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).
Selected Journal articles
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Yin Luo, Miaomiao Li and Ding Xu (2022). A disease-causing human osteoprotegerin mutant exists in hyper-oligomerized forms. Scientific Report. 2022 Sep 10;12(1):15279. doi: 10.1038/s41598-022-19522-9.
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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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Xiaoxiao Zhang, Xinyue Liu, Miaomiao Li, Guowei Su, Jian Liu, Chunyu Wang, and Ding Xu (2021). pH-Dependent and Dynamic Interactions of Cystatin C with Heparan Sulfate. Communications Biology 4(1):198. doi: 10.1038/s42003-021-01737-7.
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Miaomiao Li & Ding Xu (2020). Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site. PNAS. doi: 10.1073/pnas.2005859117. PMID: 32636266
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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. PubMed PMID: 31942981
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Yiming Xiao, Miaomiao Li, Rinzhi Larocque, Fuming Zhang, Anju Malhotra, Jianle Chen, Robert J. Linhardt, Lars Konermann, and Ding Xu (2018). Dimerization Interface of Osteoprotegerin Revealed by Hydrogen-deuterium Exchange Mass Spectrometry. J Biol Chem 293 (45), 17523-17535. PMID: 30254073.
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Miaomiao Li, Shuying Yang, Ding Xu* (2016). Heparan Sulfate Regulates the Structure and Function of Osteoprotegerin in Osteoclastogenesis . J Biol Chem 291 (46):24160-24171. PMID: 27697839.
On the horizon
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Yin Luo, Huanmeng Hao, Chihyean Ong, Zhangjie Wang, Jian Liu, Lars C. Pedersen and Ding Xu (2023). Heparan sulfate promotes TRAIL-induced apoptosis by inducing TRAIL oligomerization.
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Xiaoxiao Zhang, Yin Luo, Guowei Su, Miaomiao Li, Jian Liu, Lars C. Pedersen and Ding Xu (2023). Heparan sulfate inhibits the collagenase activity of cathepsin K by inducing its oligomerization.
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Chihyean Ong, Miaomiao Li and Ding Xu (2023). Targeting the heparan sulfate-binding site of RAGE with monoclonal antibodies.
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Ding Xu and Jeffrey D. Esko (2014). Demystifying Heparan sulfate-binding proteins. 2014;83:129-57. Annual Review of Biochemistry. PMID: 24606135
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Xu D, Arnold K, Liu J. Using structurally defined oligosaccharides to understand the interactions between proteins and heparan sulfate. Curr Opin Struct Biol. 2018 Apr 20;50:155-161. doi: 10.1016. PMID: 29684759.