Probing the interaction of dengue virus envelope protein with heparin: assessment of glycosaminoglycan-derived inhibitors.
A structure-activity relationship study was carried out to facilitate development of inhibitors of dengue virus infectivity. Previous studies demonstrated that a highly charged heparan sulfate, a heparin-like glycosaminoglycan found on the cell surface, serves as a receptor for dengue virus by binding to its envelope protein. Interventions that disrupt this binding effectively inhibit infectivity. A competitive binding assay was developed to screen polyanionic compounds for activity in preventing binding of dengue virus envelope protein to immobilized heparin; compounds tested included drugs, excipients, and larger glycosaminoglycans and their semisynthetic derivatives. Results of this competitive binding assay were used to select agents for detailed evaluation of interactions by surface plasmon resonance spectroscopy, which afforded binding on-rates, off-rates, and dissociation constants. From these data, an understanding of the structural requirements for polyanion binding to dengue virus envelope protein has been established.
Marks
R M
RM
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Lu
H
H
Sundaresan
R
R
Toida
T
T
Suzuki
A
A
Imanari
T
T
Hernáiz
M J
MJ
Linhardt
R J
RJ
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002240:Carbohydrate Sequence; D002851:Chromatography, High Pressure Liquid; D003716:Dengue Virus / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry* / Q000494:pharmacology*; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology*; D006820:Hyaluronic Acid / Q000138:chemical synthesis / Q000737:chemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry; D020349:Surface Plasmon Resonance; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*
D000925:Anticoagulants; D000998:Antiviral Agents; C051821:E-glycoprotein, Dengue virus type 2; D006025:Glycosaminoglycans; D009844:Oligosaccharides; D013431:Sulfates; D014759:Viral Envelope Proteins; D006820:Hyaluronic Acid; D006493:Heparin