Semuloparin sodium

Sepsis, characterized by dysregulated immune responses and mitochondrial dysfunction, currently has few effective therapies that directly target these cellular mechanisms, and conventional heparin and related analogues provide inadequate immunomodulatory benefits. Here, we investigated the synthetic heparin analogue octaparin, which exhibits enhanced anticoagulant safety, for its potential to mitigate sepsis by targeting mitochondrial and redox pathways. Using murine models of lipopolysaccharide (LPS)-induced endotoxemia and Salmonella typhimurium-induced sepsis, along with in vitro studies performed using murine bone marrow-derived macrophages (BMDMs) and the human acute monocytic leukemia THP-1 cell line, we demonstrate that octaparin significantly improves survival and attenuates multi-organ (lung, liver, kidney) damage. Octaparin outperformed heparin, enoxaparin, and fondaparinux in suppressing systemic inflammation including TNF-α, IL-6, IL-1β and bacterial burden. Transcriptomic analysis revealed octaparin reprograms macrophage immunometabolism, suppressing pro-inflammatory pathways while enhancing phagocytosis. Crucially, octaparin inhibited both canonical and non-canonical inflammasome activation, reduced generation of the pyroptotic executor GSDMD-N-terminal fragment (GSDMD-NT), and specifically diminished mitochondrial localization of GSDMD-NT by downregulating key cardiolipin synthesis and transport genes. Furthermore, octaparin uniquely reversed LPS-induced mitochondrial dysfunction. This restoration was accompanied by improvements in mitochondrial quality and the reestablishment of redox homeostasis. Collectively, octaparin confers multifaceted protection in sepsis, positioning it as a promising redox-targeted therapeutic for sepsis.

Heparins are sulfated polysaccharides with a heterogeneous mixture derived from animal tissues, subject to supply limitations and the risk of animal virus residues. Patients using heparin also face the risks of spontaneous bleeding and thrombocytopenia. Here we reported an efficient riclinoctaose-based approach for rapid chemical synthesis of a structurally defined heparin-like anticoagulant sulfated octasaccharide (SRO). We used sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, and sulfur trioxide-triethylamine complexes as solvents for one-pot O-sulfation and determined the optimal conditions for synthesizing SRO. Sulfur trioxide-trimethylamine provided reasonable control over the degree of substitution between 1.85 and 1.88, revealing a single molecule with a theoretical molecular weight of 2952.96 g/mol. The structural features of the SRO were carried out by Fourier transform infrared spectroscopy and one- and two- dimensional ¹H and ¹³C NMR analysis, revealing sulfation repeatedly present at the fixed positions of C-6/C-2/C-3 and reducing terminals. The anticoagulant activity of SRO was demonstrated by efficiently blocking coagulation in the blood of mice and human. SRO dose-dependently decreased ferric chloride-induced experimental thrombosis in mice. Like heparin, SRO specifically inhibits coagulation factor Xa, but significantly reduces the risk of bleeding compared to heparin. Therefore, we named it octaparin. These results support that octaparin is expected to replace animal-sourced heparin.