Structural characterization of a serendipitously discovered bioactive macromolecule, lignin sulfate.
The herpes simplex virus-1 (HSV-1) utilizes cell-surface glycosaminoglycan, heparan sulfate, to gain entry into cells and cause infection. In a search for synthetic mimics of heparan sulfate to prevent HSV infection, we discovered potent inhibitory activity arising from sulfation of a monomeric flavonoid. Yet, detailed screening indicated that the sulfated flavonoid was completely inactive and the potent inhibitory activity arose from a macromolecular substance present in the parent flavonoid. The active principle was identified through a battery of biophysical and chemical analyses as a sulfated form of lignin, a three-dimensional network polymer composed of substituted phenylpropanoid monomers. Mass spectral analysis of the parent lignin and its sulfated derivative indicates the presence of p-coumaryl monomers interconnected through uncondensed beta-O-4-linkages. Elemental analysis of lignin sulfate correlates primarily with a polymer of p-coumaryl alcohol containing one sulfate group. High-performance size exclusion chromatography shows a wide molecular weight distribution from 1.5 to 40 kDa suggesting significant polydispersity. Polyacrylamide gel electrophoresis (PAGE) analysis indicates a highly networked polymer that differs significantly from linear charged polymers with respect to its electrophoretic mobility. Overall, macromolecular lignin sulfate presents a multitude of substructures that can interact with biomolecules, including viral glycoproteins, using hydrophobic, hydrogen-bonding, and ionic forces. Thus, lignin sulfate represents a large number of interesting structures with potential medicinal benefits.
Raghuraman
Arjun
A
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
Tiwari
Vaibhav
V
Thakkar
Jay N
JN
Gunnarsson
Gunnar T
GT
Shukla
Deepak
D
Hindle
Michael
M
Desai
Umesh R
UR
D001672:Biocompatible Materials / Q000737:chemistry; D002498:Centrifugation; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D019075:Electrophoresis, Capillary; D004591:Electrophoresis, Polyacrylamide Gel; D006367:HeLa Cells; D006497:Heparan Sulfate / Q000737:chemistry; D018259:Herpesvirus 1, Human / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008031:Lignin / Q000737:chemistry*; D046911:Macromolecular Substances / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008956:Models, Chemical; D011108:Polymers / Q000737:chemistry; D013634:Tannins / Q000737:chemistry; D013997:Time Factors
D001672:Biocompatible Materials; D006497:Heparan Sulfate; D008031:Lignin; D046911:Macromolecular Substances; D011108:Polymers; D013634:Tannins; C076151:Kraft lignin