Compounds for treating and preventing net associated complications
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 • Bruestle, Anne • DAVIS, DAVID ANAK SIMON
Assignees
Australian National University • Griffith University
Publication Number
US-12239650-B2
Publication Date
2025-03-04
Expiration Date
2039-02-25
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention relates to compounds with high chemical stability and methods for inhibiting the pathological activity of NETs in a subject. In particular, the invention relates to compounds with high chemical stability, uses thereof and methods for inhibiting or ameliorating NET 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 NET 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 NET mediated ailments in subjects.
Core Innovation
The invention relates to compounds with high chemical stability and methods for inhibiting the pathological activity of neutrophil extracellular traps (NETs) in subjects. In particular, it provides compounds and methods for inhibiting or ameliorating NET mediated ailments such as sepsis, systemic immune response syndrome (SIRS), and ischemia reperfusion injury (IRI). The compounds are polyanionic sulfated cellobiosides, preferably modified with a small uncharged glycosidically linked substituent at the reducing terminus, which confers high chemical stability without reducing the therapeutic efficacy against NET mediated ailments.
The background identifies that neutrophils release NETs consisting of chromatin fibers and antimicrobial peptides to immobilize and kill pathogens, serving as a critical innate immune response. However, excessive NET formation is implicated in various pathologies including infectious and non-infectious inflammatory diseases, leading to tissue damage. NET degradation releases histones which are cytotoxic to endothelial and epithelial cells. Existing treatments are insufficient to neutralize the damaging effects of excessive NETs without hindering neutrophil function. There is thus an unmet need for compounds to effectively treat NET-induced ailments.
The invention is based on the discovery that certain anti-NET polyanionic sulfated disaccharides, such as β-O-methyl cellobioside sulfate (mCBS) and its pharmaceutically acceptable salts, electrostatically interact with NETs to neutralize their cytopathic effects. Modification of a polyanionic sulfated cellobioside with a small uncharged glycosidically linked substituent at its reducing terminus results in a molecule with high chemical stability compared to the same molecule sulfated at that position. These compounds can be used to treat or prevent a wide range of NET associated complications, including sepsis, SIRS and IRI, providing a novel therapeutic principle.
Claims Coverage
The claims include a set of independent features focused on methods of treating specific NET associated ailments using polyanionic sulfated cellobioside compounds.
Treatment of acute pancreatitis with polyanionic sulfated cellobioside compounds
A method of treating acute pancreatitis in a subject by administering a therapeutically effective amount of a polyanionic sulfated cellobioside compound with a defined general structure, or its pharmaceutically acceptable salt.
Effective amount sufficient to reduce or inhibit acute pancreatitis
The administered amount of the compound or its pharmaceutically acceptable salt is sufficient to reduce, minimize or inhibit acute pancreatitis in the subject.
Inhibition of NET cytotoxic activities
The compound amount is sufficient to reduce, minimize or inhibit neutrophil extracellular traps (NETs) that are cytotoxic to the endothelium, contribute to endothelial dysfunction, initiate coagulation by platelet activation, or induce red cell fragility and resultant anaemia in the subject.
Single dose administration
The therapeutic effective amount is administered in a single dose to the subject.
Multiple dose administration
The therapeutic effective amount is administered in multiple doses to the subject.
Specific compound selection
The polyanionic sulfated cellobioside compound is specifically a sulfated β-O-methyl cellobioside disaccharide or its sodium salt.
The claims cover methods of treating acute pancreatitis and NET-related pathologies by administering chemically stable polyanionic sulfated cellobioside compounds such as mCBS or its salts, in efficacious dosages that can be single or multiple, thus providing broad coverage over therapeutic applications using such compounds.
Stated Advantages
Compounds modified with a small uncharged glycosidically linked substituent have improved chemical stability without loss of therapeutic effectiveness.
Polyanionic sulfated cellobiosides effectively neutralize the cytotoxic effects of NETs, decreasing tissue damage in conditions such as sepsis and ischemia reperfusion injury.
The invention provides new therapeutic agents for treating or preventing NET associated ailments which were not adequately addressed by existing treatments.
The compounds are well tolerated at high doses and can be used in pre-treatment or therapeutic settings.
Documented Applications
Treatment or prevention of NET mediated ailments including sepsis, systemic immune response syndrome (SIRS), ischemia reperfusion injury (IRI), acute pancreatitis, trauma, burns, surgery-related injury, coagulation and thrombosis disorders, autoimmune and inflammatory diseases, acute respiratory distress syndrome (ARDS), cardiovascular disease, fibrosis, diabetes, chemotherapy and radiotherapy toxicities, wound healing, and central nervous system diseases.
Amelioration of cytotoxic effects of NETs on the endothelium, reduction of endothelial dysfunction, inhibition of platelet activation, and reduction of red blood cell fragility and anaemia associated with NETs.
Adjunct use with other therapeutics such as anti-inflammatory agents, antibiotics, antivirals, and antifungals in treatment of conditions involving NETs.
Interested in licensing this patent?