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. The structure and function of heparan sulfate became more complex and diverse during animal evolution, most notably during the evolution of vertebrates. To take advantage of this extremely versatile polysaccharide, hundreds of proteins have evolved to be heparan sulfate-binding proteins. By binding to heparan sulfate, heparan sulfate-binding proteins gained a brand-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. Understanding how heparan sulfate regulates the structure and function of various heparan sulfate-binding proteins is therefore a key component to fully grasp animal physiology. Such understanding will undoubtedly provide opportunities for development of novel therapeutics.
Joining Xu Lab
Xu lab just moved from SUNY Buffalo to Emory and we are actively recruiting postdoctoral scholars and PhD students to join our highly productive team (2024/07).
Applicants with backgrounds in any discipline of biomedical sciences are welcome to apply. The main appeal of joining the Xu lab is the prospect of developing your own projects and obtain a truly multidisciplinary skill sets. Regardless of your future career goals, you will for sure learn what you desire in the Xu lab. ​
Lab address:
Musculoskeletal Research Center
21 Ortho Lane
Brookhaven, GA 30329
Tel:
Email: ding.xu@emory.edu