Potential Use of Anti-Inflammatory Synthetic Heparan Sulfate to Attenuate Liver Damage

Abstract

Heparan sulfate is a highly sulfated polysaccharide abundant on the surface of hepatocytes and surrounding extracellular matrix. Emerging evidence demonstrates that heparan sulfate plays an important role in neutralizing the activities of proinflammatory damage associate molecular patterns (DAMPs) that are released from hepatocytes under pathological conditions. Unlike proteins and nucleic acids, isolation of homogenous heparan sulfate polysaccharides from biological sources is not possible, adding difficulty to study the functional role of heparan sulfate. Recent advancement in the development of a chemoenzymatic approach allows production of a large number of structurally defined oligosaccharides. These oligosaccharides are used to probe the physiological functions of heparan sulfate in liver damage under different pathological conditions. The findings provide a potential new therapeutic agent to treat liver diseases that are associated with excessive inflammation.

Structural and Substrate Specificity Analysis of 3-O-Sulfotransferase Isoform 5 to Synthesize Heparan Sulfate

“…Recently, chemoenzymatic synthesis of structurally homogeneous HS oligosaccharides has been developed . An in-depth understanding of the substrate specificity of new 3-OST isoforms permits the use of these new enzymes for the synthesis of 3- O -sulfated oligosaccharides for biological studies and the development of HS-based therapeutics . In this manuscript, we employed a series of HS octasaccharides to carry out the crystal structural analysis of 3-OST-5.…”

“…2 An in-depth understanding of the substrate specificity of new 3-OST isoforms permits the use of these new enzymes for the synthesis of 3-O-sulfated oligosaccharides for biological studies and the development of HS-based therapeutics. 32 In this manuscript, we employed a series of HS octasaccharides to carry out the crystal structural analysis of 3-OST-5. For the first time, we solved the structures of 3-OST-5 in complex with oligosaccharide substrates.…”

Heparan sulfates and heparan sulfate binding proteins in sepsis

“…• Heparin: binds to TFPI, releasing it and amplifying its binding to factor FVIIa; cotreatment with TFPI does not consistently reduce the mortality rate in septic patients Valentin et al (1994), Xu et al (2002), Abraham et al (2003), Tang et al (2007) • Heparin derivatives: sulfation dependent; N-/ O-desulfation eliminate binding ability Opal et al (1999), Heinzelmann and Bosshart (2005), Stasi et al (2017), Simpson and Trent (2019) • Bind and present LPS to CD14 and TLR4 on cell surfaces, enhance LPS recognition, or neutralize LPS sulfation patterns into circulation. HSs are responsible for multiple biological functions through interaction with various proteins in a homeostatic state; therefore HSs shedding interrupts crosstalk and communications between cells, contributing to abnormal inflammation, coagulation, and lipid metabolism systems under septic conditions (Hayashida et al, 2009;Arnold et al, 2020a). In an LPS-induced sepsis mouse model, pulmonary endothelial heparanase was activated in a TNF-α dependent manner (Schmidt et al, 2012).…”

“…The process is described as HSs shedding, which releases HSs in various sizes and sulfation patterns into circulation. HSs are responsible for multiple biological functions through interaction with various proteins in a homeostatic state; therefore HSs shedding interrupts crosstalk and communications between cells, contributing to abnormal inflammation, coagulation, and lipid metabolism systems under septic conditions ( Hayashida et al, 2009 ; Arnold et al, 2020a ). In an LPS-induced sepsis mouse model, pulmonary endothelial heparanase was activated in a TNF-α dependent manner ( Schmidt et al, 2012 ).…”

Progress and challenges in the synthesis of sequence controlled polysaccharides

“…HS binds to over hundred proteins depending on sulfation pattern and chain length. Generally, a minimal length (in most cases an octasaccharide) is required to trigger specific biological events, including interaction with cytokines and chemokines growth factors [ 396 ].…”