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PubMed | Unither Virology LLC, Public Health Agency of Canada, University of Texas Medical Branch, U.S. Army and 3 more.
Type: | Journal: Antiviral research | Year: 2016

Iminosugars are host-directed antivirals with broad-spectrum activity. The iminosugar, N-butyl-deoxynojirimycin (NB-DNJ or Miglustat

PubMed | Integrated Biotherapeutics, Inc., Utah State University, Unither Virology LLC, Emergent BioSolutions and Harvard University
Type: Journal Article | Journal: Viruses | Year: 2016

Iminosugars that are competitive inhibitors of endoplasmic reticulum (ER) -glucosidases have been demonstrated to have antiviral activity against a diverse set of viruses. A novel iminosugar, UV-4B, has recently been shown to provide protection against lethal infections with dengue and influenza A (H1N1) viruses in mice. In the current study, the breadth of activity of UV-4B against influenza was examined ex vivo and in vivo. Efficacy of UV-4B against influenza A and B viruses was shown in primary human bronchial epithelial cells, a principal target tissue for influenza. Efficacy of UV-4B against influenza A (H1N1 and H3N2 subtypes) and influenza B was demonstrated using multiple lethal mouse models with readouts including mortality and weight loss. Clinical trials are ongoing to demonstrate safety of UV-4B and future studies to evaluate antiviral activity against influenza in humans are planned.

Carocci M.,Harvard University | Hinshaw S.M.,Harvard University | Rodgers M.A.,Harvard University | Rodgers M.A.,Abbott Laboratories | And 10 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Dengue virus (DENV), a member of the Flaviviridae family, is a mosquito-borne pathogen and the cause of dengue fever. The increasing prevalence of DENV worldwide heightens the need for an effective vaccine and specific antivirals. Due to the dependence of DENV upon the lipid biosynthetic machinery of the host cell, lipid signaling and metabolism present unique opportunities for inhibiting viral replication. We screened a library of bioactive lipids and modulators of lipid metabolism and identified 4-hydroxyphenyl retinamide (4-HPR) (fenretinide) as an inhibitor of DENV in cell culture. 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia when orally administered in a murine model of DENV infection. The molecular target responsible for this antiviral activity is distinct from other known inhibitors of DENV but appears to affect other members of the Flaviviridae, including the West Nile, Modoc, and hepatitis C viruses. Although long-chain ceramides have been implicated in DENV replication, we demonstrate that DENV is insensitive to the perturbation of long-chain ceramides in mammalian cell culture and that the effect of 4-HPR on dihydroceramide homeostasis is separable from its antiviral activity. Likewise, the induction of reactive oxygen species by 4-HPR is not required for the inhibition of DENV. The inhibition of DENV in vivo by 4-HPR, combined with its well-established safety and tolerability in humans, suggests that it may be repurposed as a pan-Flaviviridae antiviral agent. This work also illustrates the utility of bioactive lipid screens for identifying critical interactions of DENV and other viral pathogens with host lipid biosynthesis, metabolism, and signal transduction. © 2015, American Society for Microbiology. All Rights Reserved.

Stavale E.J.,Integrated Biotherapeutics, Inc. | Vu H.,Integrated Biotherapeutics, Inc. | Sampath A.,Unither Virology LLC | Ramstedt U.,Unither Virology LLC | Warfield K.L.,Unither Virology LLC
PLoS ONE | Year: 2015

Our lead iminosugar analog called UV-4 or N-(9-methoxynonyl)-1-deoxynojirimycin inhibits activity of endoplasmic reticulum (ER) α-glucosidases I and II and is a potent, host-targeted antiviral candidate. The mechanism of action for the antiviral activity of iminosugars is proposed to be inhibition of ER α-glucosidases leading to misfolding of critical viral glycoproteins. These misfolded glycoproteins would then be incorporated into defective virus particles or targeted for degradation resulting in a reduction of infectious progeny virions. UV-4, and its hydrochloride salt known as UV-4B, is highly potent against dengue virus in vitro and promotes complete survival in a lethal dengue virus mouse model. In the current studies, UV-4 was shown to be highly efficacious via oral gavage against both oseltamivirsensitive and -resistant influenza A (H1N1) infections in mice even if treatment was initiated as late as 48-72 hours after infection. The minimal effective dose was found to be 80-100 mg/kg when administered orally thrice daily. UV-4 treatment did not affect the development of protective antibody responses after either influenza infection or vaccination. Therefore, UV-4 is a promising candidate for further development as a therapeutic intervention against influenza. © 2015 Stavale et al.

PubMed | Integrated Biotherapeutics, Inc., Unither Virology LLC, University of Toyama, Emergent Virology LLC and 3 more.
Type: | Journal: Antiviral research | Year: 2016

The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) -glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease.

Unither Virology Llc and University of Oxford | Date: 2014-04-30

Lipidomic markers for Hepatitis C and related conditions, treat hepatic fibrosis and hepatocellular carcinoma. An agent administered to such subject may be an cellular total fatty-acid content under iminosugar, which may be effective against hepatitis C. Such iminosugar may be, for example, one of N-substituted deoxynojrimycins and pharmaceutically acceptable salts thereof, N-substituted deoxygalactonojirimycins and pharmaceutically acceptable salts thereof and N-substituted Me-deoxygalactonojirimycins and pharmaceutically acceptable salts thereof. A method of assessing a Hepatitis C infection or a condition caused by or associated with said infection. This method comprises: obtaining a biological sample from a subject in need thereof; determining a level of at least one Hepatitis C lipidomic biomarker in said biological sample; and comparing said level of with a control level of said Hepatitis C lipidomic biomarker to assess the Hepatitis C infection or the condition caused by or associated with said infection in the subject.

University of Oxford and Unither Virology LLC | Date: 2013-06-05

Iminosugar compounds are described that have inbuilt delivery features by virtue of covalent incorporation of a tocopherol moiety, or alternative moieties that are analogues of tocopherol or select analogues of cholesterol, or its antagonist Ezitimibe; and are likely to have broad spectrum antiviral activity. The compounds differ from previous iminosugar compounds, even lipophillic ones, being more hydrophobic and resembling fats and oils in their partition behavior in vivo into lipid phases of lipoproteins, cellular lipid droplet organelles and biological membranes. These features confer a number of unique delivery attributes in vivo, favorable to the therapy of virus infections involving cells of the lymphoid system and the liver, in particular, but these features are also favorable in general for the treatment of virus infections of man and animals.

Unither Virology LLC and University of Oxford | Date: 2014-04-30

The application provides iminosugars with a high activity and specificity for inhibiting ceramide glucosyltransferase.

Plummer E.,La Jolla Institute for Allergy and Immunology | Buck M.D.,La Jolla Institute for Allergy and Immunology | Sanchez M.,La Jolla Institute for Allergy and Immunology | Greenbaum J.A.,La Jolla Institute for Allergy and Immunology | And 8 more authors.
Journal of Virology | Year: 2015

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 α-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. © 2015, American Society for Microbiology.

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