Pharmacological targeting heparan sulfate–protein interactions
While understanding novel physiological functions of heparan sulfate is always thrilling, finding ways to manipulate its functions in pathological conditions can be life-saving. Heparin, a highly sulfated form of heparan sulfate made by mast cells, has been widely used as a potent anticoagulant for over a century. Heparin works by promoting the inhibition of antithrombin towards thrombin, which drives blood coagulation. We envision that the functions of many more disease-causing HS-binding proteins can be modulated by manipulating their interactions with HS. We believe the interactions can be manipulated in two different ways. The first approach is to utilize structure-defined HS oligosaccharides or HS mimetic, which would function as antagonists or agonists to inhibit or promote the interactions between HS and HS-binding proteins. The second approach is to target the HS-binding sites of HS-binding proteins by mAbs, which would effectively antagonize their interaction with HS and block their function.
Currently, we are working with Dr. Jian Liu's group to inhibit the activity of HMGB1 using the first approach. We are also developing mAbs to inhibit RAGE activation using the second approach.
Patents:
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U.S. provisional patent application (No. 62/928,884) was filed on October 31, 2019. The application describes an anti-RAGE mAb that we developed, which inhibits HS-dependent RAGE oligomerization and RAGE signaling. Role: Principle inventor.
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U.S. Provisional Patent Application (No. 62/581,443). The application describes an structure-defined HS oligosaccharides that displays protective effect on drug-induced liver damage. Role: co-inventor (principle inventor: Dr. Jian Liu).
Pharmacological targeting heparan sulfate–protein interactions
While understanding novel physiological functions of heparan sulfate is always thrilling, finding ways to manipulate its functions in pathological conditions can be life-saving. Heparin, a highly sulfated form of heparan sulfate made by mast cells, has been widely used as a potent anticoagulant for over a century. Heparin works by promoting the inhibition of antithrombin towards thrombin, which drives blood coagulation. We envision that the functions of many more disease-causing HS-binding proteins can be modulated by manipulating their interactions with HS. We believe the interactions can be manipulated in two different ways. The first approach is to utilize structure-defined HS oligosaccharides or HS mimetic, which would function as antagonists or agonists to inhibit or promote the interactions between HS and HS-binding proteins. The second approach is to target the HS-binding sites of HS-binding proteins by mAbs, which would effectively antagonize their interaction with HS and block their function.
Currently, we are working with Dr. Jian Liu's group to inhibit the activity of HMGB1 using the first approach. We are also developing mAbs to inhibit RAGE activation using the second approach.
Patents:
-
U.S. provisional patent application (No. 62/928,884) was filed on October 31, 2019. The application describes an anti-RAGE mAb that we developed, which inhibits HS-dependent RAGE oligomerization and RAGE signaling. Role: Principle inventor.
-
U.S. Provisional Patent Application (No. 62/581,443). The application describes an structure-defined HS oligosaccharides that displays protective effect on drug-induced liver damage. Role: co-inventor (principle inventor: Dr. Jian Liu).
Heparan sulfate in Inflammation
Another main focus of the lab is to understand the biological role of HS in inflammation. The functions of HS in inflammation is well known and highly diverse. This is hardly surprising because inflamed tissue is filled with HS-binding proteins including chemokines, cytokines, coagulating factors, growth factors, adhesion molecules and various cell surface receptors. By understanding the details of how individual inflammatory proteins interact with HS and how HS regulates their activity, we expect to modulate the activity of these proteins in inflammation, which might lead to novel therapeutics.
Current work in the lab mainly focuses on the role of HS in regulating two key inflammatory mediators: HMGB1 and its receptor RAGE. HMGB1 is a founding member of the damage-associated molecular patterns (DAMPs), which is often secreted by necrotic tissue and can function as both cytokine and chemokine.
HMGB1 has been associated with many inflammatory conditions such as sepsis, drug-induced liver injury, acute lung injury, ischemia-reperfusion injury and cancer. RAGE is a single transmembrane receptor that binds a diverse group of inflammatory mediators. In addition to HMGB1, it also binds advanced glycation endproducts (AGE), S100 family proteins, and amyloid beta. Because its hyperactivation is associated with atherosclerosis, sepsis, cancer, acute lung injury and Alzheimer disease, RAGE is being pursued as an attractive drug target. Both HMGB1 and RAGE are HS-binding proteins and our lab has done seminal works in establishing the structural details of their interactions with HS. Based on these structural studies, we further demonstrated the physiological significance of HMGB1–HS and RAGE-HS interactions in drug-induced liver injury and endothelial inflammation.
Currently, we are developing new projects trying to elucidate the roles of HS-HMGB1 and HS-RAGE interactions in acute respiratory distress syndrome and sepsis.
Key publications on Inflammation:
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Miaomiao Li, Chih Yean Ong, Christophe J Langouët-Astrié, Lisi Tan, Ashwni Verma, Yimu Yang, Xiaoxiao Zhang, Dhaval K. Shah, Eric P. Schmidt and Ding Xu (2022). Heparan Sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE. eLife (2022);11:e71403 DOI: 10.7554/eLife.71403.
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Arnold K, Xu Y, Sparkenbaugh EM, Li M, Han X, Zhang X, Xia K, Piegore M, Zhang F, Zhang X, Henderson M, Pagadala V, Su G, Tan L, Park PW, Stravitz RT, Key NS, Linhardt RJ, Pawlinski R, Xu D# and Liu J#. Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure. Science Transl Med (2020). Mar 18;12(535). PMID 32188725 . #corresponding authors
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Zhang X, Ong C, Su G, Liu J, Xu D. Characterization and Engineering of S100A12–Heparan sulfate interactions. Glycobiology. (2020) doi: 10.1093/glycob/cwz111. PMID: 31942981
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Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, Esko JD. Stable RAGE-heparan sulfate complexes are essential for signal transduction. ACS Chem Biol. 2013 Jul 19;8(7):1611-20. PMID: 23679870
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Xu D, Young J, Song D, Esko JD. Heparan sulfate is essential for high mobility group protein 1 (HMGB1) signaling by the receptor for advanced glycation end products (RAGE). J Biol Chem. 2011 Dec 2;286(48):41736-44. PMID:21990362