Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo

Whitby, Kevin; Pierson, Theodore C.; Geiss, Brian J.; Lane, Kelly; Engle, Michael J.; Zhou, Yi; Doms, Robert W.; Diamond, Michael S.

doi:10.1128/jvi.79.14.8698-8706.2005

Cited by 252 publications

(231 citation statements)

References 59 publications

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“…Some of these inhibitors include mycophenolic acid (13,20), ribavirin (20)(21)(22), 6-azauridine (20), castanospermine (23), and deoxynojirimycin (23)(24)(25). Nucleoside analogues (24,25) and peptide-like ␣-keto amide backbone compounds (23) that inhibit the function of flavivirus NS3 and NS5 proteins have also been reported. Among these inhibitors, only ribavirin has been given approval for clinical use and is currently used solely in the treatment of hepatitis C flavivirus infections (21), in which it has been implicated in causing side effects such as anemia in patients (22).…”

Section: Discussionmentioning

confidence: 99%

c-Src protein kinase inhibitors block assembly and maturation of dengue virus

Chu

Yang

2007

Proc. Natl. Acad. Sci. U.S.A.

126

124

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Dengue virus is a mosquito-borne flavivirus that represents an important emerging infectious disease and is an international health concern. Currently, there is no vaccine or effective antiviral therapy to prevent or to treat dengue virus infection. The slow progress in developing antiviral agents might be alleviated by the availability of efficient high-throughput anti-dengue virus screening assays. In this study, we report an immunofluorescence imagebased assay suitable for identification of small molecule inhibitors of dengue virus infection and replication. Using this assay, we have discovered that inhibitors of the c-Src protein kinase exhibit a potent inhibitory effect on dengue virus (serotypes 1-4) and murine flavivirus Modoc. Mechanism of action studies demonstrated that the c-Src protein kinase inhibitor dasatinib prevents the assembly of dengue virions within the virus-induced membranous replication complex. These results demonstrate that this cell-based screen may provide a powerful means to identify new potential targets for anti-dengue drug development while simultaneously providing pharmacological probes to investigate dengue virus-host cell interactions at the biochemical level. gen that causes dengue fever (DF) and a severe lifethreatening illness, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) (1). DENV is a small, enveloped, positive-stranded RNA virus that belongs to the Flavivirus genus of the Flaviviridae family. Four distinct serotypes (DENV1 to -4) of dengue viruses are transmitted to humans through the bites of the mosquito species, Aedes aegypti and Aedes albopictus (2). It has been estimated that Ϸ50-100 million cases of DF, and Ϸ250,000-500,000 cases of DHF occur every year (3). Furthermore, 2.5 billion of people are at risk for infection in subtropical and tropical regions of the world (4) in the absence of effective intervention. The intracellular life cycle of DENV begins with receptor-mediated endocytosis of the virus into cells, followed by fusion of the viral envelope protein with the late endosomal membrane, which results in the release of the viral genome into the cytoplasm for replication. Replication of the viral RNA genome occurs within membrane-bound complexes formed from the endoplasmic reticulum membrane. Subsequently, virus particles are assembled and released via the host cell secretory machinery (5). Although replication of DENV involves complex interaction between viral proteins and cellular factors, many of these interactions remain unidentified and uncharacterized. Small molecules that specifically target different steps in the viral replication cycle could potentially be used as ''tool compounds'' to facilitate biochemical characterization of these host-virus interactions and might also be used to identify pharmacological intervention points for treatment of DENV infection. Although extensive studies have been carried out over the years to understand the pathogenicity of DENV infection, little progress has been made in the development of specific anti-DE...

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Section: Discussionmentioning

confidence: 99%

c-Src protein kinase inhibitors block assembly and maturation of dengue virus

Chu

Yang

2007

Proc. Natl. Acad. Sci. U.S.A.

126

124

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“…In (Whitby et al, 2004) and flaviviruses (Courageot et al, 2000;Whitby et al, 2005), it will be important to study the prolonged effect of these compounds in those systems as well.…”

Section: Lhbs Secreted Into the Culture Medium Is Reduced Following Tmentioning

confidence: 99%

α-Glucosidase Inhibitors Have a Prolonged Antiviral Effect against Hepatitis B Virus through the Sustained Inhibition of the Large and Middle Envelope Glycoproteins

Simsek

Ouzounov

et al. 2006

Antivir Chem Chemother

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Previous work has shown that the secretion of enveloped hepatitis B virus (HBV) DNA and the HBV middle envelope protein (MHBs) are sensitive to glucosidase inhibition. Here, it is shown that HBV DNA secretion remains depressed after the removal of the glucosidase inhibitor and long after glucosidase function returns to normal. For example, glycoprocessing and the secretion of α α-1 anti-trypsin returned to normal within 3 h of the removal of the glucosidase inhibitor. In contrast, the secretion of HBV did not return to normal for more than 7 days after the removal of the inhibitor. Consistent with the inhibition of HBV virion secretion, the levels of HBV L and HBV M proteins were also reduced by treatment with the glucosidase inhibitor and remained reduced for 7 days after compound withdrawal. The implications of the prolonged antiviral effect against HBV and the use of glucosidase inhibitors as antiviral agents are discussed.

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“…The selectivity index value of ± > 1 showed the highest concentration with non-cytotoxic effect and it showed less or moderate inhibitory activity against DENV2 growth in the mammalian cell line (Figure 2). However, an alkaloid isolated from the seeds of Moreton Bay chestnut (Castanospermum australe) controls DENV1-IV both in vitro and in vivo (Whitby et al 2005).…”

Section: Discussionmentioning

confidence: 99%

In vitrostudy on cytotoxic effect and anti-DENV2 activity ofCarica papayaL. leaf

Joseph¹,

Sankarganesh²,

Ichiyama

et al. 2014

Frontiers in Life Science

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Dengue fever is the most deleterious and rapidly spreading mosquito-borne viral disease, and to date it has resisted attempts to eradicate it. Carica papaya L. leaf extract is traditionally used to cure dengue fever and its associated symptoms. However, no in vitro studies have been reported for the anti-dengue efficacy of this extract. So, the present study attempted to determine the phytochemicals present in Carica papaya L. leaf extracts, as well as their cytotoxic effect and anti-DENV2 activity on the LLC-MK2 cell line. Methanolic extracts, containing triterpenoids and flavonoids, showed cytotoxic effects (CC 50 = 0.6156 mg ml −1 ), whereas a chloroform extract, rich in alkaloids, tannin and saponin, was non-cytotoxic (CC 50 = > 1 mg ml −1 ) to LLC-MK2 cells and it showed inhibitory activity (EC 50 = > 1 mg ml −1 ) against DENV2 with a selectivity index value of ± > 1. This indicates that the crude chloroform extract has moderate or less inhibitory action against DENV2 growth in in vitro conditions. The current study will help in the future development of new and novel drugs against dengue pathogens with high efficacy.

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Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo

Cited by 252 publications

References 59 publications

c-Src protein kinase inhibitors block assembly and maturation of dengue virus

c-Src protein kinase inhibitors block assembly and maturation of dengue virus

α-Glucosidase Inhibitors Have a Prolonged Antiviral Effect against Hepatitis B Virus through the Sustained Inhibition of the Large and Middle Envelope Glycoproteins

In vitrostudy on cytotoxic effect and anti-DENV2 activity ofCarica papayaL. leaf

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