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).
University of North Carolina at Chapel Hill
Professor
Dr. Liu is a leading expert in heparan sulfate biosynthesis and chemoenzymatic synthesis of heparin sulfate oligosaccharides. We are actively collaborating with Dr. Liu on multiple projects and currently sharing an NHLBI R01 grant with Dr. Liu.
National Institute of Environmental Health Sciences
Director of X-ray Crystallography Facility
Dr. Petersen is a highly prolific crystallographer with strong interest in heparan sulfate biosynthesis and HS-binding proteins. He has been a collaborator of Dr. Xu since 2004. Together we have solved 4 crystal structures and we are currently pursuing co-crystal structures of several HS-binding proteins (with HS oligosaccharide).
Rensselaer Polytechnic Institute
Professor
Dr. Wang is an expert in NMR spectrometry and has a strong interest in the role of HS in Alzheimer’s disease. We have been collaborating with Dr. Wang since 2018 using NMR to investigate the structural details of the interactions between HS and HS-binding proteins.
University of Colorado Denver
Anschutz Medical Campus
Professor
Dr. Schmidt is a Pulmonary/Critical Care physician-scientist at University of Colorado Denver with expertise in acute respiratory distress syndrome (ARDS) and Sepsis. Dr. Schmidt has a long-standing interest in the role of heparan sulfate in ARDS/Sepsis. Together we are investigating the role of HS–RAGE interaction in ARDS and sepsis.
Rensselaer Polytechnic Institute
Professor
Dr. Linhardt is a leading expert on heparan sulfate structure and heparan sulfate binding proteins. Dr. Xu has been collaborating with Dr. Linhardt group since 2005. We continue collaborating on structural analysis of HS and binding studies of HS-binding proteins.
UC San Diego
Professor
Dr. Varki is a one of the world leaders in Glycobiology who's lab focuses on understanding the biological functions of Sialic Acid. We have shared interests in understanding how HMGB1 interacts with different classes of glycans under pathological conditions and have been collaboration since 2017.
Manhattan Biosolutions
CEO
Dr. Shah is an expert in mAb therapeutics and founded Manhattan Biosolutions to discovery novel immunotherapy to treat cancer and inflammations. We have been working closely to further develop our anti-RAGE mAb.
University at Buffalo
Associate Professor
Dr. Shah is an expert in mAb therapeutics. We have been collaborating with Dr. Shah since 2019 to jointly develop anti-RAGE mAb