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Inhibition of Endoplasmic Reticulum Glucosidases Is Required for in Vitro and in Vivo Dengue Antiviral Activity by the Iminosugar UV-4

Inhibition of Endoplasmic Reticulum Glucosidases Is Required for in Vitro and in Vivo Dengue Antiviral Activity by the Iminosugar UV-4

Kelly L Warfield, Emily M Plummer, Andrew C Sayce, Dominic S Alonzi, William Tang, Beatrice E Tyrrell, Michelle L Hill, Alessandro T Caputo, Sarah S Killingbeck, P Robert Beatty, Eva Harris, Ren Iwaki, etc.

Antiviral Res. 2016 May;129:93-98.

PMID: 26946111

Abstract:

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) α-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP73465437	1-Deoxymannojirimycin hydrochloride		73465-43-7	Price

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