Antiherpesvirus Activity and Mode of Action of SP-303, a Novel Plant Flavonoid

Barnard, Dale L.; Smee, Donald F.; Huffman, John H.; Meyerson, Laurence R.; Sidwell, Robert W.

doi:10.1159/000239127

Cited by 54 publications

(36 citation statements)

References 11 publications

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“…another in fluenza virus inhibitor [II], It is unclear whether time of initiation of therapy was a significant factor in the antiviral efficacy of SP-303; the results using intraperi toneal treatment did not differ appreciably using early versus late drug treatments; the SPA therapy effects were somewhat improved when treatments began earlier, but other fac tors, including the number of treatments per day and aerosol generator used, also varied in the two SPA experiments. No work has yet been done to elucidate the mode of influenza virus inhibition by SP-303; however, we have found that this biopolymer appears to act against both respiratory syncytial virus and herpes simplex virus by inhibiting viral pene tration into cells; this inhibition was thought to occur by direct binding to the virus and/or to host cell membranes [8,14].…”

Section: Discussionmentioning

confidence: 99%

Influenza Virus-Inhibitory Effects of Intraperitoneally and Aerosol-Administered SP-303, a Plant Flavonoid

et al. 1994

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The phenolic biopolymer SP-303 was evaluated against experimentally induced influenza A (H₁N₁) virus infections in mice in a series of experiments. When 30, 10 or 3 mg/kg/day of SP-303 were administered intraperitoneally once daily for 8 days beginning either 48 h before or 4 h after virus exposure, only lung consolidation was significantly reduced; extended (p < 0.01) mean day to death was also seen in the late-therapy groups. The high dosage was lethally toxic in this experiment. A small-particle aerosol (SPA) of 10, 5 and 2.5 mg/ml of SP-303, administered for 1 h three times daily for 5 days beginning 4 h after virus exposure, exerted a similar antiviral effect. Twice-daily 1-hour SPA treatments for 3 days beginning 24 h before virus exposure using 4.3 mg/ml of SP-303 resulted in significant increases in mean day to death and reductions of lung consolidation but no inhibition of lung virus titer. Declines in influenza-induced arterial oxygen saturation, as determined by pulse oximetry, were less in all animals treated with SP-303 by SPA, but this reduced decline was significant (p < 0.01) only in the last experiment. Mice receiving SP-303 by SPA exhibited consistent but reversible hypothermia immediately after termination of treatment.

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Section: Discussionmentioning

confidence: 99%

Influenza Virus-Inhibitory Effects of Intraperitoneally and Aerosol-Administered SP-303, a Plant Flavonoid

et al. 1994

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“…It was observed that Kuwanon X had no virucidal effect on HSV-1, but could suppress viral attachment and penetration. Previous research have shown that most inhibitors of viral penetration are mainly biopolymers, such as sulfated polysaccharides, 25) poly(4-styrenesulfonic acid-comaleic acid), 33) and SP-303, 34) while Kuwanon X is a low molecular weight monomeric compound. So the inhibitory effect of Kuwanon X on HSV-1 penetration was further confirmed by confocal laser scan microscope assay (Fig.…”

Section: Discussionmentioning

confidence: 99%

Anti-HSV Activity of Kuwanon X from Mulberry Leaves with Genes Expression Inhibitory and HSV-1 Induced NF-κB Deactivated Properties

Shen

Zhang

et al. 2016

Biological & Pharmaceutical Bulletin

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Six stilbene derivatives isolated from Mulberry leaves including Kuwanon X, Mulberrofuran C, Mulberrofuran G, Moracin C, Moracin M 3′-O-b-glucopyranoside and Moracin M were found to have antiviral effects against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) at different potencies except for Mulberrofuran G. Kuwanon X exhibited the greatest activity against HSV-1 15577 and clinical strains and HSV-2 strain 333 with IC 50 values of 2.2, 1.5 and 2.5 µg/mL, respectively. Further study revealed that Kuwanon X did not inactivate cell-free HSV-1 particles, but inhibited cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, Kuwanon X reduced the expression of HSV-1 IE and L genes, and decreased the synthesis of HSV-1 DNA. Furthermore, it was demonstrated that Kuwanon X inhibited the HSV-1-induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. These results suggest that Kuwanon X exerts anti-HSV activity through multiple modes and could be a potential candidate for the therapy of HSV infection.Key words anti-herpes simplex virus (HSV) activity; Kuwanon X; penetration; gene expression; nuclear factor (NF)-κB; Mulberry Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are prevalent pathogens worldwide. HSV-1 is the main cause of orofacial herpes, cephalitis, corneal blindness, and several disorders of the peripheral nervous system; HSV-2 is usually associated with recurrent genital herpes, meningoencephalitis in neonates and meningitis in adults. Both HSV-1 and HSV-2 can cause latent infections in the neurons system, and then cause lesions at or near the point of entry into the body when they are reactivated.1,2) Recently, it was reported that HSV infections can increase the transmission of human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1).3) During the productive infection, a successful HSV replication cycle is dependent on the completion of several steps, including α (immediate-early or IE), β (early or E), γ (late or L) genes and unpaired DNA replication based on sequential expression. The IE genes, such as UL54, encode transacting regulators of gene expression. The E genes, including UL52, are involved in viral DNA synthesis and nucleotide metabolism. The L genes, mainly encode structural proteins, e.g. ICP5 encoding the main capsid protein VP5. 4)The standard therapy for HSV infections are nucleoside analogues, such as acyclovir (ACV) and penciclovir. However, the emergence of HSV strains resistant to ACV remains an important clinical concern in immunocompromised individuals.5) Therefore, it is necessary to develop new antiherpetic agents with mechanisms of action different from that of nucleoside analogues.Mulberry (Morusalba L.) is widely cultivated in several Asian countries. Its leaves, fruits, twigs and root barks have long been used in Chinese medicine to reduce fever, maintain liver health, improve eyesight and lower blood pressure. Besides, Mulberry leaf is commonly...

