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.
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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.
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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).
The Xu lab studies one of the most fascinating biomacromolecules called heparan sulfate. Heparan sulfate is a highly negatively charged unbranched polysaccharide only found in animals. With its complex structure, heparan sulfate performs its biological functions by binding to hundreds of heparan sulfate-binding proteins with different specificities and affinities. By binding to heparan sulfate, heparan sulfate-binding proteins find a new way to alter their conformations and oligomeric states, their localization at the cell membrane and in the extracellular matrix, and how they interact with other binding partners. The structural complexity of heparan sulfate is ingrained in the complexity of the body plan and physiology of animals, especially vertebrates.
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Our lab employs a highly multidisciplinary approach to investigate the novel functions of heparan sulfate in various bone and cartilage diseases such as osteoporosis, osteoarthritis and rheumatoid arthritis. In these diseases, many heparan sulfate-binding proteins play key pathophysiological roles and are regarded as important drug targets (including receptors, cytokines, chemokines and enzymes). The dependence of these proteins on heparan sulfate for normal function suggests that disrupting heparan sulfate-protein interaction could be an effective means to block the activity of these proteins. Our lab is engaged in developing novel oligosaccharide-based and monoclonal antibody-based therapeutics to target key heparan sulfate-protein interactions.
Joining Xu Lab
Prospective postdoctoral scholars and PhD students who wish to join our highly productive team can directly email Dr. Xu. Currently, the earliest start date would be 09/2026.
Lab address:
Musculoskeletal Research Center
21 Ortho Lane
Brookhaven, GA 30329
Tel: 404-251-4326
Email: ding.xu@emory.edu