for central nervous system diseases involving extracellular histones.
Diagnostic, prognostic and management methods for extracellular histone mediated ailments.
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