phosphomannopentaose-sulfate and Disease-Models--Animal

Herpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans. Although GAG mimetics, such as sulfated oligo- and polysaccharides, exhibit potent antiviral activities in cultured cells, the prophylactic application of these inhibitors as vaginal microbicides failed to protect women upon their exposure to HIV. A possible explanation for this failure is that sulfated oligo- and polysaccharides exhibit no typical virucidal activity, as their interaction with viral particles is largely electrostatic and reversible and thereby vulnerable to competition with GAG-binding proteins of the genital tract. Here we report that the cholestanol-conjugated sulfated oligosaccharide PG545, but not several other sulfated oligosaccharides lacking this modification, exhibited virucidal activity manifested as disruption of the lipid envelope of HSV-2 particles. The significance of the virus particle-disrupting activity of PG545 was also demonstrated in experimental animals, as this compound, in contrast to unmodified sulfated oligosaccharide, protected mice against genital infection with HSV-2. Thus, PG545 offers a novel prophylaxis option against infections caused by GAG-binding viruses.

Topics: Administration, Intravaginal; Animals; Antiviral Agents; Disease Models, Animal; Female; Herpes Genitalis; Herpesvirus 2, Human; Lipids; Mice, Inbred C57BL; Oligosaccharides; Saponins; Virion

Vascular endothelial growth factor (VEGF) is the most potent angiogenic mitogen, and has been associated with angiogenesis. Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains, which can induce VEGF expression. The aims of the present study were to evaluate the heparanase expression and its relationship with VEGF in the retina of oxygen-induced retinopathy (OIR) mice, and to investigate the effect of the heparanase inhibitor phosphomannopentaose sulfate (PI-88) in the OIR retinas.. Seventy-seven newborn C57BL/6 mice were involved in this study. On postnatal day 7 (P7), pups were exposed to a hyperoxia condition (75% oxygen) for 5 days, and on P12, the mice were returned to room air. Control mice were exposed to room air from birth until P17, with normally developing retinal vasculature. PI-88 was administered intraperitoneally to OIR mice at a dose of 35.7 mg/kg/day for 5 consecutive days. The expression level of heparanase and VEGF in the retinas was assayed using immunohistochemistry, Q-RT-PCR, and western blot.. The expression levels of heparanase and VEGF were increased in the OIR retinas compared with the control mice. The Q-RT-PCR results showed that the mRNA expression levels of heparanase and VEGF in OIR retina were increased 1.71 fold (p<0.0001) and 4.34 fold (p<0.0001), respectively. The western blot results showed that the protein expression levels of heparanase and VEGF were increased 1.49 fold (p<0.0001) and 1.72 fold (p<0.0001), respectively, in the OIR retinas compared with the normal retinas. The immunohistochemistry analysis revealed that the heparanase and VEGF signals were intense in the retinal vascular endothelia of the OIR mice but faint in those of the normal controls. The increased protein and mRNA expression levels of heparanase and VEGF in the mouse retinas were significantly decreased by PI-88 administration (p<0.0001).. Heparanase expression was upregulated and correlated with an increase in VEGF expression in the OIR mouse retinas, and might be involved in the progress of retinopathy of prematurity. Inhibition of heparanase expression by PI-88 could be used as a novel therapeutic method for retinopathy of prematurity.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Down-Regulation; Glucuronidase; Humans; Infant, Newborn; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Oligosaccharides; Oxygen; Retinal Neovascularization; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

To probe the intervention and mechanism of the inhibitor of heparanase (PI-88) on the experimental CNV model .. Experimental CNV was induced by laser photocoagulation in 29 mail (Brown Norway) BN rats (647 nm wave length Krypton laser, 360 mW power, 50 microm spot size, 0.05 second duration), and randomly divided into vacant control group, physiologic saline control group, preventive group and treated group, another 3 rats were acted as normal group, 15 days continuous intraperitoneal injection of PI-88 (25 mg kg(-1) d(-1) was administrated in preventive group (PI-88 was administered the same day as photocoagulation) and treated group (PI-88 was administered 1 week after photocoagulation when CNV had been formed), for the physiologic saline control group, PI-88 was replaced by physiologic saline. To comprehensively evaluate the effect of PI-88 on the CNV by the quantitation of CNV area marked by FITC-dextran in choroid-sclera flat mounts, fluorescence fundus angiography and histopathology; the changes of HPA expression were surveyed by western blot and immunohistochemistry.. CNV area of preventive group and treated group decreased 52.1% and 53.8% respectively at the time point of 3 weeks after photocoagulation; the relative thickness of CNV membrane in eyes of treated group had been decreased 46% as that of control group by histopathology; CNV occurrenced 1 week after photocoagulation both in the control group and preventive group, while the fluorescein leakage of the preventive group had been inhibited significantly; 3 weeks after photocoagulation, there had been 7 days discontinuation for the prevent group, the fluorescein leakage did not enhanced, while there had been 15 days continuous administration for the treated group, the fluorescein leakage had been decreased significantly compared to the time point of 2 week; western blot showed that the relative expressed levels of HPA protein in both preventive and treated group decreased; HPA displayed distribution at the leading edge of CNV membrane migrating toward inner retina and the vascular tissue by immunohistochemistry, the expression of HPA was inhibited significantly in treated group.. PI-88 may not only prevent CNV in certain degree, but also make it partially subsidize for the existed CNV, and the effect is associated with the inhibition of HPA production.

Topics: Animals; Choroidal Neovascularization; Disease Models, Animal; Male; Oligosaccharides; Rats; Rats, Inbred BN

Many viruses, including flaviviruses, display affinity for cell surface heparan sulfate (HS) proteoglycans with biological relevance in virus attachment/entry. This raises the possibility of the application of HS mimetics in antiviral therapy. We have evaluated the antiviral effect of the sulfated polysaccharides, suramin, pentosan polysulfate (PPS) and PI-88, which are currently approved or in trial for clinical use, against dengue virus (DEN) and the encephalitic flaviviruses, Japanese encephalitis virus, West Nile virus, and Murray Valley encephalitis virus. A flow cytometry-based method for the measurement of inhibition of virus infectivity was developed, which showed the in vitro antiviral activity of the three compounds, albeit with differences in efficiency which were virus-dependent. The 50% effective concentration (EC(50)) values for DEN inhibition were in the order: PPS

Topics: Animals; Antiviral Agents; Cell Line; Dengue; Dengue Virus; Disease Models, Animal; Drug Evaluation, Preclinical; Encephalitis Viruses, Japanese; Encephalitis, Arbovirus; Female; Flavivirus Infections; Heparitin Sulfate; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligosaccharides; Pentosan Sulfuric Polyester; Suramin; Treatment Outcome