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“…Regarding the mechanism underlying the anti-viral activities, proanthocyanidins from Croton lechleri resin and prodelphinidin B-2 3Ј-O-gallate from green tea leaf inhibit herpes simplex viruses infection by preventing the attachment and penetration of the virus into the target cells (37,39). Recently, the grapefruit flavonoid naringenin was reported to inhibit apolipoprotein B-dependent HCV secretion (40).…”

Section: Discussionmentioning

confidence: 99%

Proanthocyanidin from Blueberry Leaves Suppresses Expression of Subgenomic Hepatitis C Virus RNA

Takeshita¹,

Ishida²,

Akamatsu³

et al. 2009

Journal of Biological Chemistry

118

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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. While searching for new natural anti-HCV agents in agricultural products, we found a potent inhibitor of HCV RNA expression in extracts of blueberry leaves when examined in an HCV subgenomic replicon cell culture system. This activity was observed in a methanol extract fraction of blueberry leaves and was purified by repeated fractionations in reversed-phase high-performance liquid chromatography. The final purified fraction showed a 63-fold increase in specific activity compared with the initial methanol extracts and was composed only of carbon, hydrogen, and oxygen. Liquid chromatography/mass-ion trap-time of flight analysis and butanolHCl hydrolysis analysis of the purified fraction revealed that the blueberry leaf-derived inhibitor was proanthocyanidin. Furthermore, structural analysis using acid thiolysis indicated that the mean degree of polymerization of the purified proanthocyanidin was 7.7, consisting predominantly of epicatechin. Proanthocyanidin with a polymerization degree of 8 to 9 showed the greatest potency at inhibiting the expression of subgenomic HCV RNA. Purified proanthocyanidin showed dose-dependent inhibition of expression of the neomycin-resistant gene and the NS-3 protein gene in the HCV subgenome in replicon cells. While characterizing the mechanism by which proanthocyanidin inhibited HCV subgenome expression, we found that heterogeneous nuclear ribonucleoprotein A2/B1 showed affinity to blueberry leaf-derived proanthocyanidin and was indispensable for HCV subgenome expression in replicon cells. These data suggest that proanthocyanidin isolated from blueberry leaves may have potential usefulness as an anti-HCV compound by inhibiting viral replication.Hepatitis C virus (HCV) 2 is often associated with the development of chronic liver diseases. Infection by HCV causes chronic hepatitis at high rates and finally results in liver cirrhosis and subsequent occurrence of hepatocellular carcinoma (1-3). The number of people worldwide who are infected by HCV is estimated to be over 200 million with 2 million infections in Japan (4). The South Kyushu area of Japan, including Miyazaki prefecture, has a high prevalence of this virus, and it is now recognized as a social problem. There is no vaccine effective for HCV at present. The elimination of HCV may be achieved by a combination of pegylated ␣-interferon and ribavirin, a broad spectrum antiviral drug (4 -6). However, virological response to this combination therapy has been reported to be 80% for genotypes 2 and 3, but less than 50% for genotype 1 (7, 8). Moreover, ␣-interferon is associated with severe sideeffects, including leucopenia, thrombocytopenia, depression, fatigue, and flu-like symptoms, and ribavirin is associated with side-effects such as hemolytic anemia (9). Therefore, establishment of a new modality of treatment without serious adverse effects is still required.Considering the prolonged p...

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Antiherpesvirus Activity and Mode of Action of SP-303, a Novel Plant Flavonoid

Cited by 54 publications

References 11 publications

Influenza Virus-Inhibitory Effects of Intraperitoneally and Aerosol-Administered SP-303, a Plant Flavonoid

Influenza Virus-Inhibitory Effects of Intraperitoneally and Aerosol-Administered SP-303, a Plant Flavonoid

Anti-HSV Activity of Kuwanon X from Mulberry Leaves with Genes Expression Inhibitory and HSV-1 Induced NF-κB Deactivated Properties

Proanthocyanidin from Blueberry Leaves Suppresses Expression of Subgenomic Hepatitis C Virus RNA

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