An iminosugar with potent inhibition of dengue virus infection in vivo

Perry, Stuart T.; Buck, Michael D.; Plummer, Emily M.; Penmasta, Raju; Batra, Hitesh; Stavale, Eric; Warfield, Kelly L.; Dwek, Raymond A.; Butters, Terry D.; Alonzi, Dominic S.; Lada, Steven M.; King, K. M.; Klose, Brennan; Ramstedt, Urban; Shresta, Sujan

doi:10.1016/j.antiviral.2013.01.004

Cited by 82 publications

(114 citation statements)

References 32 publications

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“…1B). As seen in previous studies (22), treatment with UV-4B reduced viremia to 10 to 30% of that of vehicle-treated mice (Table 1; Fig. 1B).…”

Section: Resultssupporting

confidence: 61%

“…In the first passage, three mice treated with vehicle only and three mice treated with UV-4B were each infected with 1 ϫ 10 10 GE of S221. Blood was harvested by cardiac puncture at 72 h postinfection (hpi) as this time point is the peak of viremia in DENV-infected mice, occurring just prior to potentially losing mice to severe disease (22). Nonstructural proteins are present in the tissues of infected mice within 6 h of infection (41), suggesting that another replication cycle could begin as early as 6 h postinfection.…”

Section: Resultsmentioning

confidence: 99%

“…We sequenced viral populations from treated or untreated mice at the peak of viremia (22). In the UV-4B treated mice, we found that there was an overall increase in SNPs and an increase in the ratio of nonsynonymous to synonymous SNPs.…”

mentioning

confidence: 99%

“…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). Recently, we tested the iminosugar UV-4B for efficacy in a mouse model of severe dengue-like disease (22). Treatment of 129/Sv mice deficient in type I and type II interferon (IFN) receptors (AG129) with UV-4B, even when it is administered as late as 48 h postinfection, reduces viral titers and cytokine levels and promotes survival.…”

mentioning

confidence: 99%

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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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“…1B). As seen in previous studies (22), treatment with UV-4B reduced viremia to 10 to 30% of that of vehicle-treated mice (Table 1; Fig. 1B).…”

Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Dengue Virus Evolution under a Host-Targeted Antiviral

Plummer

Buck

et al. 2015

J Virol

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“…DENV serotype 2 (DENV2) strain PL046 (39), DENV2 strain S221 (28), DENV serotype 3 (DENV3) strain UNC3001 (40) (obtained from Aravinda deSilva, University of North Carolina [UNC] Chapel Hill), and DENV serotype 4 (DENV4) strain H241 (purchased from ATCC) were amplified on C6/36 cells as described in reference 41. DENV2 PL046, DENV2 S221, DENV3 UNC3001, and DENV4 H241 were quantified by standard plaque assay on baby hamster kidney (BHK) cells as previously described (42). DENV2 S221 organ titers were quantified by real-time quantitative reverse transcription-PCR (qRT-PCR) as previously described (41).…”

Section: Methodsmentioning

confidence: 99%

CD8 ⁺ T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice

Zellweger

Tang

Eddy

et al. 2015

J Virol

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Dengue virus (DENV) is a major public health threat worldwide. Infection with one of the four serotypes of DENV results in a transient period of protection against reinfection with all serotypes (cross-protection), followed by lifelong immunity to the infecting serotype. While a protective role for neutralizing antibody responses is well established, the contribution of T cells to reinfection is less clear, especially during heterotypic reinfection. This study investigates the role of T cells during homotypic and heterotypic DENV reinfection. Mice were sequentially infected with homotypic or heterotypic DENV serotypes, and T cell subsets were depleted before the second infection to assess the role of DENV-primed T cells during reinfection. Mice primed nonlethally with DENV were protected against reinfection with either a homotypic or heterotypic serotype 2 weeks later. Homotypic priming induced a robust neutralizing antibody response, whereas heterotypic priming elicited binding, but nonneutralizing antibodies. CD8 ؉ T cells were required for protection against heterotypic, but not homotypic, reinfection. These results suggest that T cells can contribute crucially to protection against heterotypic reinfection in situations where humoral responses alone may not be protective. Our findings have important implications for vaccine design, as they suggest that inducing both humoral and cellular responses during vaccination may maximize protective efficacy across all DENV serotypes. IMPORTANCEDengue virus is present in more than 120 countries in tropical and subtropical regions. Infection with dengue virus can be asymptomatic, but it can also progress into the potentially lethal severe dengue disease. There are four closely related dengue virus serotypes. Infection with one serotype results in a transient period of resistance against all serotypes (cross-protection), followed by lifelong resistance to the infecting serotype, but not the other ones. The duration and mechanisms of the transient cross-protection period remain elusive. This study investigates the contribution of cellular immunity to cross-protection using mouse models of DENV infection. Our results demonstrate that cellular immunity is crucial to mediate cross-protection against reinfection with a different serotype, but not for protection against reinfection with the same serotype. A better understanding of the mediators responsible for the cross-protection period is important for vaccine design, as an ideal vaccine against dengue virus should efficiently protect against all serotypes.T he four serotypes of dengue virus (DENV) are the etiologic agent of dengue, a rapidly spreading arboviral disease that is present in more than 120 countries (1-5). Recent estimates suggest that more than 3.5 billion people living in tropical and subtropical regions are at risk of infection, with 390 million infections per year, of which 96 million are symptomatic (1-3).Infection with DENV is often asymptomatic (6, 7), but if disease is apparent, it ranges from den...

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Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars

Dhara

Bennett

Murphy

2021

The Chemical Record

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This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

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An iminosugar with potent inhibition of dengue virus infection in vivo

Cited by 82 publications

References 32 publications

Dengue Virus Evolution under a Host-Targeted Antiviral

Dengue Virus Evolution under a Host-Targeted Antiviral

CD8 ⁺ T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars

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An iminosugar with potent inhibition of dengue virus infection in vivo

Cited by 82 publications

References 32 publications

Dengue Virus Evolution under a Host-Targeted Antiviral

Dengue Virus Evolution under a Host-Targeted Antiviral

CD8 + T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars

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Product

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CD8 ⁺ T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice