title: In vivo therapeutic protection against influenza A (H1N1) oseltamivir-sensitive and resistant viruses by the iminosugar UV-4.
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 therapeutic intervention against influenza.
authors.affiliation: Integrated Biotherapeutics, Inc., Gaithersburg, Maryland, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Stavale
authors.affiliation: Integrated Biotherapeutics, Inc., Gaithersburg, Maryland, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Vu
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, United States of America.
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, United States of America.
authors.forename: Urban
authors.initials: U
authors.lastname: Ramstedt
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, United States of America.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
mesh_terms: D017485:1-Deoxynojirimycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects*; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053139:Oseltamivir / Q000494:pharmacology*; D012449:Safety; D013997:Time Factors; D019562:Viral Load / Q000187:drug effects
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D017485:1-Deoxynojirimycin; D053139:Oseltamivir; C000604871:N-9-methoxynonyldeoxynojirimycin; C013626:nojirimycin