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Inhibition of Rotavirus Infectivity by a Neoglycolipid Receptor Mimetic
Department of Medicine, Feinberg School of Medicine, Northwestern University, 420 East Superior Street, Chicago, IL 60611, USA
Department of Pathobiology, College of Veterinary Medicine, University of Illinois, 2001 South Lincoln Avenue, Urbana, IL 61802, USA
Institute for Genomic Biology, University of Illinois, 1206 West Gregory Drive, Urbana, IL 61801, USA
These authors contributed equally to this manuscript.
* Author to whom correspondence should be addressed.
Received: 10 January 2011; in revised form: 24 January 2011 / Accepted: 16 February 2011 / Published: 17 February 2011
Abstract: Group A rotaviruses are a major cause of diarrhea in the young of many mammalian species. In rotavirus infected piglets mortality can be as high as 60%. Previous research in this laboratory has identified a porcine intestinal GM3 ganglioside receptor that is required for sialic acid-dependent rotavirus recognition of host cells. In addition, we previously demonstrated exogenously added GM3 can competitively inhibit porcine rotavirus binding and infectivity of host cells in vitro. Sialyllactose, the carbohydrate moiety of GM3, is approximately 3 orders of magnitude less effective than GM3 at inhibiting rotavirus binding to cells. Furthermore, production of therapeutic quantities of GM3 ganglioside for use as an oral carbomimetic in swine is cost prohibitive. In an effort to circumvent these problems, a sialyllactose-containing neoglycolipid was synthesized and evaluated for its ability to inhibit rotavirus binding and infectivity of host cells. Sialyllactose was coupled to dipalmitoylphosphatidylethanolamine (PE) by reductive amination and the product (SLPE) purified by HPLC. Characterization of the product showed a single primulin (lipid) and resorcinol (sialic acid) positive band by thin layer chromatography and quantification of phosphate and sialic acid yielded a 1:1 molar ratio. Mass spectroscopy confirmed a molecular weight coinciding with SLPE. Concentration-dependent binding of rotavirus to SLPE was demonstrated using a thin-layer overlay assay. Using concentrations comparable to GM3, SLPE was also shown to inhibit rotavirus binding to host cells by 80%. Furthermore, SLPE was shown to decrease rotavirus infection of host cells by over 90%. Finally, preliminary results of in vivo animal challenge studies using newborn piglets in their natural environment, demonstrated SLPE afforded complete protection from rotavirus disease. The efficacy of SLPE in inhibiting rotavirus binding and infection in vitro and in vivo, coupled with its relatively low-cost, large-scale production capabilities make SLPE a promising candidate for further exploration as a possible prophylactic or therapeutic nutriceutical for combating rotavirus disease in animals. Most importantly, the results presented here provide proof of concept that the nutriceutical approach of providing natural or synthetic dietary receptor mimetics for protection against gastrointestinal virus infectious disease in all species is plausible.
Keywords: nutriceutical; carbomimetic; receptor therapy; neoglycolipid; rotavirus; ganglioside; infectious; disease
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Bergner, D.W.; Kuhlenschmidt, T.B.; Hanafin, W.P.; Firkins, L.D.; Kuhlenschmidt, M.S. Inhibition of Rotavirus Infectivity by a Neoglycolipid Receptor Mimetic. Nutrients 2011, 3, 228-244.
Bergner DW, Kuhlenschmidt TB, Hanafin WP, Firkins LD, Kuhlenschmidt MS. Inhibition of Rotavirus Infectivity by a Neoglycolipid Receptor Mimetic. Nutrients. 2011; 3(2):228-244.
Bergner, Daniel W.; Kuhlenschmidt, Theresa B.; Hanafin, William P.; Firkins, Lawrence D.; Kuhlenschmidt, Mark S. 2011. "Inhibition of Rotavirus Infectivity by a Neoglycolipid Receptor Mimetic." Nutrients 3, no. 2: 228-244.