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 cartilage diseases
Another focus of the lab is to understand the pathophysiological role of HS in cartilage homeostasis and diseases. Cartilage is a unique connective tissue that plays essential roles in facilitating joint movement. The main components of cartilage tissue are large volume of extracellular matrix (mostly type II collagen and chondroitin sulfate proteoglycans), and chondrocytes that are embedded in the extracellular matrix. Chondrocytes are responsible for maintaining the homeostasis of cartilage by regulating their anabolic and catabolic activities. Under disease conditions such as osteoarthritis and rheumatoid arthritis, the balance of anabolic and catabolic activities within the cartilage is disrupted, which leads to cartilage degeneration.
While chondroitin sulfate is the dominant glycosaminoglycans in the extracellular matrix of cartilage, HS is found abundantly at the cell surface of chondrocytes and in the pericellular matrix, a thin layer of matrix immediately surrounding the chondrocytes. In addition, many proteases that play essential roles in cartilage homeostasis are HS-binding proteins. The goal of the lab is to understand the physiological role of HS in regulating chondrocyte biology and develop novel therapeutic that target HS-binding proteases that play essential roles in cartilage diseases.
Currently, the lab focuses on understanding the role of HS in regulating matrix metalloproteinase 13 (MMP13) biology. MMP13 is a potent collagenase secreted by chondrocytes that is predominantly responsible for digestion of type II collagen in cartilage. Although MMP13 is known to bind HS, how HS regulates the biological functions of MMP13 remains completely unknown. Our data suggests that heparan sulfate regulates the localization, stability and collagenase activity of MMP13. By using a combination of biophysical, biochemical, physiological and pharmacological methods, we aim to better understand the role of HS-MMP13 interactions in cartilage biology and hopefully develop novel therapeutics that target the collagenase activity of MMP13.
Key publications on HS-binding proteins in cartilage biology:
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Huanmeng Hao, Guowei Su, Jian Liu and Ding Xu (2026) Heparan sulfate selectively inhibits the collagenase activity of matrix metalloproteinase 13. BioRvix preprint; doi: https://doi.org/10.64898/2026.08.21.746339
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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.