Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo

Chang, Jinhong; Schul, Wouter; Butters, Terry D.; Yip, Andy M.; Liu, Boping; Goh, Anne; Lakshminarayana, Suresh B.; Alonzi, Dominic S.; Reinkensmeier, Gabriele; Pan, Xiao‐Ben; Qu, Xiaowang; Weidner, Jessica M.; Wang, Limin; Yu, Wenquan; Borune, Nigel; Kinch, Mark A.; Rayahin, Jamie; Moriarty, Robert M.; Xu, Xiaodong; Shi, Pei Yong; Guo, Ju Tao; Block, Timothy M.

doi:10.1016/j.antiviral.2010.11.002

Cited by 84 publications

(102 citation statements)

References 33 publications

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“…This impressive SI is largely due to the low cytotoxicity observed in this assay-a result consistent with the current safe use of NB-DNJ in humans. Other DNJ derivatives with more potent antiviral activity than NB-DNJ (shown in studies by ourselves and others) (7,9,36) generally show greater toxic effects on cells in vitro. In support of this trend, the cytotoxicity of the four iminosugars we tested (NB-DNJ, NN-DNJ, N9-MON-DNJ, and NAP-DNJ) was correlated with antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

“…In trials as an anti-HIV therapy, administration of free drug did not sustain sufficiently high serum concentrations to achieve an antiviral effect (14). Since that time, iminosugars with improved in vitro potency (but concurrently greater cellular toxicity) have been developed (1,7,9,16,24,33). As a parallel approach to enhance NB-DNJ potency, liposome-mediated intracellular delivery of iminosugars shows great promise (30).…”

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confidence: 99%

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Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Miller

Lachica

Sayce

et al. 2012

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Miller

Lachica

Sayce

et al. 2012

Antimicrob Agents Chemother

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“…These results strongly argue that, unlike drugs targeting viral functions, inhibition of host cellular functions essential for HCV replication, such as ␣-glucosidases, has a low likelihood of developing resistant mutants. This unique property, in combination with much-improved antiviral efficacy, makes PBDNJ0804 a promising antiviral candidate for combination therapy with IFN-␣ or drugs that inhibit viral functions (7).…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of Endoplasmic Reticulum α-Glucosidases Potently Suppress Hepatitis C Virus Virion Assembly and Release

Pan

Weidner

et al. 2011

Antimicrob Agents Chemother

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␣-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that downregulation of the expression of ␣-glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of ␣-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of imino sugar derivatives, which are competitive inhibitors of ␣-glucosidases, did not affect intracellular HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for imino sugars with better antiviral activity, we found that a novel imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.Hepatitis C virus (HCV) chronically infects more than 170 million people worldwide. Current standard therapy for chronic hepatitis C, the combination of pegylated alpha interferon (IFN-␣) and ribavirin, is associated with a less than 50% sustained virological response in patients infected with genotype 1 virus. In the search for more effective therapeutic agents, the development of direct-acting antiviral agents to target viral functions, such as NS3/4A protease and NS5B RNA-dependent RNA polymerase, has been the main focus during the last 2 decades (26). However, an important lesson learned from clinical studies is that although inhibition of the essential viral functions potently inhibited HCV replication and resulted in a rapid drop in viremia, development of drug resistance eventually limited the antiviral efficacy of these drugs (22,32,36). Therefore, viral function inhibitors will likely be used not as monotherapeutic agents but rather as part of therapeutic regimens in combination with IFN-␣ and/or other HCV inhibitors.Like all other viruses, HCV relies on many host functions to propagate. In addition, the virus needs to counteract or evade the cellular antiviral response to colonize its host cells (23). Therefore, an alternative approach to inhibiting HCV infection is to target host cellular functions required for HCV replication and/or activate the host cellular antiviral response (17, 24, 37). In fact, compared to targeting viral functions, an obvious advantage of targeting host functions is the low likelihood of drug resistance (28). Currently, inhibitors targeting several cellular proteins, including 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (19, 41)...

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“…Compounds that disrupt glycosylation can cause viral glycoproteins to misfold, ultimately resulting in reduced assembly, secretion, and infectivity of viral particles (17,18). Iminosugars are monosaccharides that target the host enzymes ␣-glucosidase I and II (19,20). It has been shown that iminosugars affect the folding of the prM protein of DENV and subsequently the formation of the prM-E complex (21).…”

mentioning

confidence: 99%

Dengue Virus Evolution under a Host-Targeted Antiviral

Plummer

Buck

et al. 2015

J Virol

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The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the ␣-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals. IMPORTANCEAlthough hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a hosttargeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity. Dengue virus (DENV) is the most common mosquito-borne human pathogen. DENV can cause illnesses ranging from self-limited mild disease to severe and potentially life-threatening dengue hemorrhagic fever/dengue shock syndrome. Approximately 400 million people are infected each year with DENV (1), generally in tropical and subtropical areas, with 20,000 infections resulting in death (2). The current standard of care consists of fluid replacement and other supportive care. There is presently no vaccine to prevent or antiviral to treat DENV infection. Recent phase IIb and III trials of an attenuated, tetrameric vaccine showed limited efficacy, especially in naive individuals...

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Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo

Cited by 84 publications

References 33 publications

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Inhibitors of Endoplasmic Reticulum α-Glucosidases Potently Suppress Hepatitis C Virus Virion Assembly and Release

Dengue Virus Evolution under a Host-Targeted Antiviral

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