In vivo therapeutic protection against influenza A (H1N1) oseltamivir-sensitive and resistant viruses by the iminosugar UV-4

PloS One
Eric J StavaleKelly Warfield

Abstract

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 oseltamivir-sensitive 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 th...Continue Reading

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Citations

Jul 28, 2016·Proceedings of the National Academy of Sciences of the United States of America·Alessandro T CaputoNicole Zitzmann
Apr 15, 2017·Biochemical Society Transactions·Dominic S AlonziNicole Zitzmann
Dec 10, 2016·Critical Reviews in Microbiology·Beatrice Ellen TyrrellNicole Zitzmann
Feb 16, 2020·Medicinal Research Reviews·Xingyue Ji, Zhuorong Li
May 6, 2017·Nature Reviews. Drug Discovery·Veaceslav BoldescuChristian D Klein
Aug 10, 2020·Antiviral Research·Lisa Evans DeWaldKelly L Warfield
Aug 3, 2021·European Journal of Medicinal Chemistry·Tian-Tian LuChu-Yi Yu

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Methods Mentioned

BETA
protein folding
glycosylation

Software Mentioned

GraphPad Prism
GraphPad

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